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Nicotine and the Behavioral Mechanisms of Impulsive Choice

Permanent Link: http://ufdc.ufl.edu/UFE0022575/00001

Material Information

Title: Nicotine and the Behavioral Mechanisms of Impulsive Choice
Physical Description: 1 online resource (97 p.)
Language: english
Creator: Locey, Matthew
Publisher: University of Florida
Place of Publication: Gainesville, Fla.
Publication Date: 2008

Subjects

Subjects / Keywords: chains, choice, concurrent, delay, discounting, enhancement, impulsive, lever, magnitude, nicotine, press, progressive, ratio, rats, reinforcer, risky, sensitivity
Psychology -- Dissertations, Academic -- UF
Genre: Psychology thesis, Ph.D.
bibliography   ( marcgt )
theses   ( marcgt )
government publication (state, provincial, terriorial, dependent)   ( marcgt )
born-digital   ( sobekcm )
Electronic Thesis or Dissertation

Notes

Abstract: Our study had two basic aims: (1) to examine the behavioral mechanisms of action responsible for nicotine effects on impulsive choice in rats, and (2) to evaluate a contemporary mathematical model of choice - assessing the likelihood that it accurately describes how reinforcer magnitude and delay contribute to reinforcer value. Four experiments were conducted to accomplish the above aims. Experiment 1 used a risky choice procedure to isolate the effects of nicotine on the delay sensitivity of rats. The lack of any increase in risky choice in Experiment 1 suggested that nicotine did not affect delay sensitivity. Experiment 2 was a systematic replication of Experiment 1 in which different reinforcer magnitudes were introduced. This single change in the procedure resulted in dose-dependent increases in risky choice, suggesting that nicotine decreased magnitude sensitivity. Experiment 3 used a concurrent progressive ratio schedule to compare responding for 1 pellet vs. 5 pellets. Although the results were inconsistent across rats, the averaged data indicate an increase in responding for the small reinforcer and a decrease in responding for the large reinforcer. Experiment 4 used concurrent variable interval schedules with a magnitude group and a delay group of rats. In the magnitude group, nicotine produced dose-dependent decreases in preference for a 3-pellet reinforcer relative to a 1-pellet reinforcer. In the delay group, nicotine produced no dose-dependent effects. Collectively, these experiments indicated that (1) nicotine increases impulsive choice by decreasing magnitude sensitivity and (2) any complete account of how delay and magnitude contribute to reinforcer value needs a magnitude sensitivity parameter.
General Note: In the series University of Florida Digital Collections.
General Note: Includes vita.
Bibliography: Includes bibliographical references.
Source of Description: Description based on online resource; title from PDF title page.
Source of Description: This bibliographic record is available under the Creative Commons CC0 public domain dedication. The University of Florida Libraries, as creator of this bibliographic record, has waived all rights to it worldwide under copyright law, including all related and neighboring rights, to the extent allowed by law.
Statement of Responsibility: by Matthew Locey.
Thesis: Thesis (Ph.D.)--University of Florida, 2008.
Local: Adviser: Dallery, Jesse.

Record Information

Source Institution: UFRGP
Rights Management: Applicable rights reserved.
Classification: lcc - LD1780 2008
System ID: UFE0022575:00001

Permanent Link: http://ufdc.ufl.edu/UFE0022575/00001

Material Information

Title: Nicotine and the Behavioral Mechanisms of Impulsive Choice
Physical Description: 1 online resource (97 p.)
Language: english
Creator: Locey, Matthew
Publisher: University of Florida
Place of Publication: Gainesville, Fla.
Publication Date: 2008

Subjects

Subjects / Keywords: chains, choice, concurrent, delay, discounting, enhancement, impulsive, lever, magnitude, nicotine, press, progressive, ratio, rats, reinforcer, risky, sensitivity
Psychology -- Dissertations, Academic -- UF
Genre: Psychology thesis, Ph.D.
bibliography   ( marcgt )
theses   ( marcgt )
government publication (state, provincial, terriorial, dependent)   ( marcgt )
born-digital   ( sobekcm )
Electronic Thesis or Dissertation

Notes

Abstract: Our study had two basic aims: (1) to examine the behavioral mechanisms of action responsible for nicotine effects on impulsive choice in rats, and (2) to evaluate a contemporary mathematical model of choice - assessing the likelihood that it accurately describes how reinforcer magnitude and delay contribute to reinforcer value. Four experiments were conducted to accomplish the above aims. Experiment 1 used a risky choice procedure to isolate the effects of nicotine on the delay sensitivity of rats. The lack of any increase in risky choice in Experiment 1 suggested that nicotine did not affect delay sensitivity. Experiment 2 was a systematic replication of Experiment 1 in which different reinforcer magnitudes were introduced. This single change in the procedure resulted in dose-dependent increases in risky choice, suggesting that nicotine decreased magnitude sensitivity. Experiment 3 used a concurrent progressive ratio schedule to compare responding for 1 pellet vs. 5 pellets. Although the results were inconsistent across rats, the averaged data indicate an increase in responding for the small reinforcer and a decrease in responding for the large reinforcer. Experiment 4 used concurrent variable interval schedules with a magnitude group and a delay group of rats. In the magnitude group, nicotine produced dose-dependent decreases in preference for a 3-pellet reinforcer relative to a 1-pellet reinforcer. In the delay group, nicotine produced no dose-dependent effects. Collectively, these experiments indicated that (1) nicotine increases impulsive choice by decreasing magnitude sensitivity and (2) any complete account of how delay and magnitude contribute to reinforcer value needs a magnitude sensitivity parameter.
General Note: In the series University of Florida Digital Collections.
General Note: Includes vita.
Bibliography: Includes bibliographical references.
Source of Description: Description based on online resource; title from PDF title page.
Source of Description: This bibliographic record is available under the Creative Commons CC0 public domain dedication. The University of Florida Libraries, as creator of this bibliographic record, has waived all rights to it worldwide under copyright law, including all related and neighboring rights, to the extent allowed by law.
Statement of Responsibility: by Matthew Locey.
Thesis: Thesis (Ph.D.)--University of Florida, 2008.
Local: Adviser: Dallery, Jesse.

Record Information

Source Institution: UFRGP
Rights Management: Applicable rights reserved.
Classification: lcc - LD1780 2008
System ID: UFE0022575:00001


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NICOTINE AND T HE BEHAVIORAL MECHANISMS OF IMPULSIVE CHOICE By MATTHEW L. LOCEY A DISSERTATION PRESENTED TO THE GRADUATE SCHOOL OF THE UNIVERSITY OF FLOR IDA IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF DOCTOR OF PHILOSOPHY UNIVERSITY OF FLORIDA 2008 1

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2008 Matthew L. Locey 2

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ACKNOWL EDGMENTS I would like to thank everyone who made my dissertation poss ible. First and foremost, I would like to thank Dr. Jesse Dallery for the pe rfect combination of freedom and guidance that made all of my research endeavors worthwhile what ever the results. I am also indebted to Drs. Henry Pennypacker, Jr., Timothy Hackenberg, and C ynthia Pietras for first revealing to me the intellectual path that I intend to tread for many years to come. I would also like to thank the members of my committee, Drs. Marc Branc h, Drake Morgan, Neil Rowland, David Smith, and Timothy Hackenberg, for their helpful comments. Further thanks are du e to Julie Marusich, Bethany Raiff, and Steven Meredith for their ex cellence as labmates and for years of assistance in implementing the present experiments. I woul d also like to thank all of the students and faculty of the University of Florida Behavior Analysis area fo r providing the environment that facilitated my development and success as a student and scientist. Finally, I would like to thank my siblings Christopher, Rach el, and Phillip for their unwa vering love and support; and my mother, Kathryn Locey, who has long been a beacon of wisdom in a weary world. 3

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TABLE OF CONTENTS page ACKNOWLEDGMENTS ...............................................................................................................3 LIST OF TABLES ...........................................................................................................................6 LIST OF FIGURES .........................................................................................................................7 ABSTRACT .....................................................................................................................................8 CHAP TER 1 INTRODUCTION................................................................................................................. .10 Overview .................................................................................................................................10 Historical Overview ................................................................................................................11 Purpose ...................................................................................................................................17 2 EXPERIMENT 1: EFFECTS OF NICOTI NE ON DELAYBASE D RISKY CHOICE.......22 Introduction .............................................................................................................................22 Method ....................................................................................................................................23 Subjects ............................................................................................................................23 Apparatus .........................................................................................................................23 Procedure .........................................................................................................................24 Data Analysis ...................................................................................................................27 Results .....................................................................................................................................28 Discussion ...............................................................................................................................29 3 EXPERIMENT 2: EFFECTS OF NI COTINE ON RISKY C HOICE WITH DIFFERENT REINFORCER MAGNITUDES.....................................................................37 Introduction .............................................................................................................................37 Method ....................................................................................................................................37 Subjects ............................................................................................................................37 Apparatus .........................................................................................................................37 Procedure .........................................................................................................................38 Results .....................................................................................................................................39 Discussion ...............................................................................................................................42 4 EXPERIMENT 3: EFFECTS OF NICO TINE ON CONCURRENT PR OGRESSIVE RATIOS WITH DIFFERENT REINFORCER MAGNITUDES...........................................53 Introduction .............................................................................................................................53 Method ....................................................................................................................................56 Subjects ............................................................................................................................56 4

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Apparatus .........................................................................................................................56 Procedure .........................................................................................................................56 Results .....................................................................................................................................58 Discussion ...............................................................................................................................59 5 EXPERIMENT 4: EFFECTS OF NI COTINE ON CONCURRENT-CHAINS PERFORM ANCE WITH DIFFERENT REINFORCER MAGNITUDES AND DELAYS.................................................................................................................................63 Introduction .............................................................................................................................63 Method ....................................................................................................................................65 Subjects ............................................................................................................................65 Apparatus .........................................................................................................................65 Procedure .........................................................................................................................65 Results .....................................................................................................................................67 Discussion ...............................................................................................................................69 6 GENERAL DISCUSSION.....................................................................................................77 Summary of Findings .............................................................................................................77 Implications for Interpretations of Drug Action .....................................................................79 Nicotine Effects ...............................................................................................................79 Treatment Implications ....................................................................................................81 Effects of Other Drugs .....................................................................................................82 Implications for an Equation of Reinforcer Value .................................................................83 APPENDIX: DERIVATION OF EQUAT ION 62 FROM EQUATION 6-1 ...............................88 LIST OF REFERENCES ...............................................................................................................92 BIOGRAPHICAL SKETCH .........................................................................................................97 5

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LIST OF TABLES Table page 2-1. Number of sessions and preference in the pre-baseline and baseline conditions. .................33 3-1. Number of sessions and preference in the pre-baseline and baseline conditions. .................47 6

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LIST OF FI GURES Figure page 1-1. Hypothetical curves showing reinfo rcer value as a function of delay ....................................21 2-1. Average latency to respond as a function of nicotine dose ....................................................34 2-2. Session average titrated dela y as a function of nicotine dose .................................................35 2-3. Proportion of choices for the titrated delay as a function of nicotine dose. ...........................36 3-1. Average latency to respond as a function of nicotine dose ....................................................48 3-2. Session average titrated delay as a function of nicotine dose in Experim ent 1 & 2 ...............49 3-3. Proportion of choices for the titrated delay as a function of dose in Experim ent 1& 2. ........50 3-4. Proportion of choices as a function of dose in Exp 1 & 2 and Dallery & Locey (2005) .......51 3-5. Proportion of choices for titration dur ing acute dosing, cont rol, & free-feeding ...................51 3-6. Average latency to respond during acute nicotine dosing, control, & free-feeding.. .............52 4-1. Session responses for small and large as a proportion of responses under vehicle. ...............62 5-1. Proportion of responses for the large le ver during the final 10 sessions of baseline .............73 5-2. Proportion of responses for the short-delay lever during the final 10 sessions of baseline ...73 5-3. Proportion of responses for the large (3-pellet) lever as a f unction of nicotine dose .............74 5-4. Proportion of responses for the short (1 s) delay lever as a function of nicotine dose ...........75 5-5. Responses for the large and small levers as a proportion of re sponses under vehicle.. .........76 7

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Abstract of Dissertation Pres ented to the Graduate School of the University of Florida in Partial Fulfillment of the Requirements for the Degree of Doctor of Philosophy NICOTINE AND THE BEHAVIORAL MECHANISMS OF IMPULSIVE CHOICE By Matthew L. Locey August 2008 Chair: Jesse Dallery Major: Psychology Our study had two basic aims: (1) to examin e the behavioral mechanisms of action responsible for nicotine effects on impulsive choice in rats, and (2) to evaluate a contemporary mathematical model of choice assessing th e likelihood that it accurately describes how reinforcer magnitude and delay co ntribute to reinforcer value. Four experiments were conducted to accomplis h the above aims. Experiment 1 used a risky choice procedure to isolate th e effects of nicotine on the delay sensitivity of rats. The lack of any increase in risky choice in Experiment 1 suggested that nicotin e did not affect delay sensitivity. Experiment 2 was a systematic replication of Experiment 1 in which different reinforcer magnitudes were introduced. This sing le change in the proc edure resulted in dosedependent increases in risky choice, suggesting that nicotine decreased magnitude sensitivity. Experiment 3 used a concurrent progressive ra tio schedule to compare responding for 1 pellet vs. 5 pellets. Although the results were inconsistent across rats, the averag ed data indicate an increase in responding for the small reinforcer and a decrease in responding for the large reinforcer. Experiment 4 used concurrent vari able interval schedules with a magnitude group and a delay group of rats. In the magnitude gr oup, nicotine produced dose-dependent decreases 8

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9 in preference for a 3-pellet rein forcer relative to a 1-pellet reinforcer. In the delay group, nicotine produced no dose-dependent effects. Collectively, these experiments indicated that (1) nicotine increases impulsive choice by decreasing magnitude sensitivity and (2) any complete account of how delay and magnitude contribute to reinforcer value needs a ma gnitude sensitivity parameter.

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CHAP TER 1 INTRODUCTION Overview A hungry lion pounces on a small wildebeest ca lf rather than movi ng to intercept the much larger prey in the herd a few hundred yards beyond. A 5th-grader plays hooky on the day of a big test despite the severe consequences that are certain to follow. On a business trip to Vegas, a man gambles away his sons tuiti on money. Her job already in jeopardy, a young woman continues to inject hersel f with heroin on a daily basis. A college student rolls over and hits the snooze button. In all likelihood, these are a ll examples of impulsive choices. That is, choices for a smaller-sooner reinforcer over a larger-later one. Such choices are commonplace in the wild and perhaps even more so within human society. From simple procrastination to unsafe sexual practices with extra-marital partners, from pe tty theft to decisions by world leaders with potentially catastrophic long-term global conseque nces, human beings are constantly faced with such choices. Quite often, the smaller-sooner reinfo rcer is chosen. Considering the ubiquity of the phenomenon, any thorough-going science of behavior should be able to account for such impulsive choices. In some cases, preference for smaller-s ooner over larger-later reinforcers can be accounted for entirely in terms of reinforcemen t maximization. Given a choice between (A) 1 food pellet every 30 seconds or (B) 3 food pellets every 2 minutes, a food-deprived animal will almost certainly prefer option A. Although the shorter delay between each reinforcer presentation with option A might exert some in fluence on the degree of preference in such an arrangement, the simple preference for A over B can easily be accounted fo r by the higher rate of reinforcement for option A which yields 0.5 pellet s/minute more than option B. As such, this 10

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would seem a trivial instance of impulsive choi ce which indicates the need to modify our definition of that term. Henceforth, impulsi ve choices will refer to choices for a smallersooner reinforcer under conditions in which such choices cannot be accounted for by differences in overall rate of reinforcement. In pursuing the determinants of impulsive choice, we are th ereby restricting our interest to the effects of pre-reinforcer delays (the de lay between the choice-poi nt and the reinforcer delivery) and reinforcer magnitude s on choice. In the laboratory, inter-trial intervals are typically arranged to eliminate the possibili ty of preference for the smalle r-sooner reinforcer being driven by a higher rate of reinforcement (e.g., Mazur, 1987; Rachlin & Green, 1972). This is normally accomplished by holding constant the time between trial onsets. What we need then is a scientific acc ount of how reinforcer delays and reinforcer magnitudes interact to produce pr eference for one altern ative over another. In extra-laboratory situations, such choices will of ten involve alternatives that differ along both quantitative and qualitative dimensions. Nevertheless, on a funda mental level, both reinforcer dimensions of interest: delay and magnitude, are quantitative. Given that the variables of interest are quantitative and given that the most precise and generalizable scientific account possible would be a quantitative account, what we need is a qua ntitative account of how reinforcer delay and magnitude contribute to produce pr eference between two alternatives. Historical Overview Experiments with humans, monetary reinforc ers (or points exchangeable for money), and short delays (e.g., delays of less than 1-day) indicate that dela y has no effect on choice (see Navarick, 2004). That is, humans will select wh ichever options result in maximizing monetary earnings within a session. When those delays ar e extended (e.g., to months or years typically with hypothetical, monetary amounts), delay ha s been found to have the same effect on 11

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preference as is found with short delays and consum able reinforcers (e.g., food, water, and video-access) in both humans and non-hum an animals (see Frederick, Loewenstein & ODonoghue, 2002; Green & Myerson, 2004 for reviews). Given that the effe ct of delay is only found with much larger delays when using moneta ry reinforcers, same effect is not meant to imply the same magnitude of effect, but instead to imply that the basic mathematical function that best describes both effects, is the same. What then, is that basic mathematical function? Given that inter-trial intervals are typically not arranged to hold trial durations constant outside the laboratory, there might be some intu itive appeal in the po ssibility that preference1 is determined entirely by reinforcement rate fr om choice point to reinforcer delivery. In quantitative terms, preference ( P ) for A over B might equal: BB AA ADM DM P / / (1-1) where M represents magnitude2 and D represents delay. This was, in essence, the equation proposed by Baum & Rachlin (1969). In the pr evious example, 1 pellet delayed 30 seconds would be 33% more preferred than 3 pellets de layed 2 minutes. Baum & Rachlin derived this equation from the matching law which states th at the relative rate of responding equals the relative rate of reinforcement. By interpreti ng rate of reinforcement to mean reinforcer magnitude per unit time, and relative rate of responding to mean preference, the simple matching law can be reduced to Equation 1-1. One limitation of Equation 1-1 is that it predicts preference for A will approach infinity as the delay to A approaches zero. Thus, any immediate reinforcer, no matter how small, would be infinitely preferred to any other reinforcer delayed only one second. This limitation can be solved by assuming that the impact of a reinforcer on preference will never exceed the magnitude of that reinforcer. Mathematically, this would mean: 12

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)1/( )1/( BB AA ADM DM P (1-2) A second limitation of Equation 1-1 is that it does not allow for individual differences in sensitivity to delay. There is a substantial body of research i ndicating sometimes considerable individual differences in the extent to which delay affects preference (e.g., Green & Myerson, 2004; Johnson & Bickel, 2002; Mazur, 1984; 1986; 1987; Rachlin, Raineri, & Cross, 1991). As such, a delay sensitivity parameter, k is needed to account for these differences. )1/( )1/( BB AA AkDM kDM P (1-3) Interpreting Equation 1-3 to indicate that preference for A over B is equal to the relative value of A divided by the value of B, we can extract the terms of our equation to indicate that the value (V) of any reinforcer is determined by Equation 1-4: kD M V 1 (1-4) This is exactly the equation proposed by Mazur (1987) to describe how reinforcer magnitude and delay contribute to produce reinfo rcer value. Where E quation1-4 has been used, reinforcer value is typically translated in te rms of what immediatel y delivered reinforcer magnitude would be equally preferred to the reinforcer in question. For example, if k=1, $100 ( M) delayed 9 months (D ) would be equally valued to $10 delivered immediately ( V =$10). Equation 1-4 is generally referred to as a delay discounting function, give n that it shows how the value of a reinforcer is discounted as a function of delay. It is important to note that the equation also shows how the value of a reinforcer increa ses as a function of reinforcer magnitude, but likely due to the simple proportional relation between reinforcer magnitude and reinforcer value, that aspect of the equation is rarely a focus of any r eal interest. 13

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Equation 1-4 is shown graphically in Figure 1-1. For now, just c onsider the top left panel. The vertical bars represent reinforcers available after different delays, and their heights reflect the magnitude of the reinfo rcer. Tracing the curves to th e ordinate (time 0) gives you the current value (V) of the delayed reinforcers. As reinforcer value is a negatively decelerating function of delay, decreasing the delay from t to t x increases the value of the reinforcer more than increasing the delay from t to t + x decreases the value of the re inforcer (Zabludoff, Wecker, & Caraco, 1988). Equation 1-4 has been used to account for choice in at least two contexts: impulsive choice (e.g., Johnson & Bickel, 2002; M azur, 1987; Rachlin, Raineri, & Cross, 1991) and risky choice (Mazur, 1984; 1986). The curves in the top panels in Figure 1-1 illustrate an impulsive choice arrangement in which the values of two reinforcers change as th e delay to their receipt decreases. Because the values determine choice, we can see how prefer ence changes between a 5unit reinforcer with a delay of 5 s and a 10-unit reinforcer with a delay of 10 s (reinforcer amount in arbitrary units). The left panel (small k) predicts self-control, or preference for the larger-l ater reinforcer, until the delay to both reinforcers is reduced by about 2. 5 s, at which point the intersecting lines predict indifference. The right panel (large k ) predicts (1) almost-immediate indifference and (2) impulsive choice (at a delay of less than 3 s) much sooner than the left panel. Both panels predict impulsive choice as the small reinforcer delivery becomes imminent (i.e., as the delay approaches 5 s). However, the right panel indicates a greater degree of im pulsive choice. The relative value of the sma ller-sooner reinforcer compar ed to the larger-later reinforcer is always greater on the right panel than on the left panel. Thus, k is frequently referred to as a measure of impulsive choice. 14

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Furtherm ore, k might also be referred to as a meas ure of risky choice. Risky choice can be defined as preference for a variable over a fixed delay to reinforcement (see Bateson & Kacelnik, 1995 for a more complete definition). For instance, a variable delay might be programmed according to a simple, mixed time (MT) schedule (a schedule that randomly fluctuates between two delays from reinforcer to reinforcer) to deliver a single reinforcer either immediately or after a delay of 2 t Given a choice between this MT schedule and another alternative that delivers a singl e reinforcer after a fixed delay t the alternative producing the variable delays will be preferred (Bateson & Kacelnik, 1995; Cicerone, 1976; Mazur, 1984, 1986; Pubols, 1958). This can be seen in the bottom panels of Figure 1-1. The average value of R1 and R2, as indicated by the arrows (4.9 on the left panel and 2.7 on the right), is always greater than the value of F (3.2 or 1.0 on the left and right panels, respectively). As k increas the value of the variable altern ative increases relative to the fi xed alternative. Compare the bottom left panel (small k) and the bottom right panel (large k) in Figure 1-1. In the bottom lef panel the value of the variable alternative (as indicated by the a rrow) is about 150% of the value of the fixed alternative F When k is increased, the variable alternative value becomes over 250% of the value of F Thus, a larger k would also indicate a greate r degree of risky es, t choice. It should be clear that an environmental or pharmacological mani pulation that alters k should affect choice in both ri sky and impulsive choice procedur es. Similarly, according to Equation 1-4, any manipulation that affects impu lsive choice should have a similar effect on risky choice. For example, consider the following hypothetical situation: A rat equally prefers 1 pellet delayed 1 s and 3 pellets de layed 5 s. According to Equati on 1-4, the only interpretation of this indifference point is that k (the delay discounting paramete r) equals 1. If a 0.3 mg/kg nicotine injection changes that indifference point such that 1 pellet delayed 1 s becomes equally 15

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preferred to 3 pellets delayed 4 s, the only in terpretation provided by Equation 1-4 is that nicotine increased k from 1 to 2. If 0.3 m g/kg increases k from 1 to 2, then that same dose of nicotine should produce a similar increase in risky choice. Thus, the same rat might initially be indifferent between an MT 5 s sc hedule (with a 1 s and 9 s delay) and a fixed-time (FT) schedule of 2.3 s. The 0.3 mg/kg nicoti ne dose should increase preference fo r the variable a lternative such that it is equally preferred to an FT 2.1 s. A ll of this follows from Equation 1-4 which indicates that changes in impulsive choi ce and risky choice are both synony mous with changes in delay discounting ( k). Dallery and Locey (2005) found that nicotine produced dose-dependent increases in impulsive choice with rats. Th at experiment used an adjust ing delay procedure in which a computer adjusted the delay to a 3-pellet reinforc er until it was equally preferred to a 1-pellet reinforcer delayed 1 s. Then, twice per week th ey administered a different dose of nicotine and found that nicotine produced dose-dependent increases in pref erence for the smaller-sooner reinforcer (i.e., dose-dependent in creases in impulsive choice). If this increase in impulsive choice was due to an increase in delay discounting (an increase in k, i.e., an increase in apparent differences in delays between the smaller-sooner and larger-later reinforcers), then nicotine should produce similar increas es in risky choice. However, there is another possible mechanis m by which nicotine might increase impulsive choice. A decrease in magnitude sensitivity (i.e ., a decrease in the apparent differences in magnitudes between the smaller-soo ner and larger-later reinforcer ) could just as easily account for the increased impulsive choice observed in the Dallery and Locey (2005) experiment. If that were the case, then nicotine would not be expe cted to produce any change in risky choice given that the two alternatives in a risky choice procedure would have identical reinforcer magnitudes 16

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(e.g., 1 pellet in the hypothetical situation previously de scribed). As such, the critical advantage of a risky ch oice procedure is experimental contro l: the choice alternatives can be made to differ in delay only, whereas in impulsive choice preparat ions, one alternative differs from the other in both reinforcer magnitude and delay. Purpose The present experiments were designed with two basic aims: (1) to more carefully examine the behavioral mechanisms of action responsible for nicotine effects on im pulsive choice, and (2) to evaluate Equation 1-4, and the likelihood that it accurately describes how reinforcer magnitude and delay contribu te to reinforcer value. Experiment 1 used a risky choice procedure to isolate the effects of nicotine on delay sensitivity. The procedure, similar to that used by Mazur (1984), was used to assess the effects of acute nicotine administration on choice controlled by delay. E qual reinforcer magnitudes (1pellet) were available on each alte rnative. The procedure identifi ed the titrated delay that was equally preferred to the variable delay, i.e., th e indifference point between the two alternatives. This indifference point was then used as the initial titrating delay in all subsequent sessions. If nicotine increases preference for the variable alternative, which would necessarily occur if nicotine increases k (see above), the proportion of choices for the titrating alternative should decrease. As previously explai ned, Equation 1-4 predicts that an increase in delay discounting will increase the proportion of choices for the va riable, risky alternative (thus decreasing choice for the titrating alternative). However, nicotine did not increase risky choice in Experiment 1, suggesting that some other behavi oral mechanism is responsible fo r the robust effect of nicotine on impulsive choice (Dalle ry and Locey, 2005). Experiment 2 was a systematic replication of Experiment 1. The only change in the procedure was a modification of the reinforcer ma gnitude available on the titrating alternative. 17

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Instead of 1-pellet on each alternative, the titra ting delay was followed by a 3-pellet reinforcer. Under this preparation, nicotine produced incr eases in risky choice very similar to the dosedependent increases in impulsi ve choice previously found by Da llery and Locey (2005). The collective results of Experiment 1 and Experi ment 2 cannot be accounted for by a change in delay discounting ( k) or, by extension, Equation 1-4. Bo th experiments (and the Dallery and Locey experiment) can, however, be accounted for by a nicotine-induced d ecrease in magnitude sensitivity. To extend the generality of the findings in the first two experiments and to learn more about the degree to which nicotine impacts magn itude sensitivity, another group of rats were exposed to concurrent progressive ratio schedules. Progressive ratio (PR) schedules are fairly simple response-based schedules in which a fixe d number of responses produces a reinforcer, but the fixed number of responses required for rein forcement increases afte r each reinforcer is earned. PRs are typically used to determine th e value of a reinforcer by assessing the breakpoint: the response requirement at which the animal st ops responding. In this experiment, concurrent PRs were established to assess allocation of respon se effort when one PR resulted in 1 pellet and the other resulted in 5 pellets. Nicotine produced dose-dependent decreases in responses on the 5-pellet PR relative to the 1-pellet PR, as would be produced by a decrease in magnitude sensitivity. To further extend the generality of the fi ndings from Experiments 1-3 and to further examine the effects of nicotine on magnitude and delay sensitivity, Experiment 4 used a concurrent-chains procedure to assess nicotine effects on choi ce between different magnitudes and different delays. Concurrent chains have long been used to assess relative preference for one option over another (see Mazur, 2006 ). Equivalent concurrent sc hedules can be arranged such 18

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that responding on one alternative produces reinforcem ent schedule A and responding on the other alternative produces reinforc ement schedule B. If arrang ed properly, relative preference during the concurrent schedules ca n indicate relative preference for schedule A over schedule B. This basic logic was used to assess preference between a large reinforcer magnitude (3 pellets) and a small reinforcer magnitude (1 pellet) for one group of rats and between a short delay (1 second) and a long delay (9 seconds) for anot her group of rats. Ni cotine produced a shift towards indifference for the magnitude group, suggesting a decrease in magnitude sensitivity, but had no effect on preference for the delay group, suggesting that the e ffect observed in the magnitude group was not the result of some ot her behavioral mechanism (e.g., a decrease in stimulus control, a simple rate-dependent effect, etc.). Collectively, these experiments indicate that (a) nicotine increases impulsive choice by decreasing magnitude sensitivity and (b) any complete account of how delay and magnitude contribute to reinforcer value n eeds a magnitude sensitivity parame ter. These findings also call into question all past interpretations of effect s on impulsive choice. For instance, it is now unclear whether other drug-induced changes in impulsive choice, in cluding opioids (Kirby, Petry, & Bickel, 1999; Madden, Bickel, & Jaco bs, 1999; Madden, Petry, Badger, & Bickel, 1997), alcohol (Petry, 2001; Vuchinich & Simp son, 1998), and cocaine (Coffey, Gudleski, Saladin, & Brady, 2003) are due to effects on delay discounting (as is typically inferred due to Equation 4) or due to effects on magnitude sensiti vity. Clarifying this issue will require the use of alternative procedures, such as those us ed in the present set of experiments. Notes 1. The present manuscript uses the term prefere nce as an interven ing variable, or a summary term, for various measures of choice. The degree of preference for opti on A is the behavioral result of the relative value of option A over option B. However, the exact behavioral result will differ depending upon the procedure involved. For inst ance, if the relative value of alternative A relative to alternative B is 0.75 (i.e., preference of 0.75), 75% of responses would be allocated to 19

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option A in a concurrent variable -interval (V I) arrangement. In a discrete trial arrangement (or any standard concurrent fixed ratio arrangement), any preference greater than 0.5 would result in exclusive (or very nearly exclusive) preference fo r the more valuable alternative. Determination of preference can also allow precise predictions under other mo re complicated procedures (see Mazur, 2006 for examples). 2. The present manuscript uses the term reinforcer m agnitude rather than reinforcer amount. The use of reinforcer amount may be more commonplace in the relevant literature and oftentimes more specific. However, it is my position that differences in reinforcer amount represent a sub-class of differences in reinforcer magnitude. For instance 3-pellets vs. 1-pellet and $100 vs. $10 are both examples of differen ces in reinforcer amount and reinforcer magnitude. However, what about the differen ce between 1 s of hopper access versus 3 s of hopper access? What about the difference betwee n a 1% sucrose solution versus a 10% sucrose solution? What about the difference between an entire candy bar versus a small piece of that candy bar? Certainly all of thes e differences could be converted into something measurable in terms of amount (e.g., number of grains, mg of sucrose, grams of candy), but the term magnitude can be applied without the need fo r any such conversion. Furthermore, such conversions could result in erroneous conclusions with qualitatively different reinforcers. Reinforcers in pigeon operant experiments are ra rely homogenous grains, for example. As such, an analysis of reinforcer value based on the amount of seeds would be more likely to fail than an analysis of reinforcer value based on reinforcer magnitude (e.g., seconds of access). Given that magnitude is a more generally applicable term than amount, it will be used throughout the present manuscript. This includes the substitution of reinforcer magnitude ( M) terms within Equations that have tradi tionally included parameters for reinforcer amount ( A ) instead. 20

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21 Figure 1-1. Hypothetical curves showing reinforcer value (based on Equation 1-4) as a function of delay with a small k (left panels) and a large k (right panels). The top panels show the value of a 5-unit re inforcer delayed 5 s and a 10-unit reinforcer delayed 10 s. The bottom panels show the value of a 5.4 s delay (F ), the value of a 0.8 s delay ( R1), and the value of a 10 s delay ( R2). The arrows indicate the average value of a variable delay composed of both R1 and R2.

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CHAP TER 2 EXPERIMENT 1: EFFECTS OF NICOTINE ON DELAY-BASED RISKY CHOICE Introduction Titrating procedures have been used in psychophysics for over 50 years (e.g., Bekesy, 1947; Blough, 1958). Their initial a pplication to the study of reinforc er value is often attributed to Mazur (1987), in which a de lay to a high-magnitude reinfo rcer was titrated towards indifference with a low-magnitude, immediate rein forcer with pigeons. This impulsive choice procedure, and a human analog using hypotheti cal monetary outcomes over greatly extended delays (months or years rather than seconds), have been repeatedly re plicated (see Green & Myerson, 2004 for review). Ind eed, these titrating-delay tasks, in conjunction with similar titrating-amount tasks, have provided the prim ary support for Equation 1-4 (see Mazur 1997 for review). Such tasks have also provided a seem ingly useful baseline fo r studying the effects of pharmacological and direct neur al manipulations on impulsive choice (Dallery & Locey, 2005; Ho et al., 1998; Wogar, Bradshaw, & Szabadi, 1993). Due to delays in publication, the impulsive choice version of th e titrating-delay task was prece ded by a risky choice version (Mazur, 1984), also with pigeons. Since that first experiment, titrating-delay tasks have only rarely been used in studies of risky choice (e.g., Mazur, 1986). Experiment 1 is the first to implement such a procedure with rats. The logic behind these titrating-delay tasks is fairly simple. In the case of risky choice procedures like Experiment 1, the fixed delay (lever A) is titrate d to find the fixed delay that would be equally preferred to a variable delay (lev er B). If a rat prefer s the variable delay on a given trial, then the fixed delay must be lowe red to eliminate any pref erence. If the fixed delay is preferred, then that delay must be increa sed to eliminate any preference. Eventually, this 22

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titration of the fixed delay shou ld produce an indifference point, th e delay at which the titrating (fixed) alternative is equally pr eferred to the other (in this case, variably-delayed) alternative. If nicotine increases delay discounting as suggested by Da llery & Locey (2005), then nicotine should increase preference for the variab le delay in Experiment 1. In other words, nicotine should decrease the titrated delay, rela tive to vehicle, in a dose-dependent manner. Method Subjects Nine Long-Evans hooded male rats (Harlan, In dianapolis, IN) were housed in separate cages under a 12:12 hr light/dark cycle with continuous access to water. Each rat was maintained at 80% of its free-feeding weight as determined at postnatal day 150. Supplemental food was provided in each rats home cage fo llowing each session. The weight of food supplements were calculated daily for each rat, using the difference between each rats presession weight and its 80% weight. Seven of the nine rats were experime ntally nave, whereas Rats 100 and 103 had extensive histories with similar choice procedures. Apparatus Seven experimental chambers (30.5 cm L x 24 cm W x 29 cm H) in sound-attenuating boxes were used. Each chamber had two (2 cm L x 4.5 cm W) non-retractable levers 7 cm from the chamber floor. Each lever required a force of approximately 0.30 N to re gister a response. A 5 cm x 5 cm x 3 cm food receptacle was located 3.5 cm from each of the two levers and 1.5 cm from the chamber floor. The food receptacle wa s connected to an automated pellet dispenser containing 45 mg Precision Noye s food pellets (Formula PJPPP) Three horizontally aligned lights (0.8 cm diameter), separated by 0.7 cm, were centered 7 cm above each lever. From left to right, the lights were colored red, yellow, and green. A ventilation fan within each chamber and white noise from an external speaker masked extraneous sounds. A 28V yellow house light was 23

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mounted 1.5 cm from the ceiling on the wa ll opposite the intelligence panel. Med-PC hardware and software controlled data collection and experimental events. Procedure Training. Lever pressing was initially trained on an alternative fixed ratio (FR) 1 random time (RT) 100 schedule. The houselight was turned on for the duration of each training session. Training trials began with the onset of all three left lever li ghts. In the initial trial, both levers were active so that a si ngle response on either lever resu lted in immediate delivery of 1 food pellet. The RT schedule was initiated at th e beginning of each trial so that a single pellet was delivered, response-independently, approxima tely every 100 s. Both response-dependent and response-independent food deliv eries were accompanied by the te rmination of all three lever lights. After a 2 s feeding period, the lights were illuminated and a new trial began. After two consecutive presses of one lever, that lever was deactivated until the other lever was pressed. After a total of 60 food deliverie s, the session was terminated. Training sessions were conducted for 1 week, at the end of which all re sponse rates were above 10 per minute. After lever pressing was establis hed, the rats were exposed to 1 week of lever-alternation training. During these sessions, all three lights above each active lever flashed on a 0.3 s on/off cycle. Sessions consisted of 30 blocks of 2 tria ls. In the first trial of each block, both levers were active. In the second trial of each block, the lever that the rat pressed in the preceding trial was deactivated and the lights above that lever we re turned off. A single response to an active lever resulted in an immediate pellet delivery and a 2 s blackou t during which all lights above both levers were extinguished. Titrated Delay Procedure (Pre-baseline). Following initial training, experimental sessions were conducted 7 days a week at approx imately the same time every day during the 12 hr light cycle. Sessions were preceded by a 10 minute blackout period during which the chamber 24

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was dark and responses on either lever had no pr ogramm ed consequences. At the end of the presession blackout period, the houselig ht, the green light above the le ft lever, and the red light above the right lever were illumi nated. The left, green-lit le ver was the variable lever, on which a single response resulted in a single pellet delivery after a va riable delay: either 1 s (p=.5) or 19 s (p=.5). The right, red-lit lever was the ti trated-delay lever. A single response on this lever resulted in a single pellet delivered after a delay. Following a lever press, the lights above both levers were extinguished a nd the appropriate delay period was initiated. During the delay period, the light corresponding to the pressed lever flashed 10 tim es. The flash intervals were equally spaced and determined by the duration of the delay period such that there were 11 equalinterval off-periods, the last of which terminated in food delivery rather than light illumination. The houselight was extinguished following the 2 s feeding period and remained off for the duration of the inter-trial interval (ITI). The ITI was 60 s minus the duration of the previous delay, so each new trial began 60 s after the prec eding choice. Immediately following the ITI, a new trial began with the onset of the houselight, the green, left-lever light; and the red, rightlever light. Each session consisted of 60 trials. The titrated (fixed) delay began at 10 s in the first session. Each response on the variable lever decreased the delay by 10% during th e ensuing trial, to a minimum of 1 s. Each response on the titrated lever incr eased the delay by 10% during the ensuing trial. If the same lever was pressed in two consecutive choice trials, th at lever was deactivated in the ensuing trial. The light corresponding to a deac tivated lever was not illuminate d and responses on that lever had no programmed consequences. Responses during these forced trials had no effect on the value of the titrated delay. Choi ce trials resumed after each forced trial. In subsequent sessions, the titrated delay began at the fina l value from the preceding session. 25

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This pre-b aseline condition continued for a mi nimum of 60 sessions and until the titrated delay was stable for seven consecutive days. Stability was determined based on the average titrated delay in each session according to three crit eria. First, each of the 7-session averages had to be within 20% or 1 s of th e average of those 7 values. Second, the average of the first 3session averages and the average of the last 3-session averages were required to be within 10% or 1 s of the 7-session average. Third, there could be no in creasing or decreasing trend in average titrated delay across the final 3 sessions (i.e., th ree consecutive increases or decreases in the average titrated delay). Once stability was achieved, the average adjusted delay for the 7 stable sessions was considered the indifference point: the titrated de lay which was equally pref erred to the variable delay used in this procedure. If the stability criteria were no t met within 100 sessions (Rats 136, 139, and 140), the median of the average titrated delays for the last 20 sessions was considered the indifference point (except for Rat 118 whic h continued the pre-ba seline condition for 212 sessions before reaching stabilit y, as shown in Table 1). Th e indifference point determined during the pre-baseline pe riod was then fixed, and it was used as the initial delay value in all subsequent sessions. Baseline. For the first trial of each session, the va lue of the titrated delay started at the indifference delay determined for th at particular rat. All other as pects of the procedure remained the same as described above. The baseline was continued for a minimum of twenty sessions and until the proportion of choices for the titrated al ternative was stable. Stability was determined based on three criteria. First, each of the last 7-session choice proportions had to be within 10% of the average of those 7 sessions. Second, the average of the first 3-session choice proportions and the average of the last 3-se ssion choice proportions were required to be within 5% of the 726

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session average. Finally, there could be no increasing or decreas ing trend in choice proportions across the f inal 3 sessions (i.e., th ree consecutive increases or decr eases in choice proportions). Acute Drug Regimen. The same procedure describe d in the baseline was used throughout the drug regimen. Nicotine was disso lved in a potassium phosphate solution (1.13 g/L monobasic KPO4, 7.33 g/L dibasic KPO4, 9 g/L NaCl in distilled H2O; Fisher Scientific, Pittsburgh, PA) to adjust pH to 7.4. Subj ects were administered nicotine by subcutaneous injection immediately prio r to the 10-minute pre-session blackout period. Doses were 1.0, 0.3, 0.1, and 0.03 mg/kg nicotine (Sigma Chemical Co., St. Louis, MO). Doses of nicotine were calculated as the base and injection volume was based on body weight at the time of injection (1 ml/kg). Injections occurred tw ice per week (Wednesday and Sunda y). During each phase, rats experienced two cycles of each dose in descendi ng order with each cycle preceded by a vehicle injection. Data Analysis Primary data analysis for Experiment 1 a nd all subsequent experiments was conducted by visual analysis (Sidman, 1960). This is a useful first step in the analysis due to the many complex discriminations necessary for determining the nature of effects given the experimental designs used in this set of experiments (e.g., [1] distribution of results at each dose, [2] magnitude of dependent variable (DV) measur es at each dose, comparisons of dose-effect functions across rats with resp ect to 1 and 2 at corresponding doses as well as non-corresponding doses [i.e., similarity of function across rats despite variety in sensitivity to drug]). Statistical analyses have also been provided throughout this se t of experiments to supplement visual analyses. Friedman ANOVAs have been conducted for all dose-effect functions. The Friedman ANOVA is a non-parametr ic test that ranks the DV measures across doses for each subject, and then sums the ranks for each dose across rats. The Friedman statistic, 27

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F is repor ted for all such analyses, which is ca lculated from these ranked sums and the sample size. The P value reports the chance that random samp ling would result in sums of ranks as far apart (or more so) than those observed in the experiment. Dunns multiple comparison test is also reported for dose-effect re sults. Also known as the Friedman post-test, this test compares the Friedman ranks for each dose (across animal s) to determine significant differences between particular doses (e.g. 1.0 mg/kg relative to ve hicle). For Dunns multiple comparison tests, the P value is set to 0.05 for all analyses and the rank differences ( D ) are also reported. Results Table 2-1 shows the number of sessions each rat spent under the experimental (prebaseline) condition prior to the determination of an indifference delay an d the number of sessions spent under the baseline condition prior to drug admi nistration. The percentage of choices for the titrating-delay lever during the last seven sess ions of each of those conditions is also shown in Table 1. Finally, the indifference delay used for the baseline and subsequent conditions for each rat is indicated in the same table. Figure 2-1 shows the average latency to ma ke a choice as a function of dose, during nicotine administration. Note the logarithmic y-axis. C and V indicate control (no injection) and vehicle (potassium phosphate) injection, respectively. Ver tical lines represent standard errors of the mean. Latency was measured for each trial as the time from the onset of the stimulus lights (at the beginning of each trial) to the first response on either lever. Consistent with previous research (Dallery & Locey, 2005) only the largest dose of nicotine had any substantial effect on choice latencies relative to vehicle and control sessions. Friedman ANOVA indicated a significant effect of dose on choice la tency [F = 21.63, P = 0.0006]. Dunns multiple comparison test indicated a significant effect of only 1.0 mg/kg ni cotine relative to vehicle [D = 26; P < 0.05]. 28

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Figure 2-2 shows the effects of nicotine on choice for each subject during nicotine administration. Specifically, the av erage titrated delay from each session is shown for each dose. Note the logarithmic y-axis. If nicotine enhan ced delay discounting, th e titrated delay should have decreased in a dose-dependent manner. None of the rats s howed any consistent decrease in titrated delay relative to vehicl e and control sessions (with the possible exception of 136). Several rats (e.g., 103 and 118) actually showed a dose-dependen t increase in titrated delay relative to control sessions. The titrated delay also consistently increased following nicotine administration for Rat 100 with the peak effect under a relatively small (0.1 mg/kg) dose. Across rats, nicotine had no consistent dose-dependent effect on risky choice. Friedman ANOVA did not indicate any signifi cant effect of dose on titrated delay [ F = 5.635, P = 0.3434]. Dunns multiple comparison test also did not indicate any significant effect of any dose relative to vehicle [ P < 0.05]. Figure 2-3 shows the effects of nicotine on th e proportion of choices fo r the titrated delay during nicotine administration. As with Figure 2-2, if nicotine enhanced delay discounting, the proportion of choices should have de creased as a function of nicoti ne dose. However, Figure 2-3 shows no consistent effects of nicotine on ri sky choice. Friedman ANOVA indicated no significant effect of dos e on choice proportions [ F = 5.190, P = 0.3931]. Dunns multiple comparison test indicated no significant effect of any dose relative to vehicle [ P < 0.05]. Discussion In the present experiment, once an indiffere nce point was determined under pre-baseline conditions, it was used as the starting delay for th e titrating delay for all subsequent baseline and acute drug regimen sessions. This should have provided a sensitive baseline of indifference by which to observe any shifts in preference that mi ght be produced by nicotine. As can be seen in Figure 2-2, there were no consistent effects of nicotine on the ti trating delay. If nicotine 29

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increased delay discounting, the titrated delay sh ould have decreased relative to vehicle in a dose-dependent m anner. Rat 136 is the only rat to show such an effect. Rat 100, 119, and 137 show a decreasing effect of the two largest dose s relative to 0.1 mg/kg, but not relative to vehicle. Similarly, Rat 140 shows a slight decr ease in the titrated delay under some doses of nicotine but even those minimal decreases do no t appear to be dose-dependent effects. If nicotine had any substantial effect on the titrat ed delay, it was in the opposite direction increasing the titrated delay by over 370% of base line at the most effective dose for Rats 100, 103, 118, and 137. The mean data show an in crease to about 310% under the 0.1 mg/kg and 0.3 mg/kg doses. With the titrating delay procedure, once an indifference point is reached, every single response on the titrating alternat ive should shift preference towa rds the other alternative and vice-versa. As such, this procedure should even tually produce rapid alte rnation between the two alternatives. However, this is not what actually occurs under these pro cedures (e.g., Mazur, 1987). Instead, animals tend to respond on one alternative repeated ly before switching preference and responding repeatedly on the other al ternative. This might be expected if an indifference range, rather than a specific indiffere nce delay (or point), is produced by the titrating procedure. However, given the sometimes extrem e perseveration on each alternative, it seems a more likely explanation that choi ce is not sensitive to the dela y on the present or immediately preceding trial, but instead to some aggregate of preceding trials (Car dinal, Daw, Robbins, & Everitt, 2002). In other words, it simply does not happen that the rat switches the moment the titrated-delay reinforcer becomes more or less valuable than the non-t itrating alternative. Instead, responding under this proced ure seems to be controlled more by molar variables (the VT schedule on the titrating lever) than molecular va riables (the particular FT schedule currently 30

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available on the titr ating lever), so the terminal ti trated delay, or even the average titrated delay as shown in Figure 2-2, may not be the most appropriate measure of preference in this procedure. If responding on one lever or the other is no t determined by the current delay but by the aggregate of recent delays produced by that leve r, then the proportion of choices for the whole session should better indicate the general preferen ce for that lever. As such, Figure 2-3 shows the proportion of choices for the titrating delay. Again however with the possible exception of Rat 136, there is little evidence that nicotine has any increasi ng effect on delay discounting, which would produce a decrease in the proportion of choices for the titrating delay. Instead, the most effective dose of nicotine produced an ove r 70% preference for the titrated delay for 6 of the 9 rats, and over 80% preference for 4 of those 6. This is reflected in 67% mean preference for the titrated delay under the 0.1 mg/kg and 0.3 mg/kg doses. This 15% increase in preference is small and not representative across rats, but it does suggest that nicotine does not increase delay discounting as pr edicted by previous research examining the relation between smoking or nico tine administration and inter-temporal choice (Baker et al., 2003; Bickel, Odum, & Madden, 1999; Dallery & Locey, 2005; Mitchell, 1999). However, all of these previous studies have used impulsive choice procedures, making it impossible to separate nicotine effects on magnit ude sensitivity and delay discounting. Perhaps due to the many successful applications of Equati on 1-4, the authors of these studies interpreted the relationship between nicotine and increased impulsive choice in terms of increased delay discounting. If nicotine does increase delay discounting, then it should have produced an increase in risky choice (decrease in preference for the tit rated delay) in the present experiment. As can be seen in Figure 2-2 and 2-3, if there was any effect of nico tine on risky choice, it 31

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produced the opposite effect: increas ing preference for the titrated (fixed) delay (e.g., Rats 100, 103, and 118). How can these seemingly contradictory findings be reconciled? According to Equation 1-4, reinforcer value is determ ined solely by M (magnitude), D (delay), and k (delay discounting). Reinforcer magnitude and delay are both directly controlled by the experimenter (i.e., levers produce the same consequences in terms of number of pellets and delay to pellet presentation re gardless of nicotine dose), so a ny change in reinforcer value (indicated by a change in proportion of choices) must be due to a change in delay discounting, k. Given that nicotine has been shown to increase the value of a smaller-s ooner reinforcer over a larger-later reinforcer, nicotine-i nduced increases in impulsive choi ce must be due to increases in delay discounting and ther efore there must be concomitant incr eases in risky choice. But there were no such increases in risky choice in Phas e 1. Thus, Equation 1-4 cannot be used to reconcile these findings. However, if nicotine increases impulsive c hoice by decreasing magnitude sensitivity, there would be no predicted eff ect of nicotine on risky choice in Experiment 1. Given the minimal impact of nicotine on risky choice and it s implications for a slight decrease in delay discounting rather than any increase, the pres ent findings are consistent with a magnitudesensitivity-effect of nicotine. Experiment 2 was conducted to de termine the likelihood of such a magnitude-sensitivity effect. 32

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Table 2-1. Num ber of sessions and percentage of choices for th e titrating-delay lever during the last 7 sessions for the pre-baseline and ba seline conditions. Al so, the indifference delay (in seconds) determined fr om the pre-base line condition. 33

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Mean CV0.030.10.31 1 10 100 Average Latency (seconds) 125 CV0.030.10.31 1 10 100 136 CV0.030.10.31 118 1 10 100 100 1 10 100 119 103 Nicotine Dose (mg/kg) 140 CV0.030.10.31 139 137 Nicotine Dose (mg/kg) Figure 2-1. Average latency to re spond as a function of nicotine dose. Note logarithmic y-axis. C and V indicate contro l (no injection) and vehi cle (potassium phosphate) injection, respectively. Vertical lines re present standard errors of the mean. 34

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Mean CV0.030.10.31 0.1 1 10 Average Titrated Delay as Proportion of Vehicle 125 CV0.030.10.31 0.1 1 10 136 CV0.030.10.31 118 0.1 1 10 100 0.1 1 10 119 103 Nicotine Dose (mg/kg) 140 CV0.030.10.31 139 137 Nicotine Dose (mg/kg) Figure 2-2. The session average titrated delay as a function of nicotine dose. Note logarithmic yaxis. C and V indicate control (no injection) and vehicle (potassium phosphate) injection, respectively. Vertical lines represent standard errors of the mean. 35

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36 Proportion of Choices for the Titrating Delay 125 CV0.030.10.31 0.0 0.2 0.4 0.6 0.8 136 CV0.030.10.31 118 0.0 0.2 0.4 0.6 0.8 100 0.0 0.2 0.4 0.6 0.8 119 103 Nicotine Dose (mg/kg) 140 CV0.030.10.31 139 137 Mean CV0.030.10.31 0.0 0.2 0.4 0.6 0.8 Nicotine Dose (mg/kg) Figure 2-3. The proportion of choices for the titr ated delay as a function of nicotine dose.

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CHAP TER 3 EXPERIMENT 2: EFFECTS OF NICOTINE ON RISKY CHOICE WITH DIFFERENT REINFORCER MAGNITUDES Introduction In Experiment 1 nicotine had no consistent imp act on delay-based risky choice. This lack of effect in combination with the systematic impulsive choice-enhanc ing effects of nicotine observed in Dallery & Locey (2005) suggests that nicotine might decrease magnitude sensitivity rather than increase delay discount ing. If nicotine does, in fact decrease magnitude sensitivity, then this should become apparent by adding differe nt reinforcer amounts to the procedure used in Experiment 1. By changing only the number of pellets produced by the titrating alternative, any observed increase in risky choice mu st be attributed to the change in reinforcer magnitude. If such an experiment were to show that nicotin e increased delay-based ri sky choice only in the presence of different magnitude reinforcers, that would provi de substantial support for the interpretation of nicotine-induced impulsive c hoice effects being the result of decreases in magnitude sensitivity. As such, Experiment 2 was conducted as a systematic replication of Experiment 1 with only a single procedural change: the titrated-del ay alternative produced three pellets instead of one. Method Subjects Nine Long-Evans hooded male rats (Harlan, In dianapolis, IN) were housed in separate cages under a 12:12 hr light/dark cycle with conti nuous access to water. The weight restriction used in Experiment 2 was the same as Experiment 1. Five of the 9 rats were experimentally nave, while Rats 136, 137, 139, and 140 had prev iously participated in Experiment 1. Apparatus The Apparatus was the same as described in Chapter 2. 37

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Procedure Training. Rats that had completed Experiment 1 received no additional training. Experimentally nave rats experienced the sa me training as described for Experiment 1. Titrated Delay Procedure (Pre-baseline). The titrating delay procedure was identical to that used in Experiment 1 with the sole ex ception that a choice for the titrating alternative produced three pellets instead of one. In other words, the left green-lit lever was again the variable lever, on which a single response resulted in a single pellet deliv ery after a variable delay: either 1 s (p=.5) or 19 s (p=.5). The right red-lit lever was again the titrating lever, on which a single response resulted in three pellets delivered after some titrating delay. The stability criteria for de termining pre-baseline indifference points were the same as described for Experiment 1. For two of the ni ne rats (139 and 161), stability was not reached within the first 100 sessions. For these rats, the median of the average ad justing delays for the last 20 sessions was considered the indiffe rence point for all subsequent sessions. Baseline. For the first trial of each session, the value of the titrating delay started at the indifference delay determined for th at particular rat. All other as pects of the procedure remained the same as described previously. The baseline was continued for a minimum of twenty sessions and until the adjusting delay was stable. For all rats, stability was determined based on the same criteria used in the pre-baseline condition. Acute Drug Regimen. The same procedure describe d in the baseline was used throughout the drug regimen. Subj ects were administered nicotine twice per week (Tuesday and Saturday) as described for Experiment 1. Free-Feed. Seventy five sessions after comple tion of the drug regimen, rats were allowed free access to food in the home cages. Daily sessions continued as before except that 38

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sessions were term inated after 90 minutes if 60 tr ials had not yet been completed. Free-feed sessions continued for 20 days after 100% free-feeding weight was reached. Results Table 3-1 shows the number of sessions each rat spent under the experimental (prebaseline) condition and the indifference delay that was determined during that condition. Note that for 2 subjects (139 and 161), the pre-baseline condition was terminated after 100 sessions in the absence of stable choice proportions. However, all 9 rats did meet the stability criteria during the baseline condition. Rat 157 di ed under the initial dos e of nicotine during the second acute cycle (1.0 mg/kg). Therefore, only acute dosi ng data from the first administration cycle is presented for Rat 157. Figure 3-1 shows the average latency to make a choice as a function of dose for each rat, during acute administration. Note the logar ithmic y-axis. C and V indicate control (no injection) and vehicle (potassium phosphate) injection, respectivel y. Vertical lines represent standard errors of the mean. Latency was measur ed as the time from the onset of the stimulus lights (at the beginning of each tr ial) to the first response on either lever. Friedman ANOVA indicated a significant effect of dose on choice latency [ F = 33.57, P < 0.0001]. As with Experiment 1, only the highest dose of nicotin e had any substantial effect (Dunns multiple comparison test between 1.0 mg/kg a nd the other three nicotine doses: D = -33, -37, and -34, P < .05). Figure 3-2 shows the average tit rated delay as a function of nicotine dose (open circles) for each rat and the group mean. Note the logarithmic y-axis. Fo r ease of comparison, data from Experiment 1 (Figure 2-2) is also presented here (closed circles). Sim ilarly, Figure 3-3 shows the proportion of choices for the titrated delay for both Experiment 1 (closed circles) and Experiment 2 (open circles). Unlike Experiment 1, all rats showed an increase in preference for 39

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the m ore variable option under nico tine administration. In most cases, the increase was a dosedependent escalation as reflected in the mean data. Friedman ANOVA indicated a significant effect of dose for both the titrated delay [Figure 3-2, F = 26.02, P < 0.0001] and choice proportions [Figure 3-3, F = 33.44, P < 0.0001]. Dunns multiple comparison test indicated a significant effect of 0.3 mg/kg and 1.0 mg/kg relative to vehi cle for the titrated delay [ D = 28, 31; P < 0.05] and the proportion of choices [ D = 30, 33; P < 0.05]. The descending order of doses did not seem to be responsible for any obs erved effects: across the 8 rats experiencing both cycles, exactly 50% of the first cycle doses had greater effect than the corresponding dose during the second cycle with respect to proportion of choices under the three smallest acute doses of nicotine. Figure 3-4 shows the mean proportion of choices for the titrated alte rnative as a function of acute nicotine dose for rats in Experiment 1 (closed circles), rats in Experiment 2 (open circles), and rats in the Dallery and Locey (2005) impulsive choice study (closed triangles). For Experiment 2 and the impulsive choice study, the titrated alterna tive was a 3-pellet reinforcer whereas the other alternative was a 1-pellet rein forcer after a variable (Experiment 2) or immediate (impulsive choice) delay. Any effect on choice in Experi ment 1 is not consistent with either of the other two proce dures which used different re inforcer magnitudes on the two alternatives. Experiment 2 results indicate a dose-dependent increase in preference for the smaller (1-pellet), variably-delayed (1 s or 19 s) reinforcer, which is very similar to the dosedependent increase in preference for the smaller (1-p ellet), sooner (1 s) reinforcer in the Dallery & Locey impulsive choice study. The titrating delay could change by a maximu m of 21% per 3 trials in the present study and only 10% per 6 trials in the Dallery & Locey (2005) study. As such, a similar effect on 40

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indifference delays should be reflected by a sm a ller effect on proportion of choices in the present study relative to the Dallery & Locey study. Cons idering the differences in the speed with which adjusting could occur, the dose-de pendent increase in risky choi ce in Experiment 2 is nearly identical to the dose-dependent increase in impulsive choice in the Dallery & Locey (2005) study. Four rats survived to complete the free-feed condition (136, 139, 140, 141). Figure 3-5 shows the mean proportion of choice s for the 3-pellet, titrating a lternative for those rats. The mean during the final 20 sessions of the food-restri cted diet (control, C), the mean during the final 20 sessions of the free-f eeding condition (F), and the mean under each acute nicotine dose (from Figure 3-3) are included for ease of comparison. There was no increase in risky choice over the course of the free-feeding conditi on. Only two of the four rats showed any increase in risky choice during fr ee-feeding relative to control. The mean increase in risky choice produced by free-feeding wa s substantially less than the in crease produced by all but the smallest (.03 mg/kg) dose of nicotine. Friedm an ANOVA indicated a significant effect of dose on choice [ F = 18.5, P = 0.0099]. Dunns multiple comparison te st indicated a significant effect of only 1.0 mg/kg relative to vehicle [ D = 22; P < 0.05], indicating no sign ificant effect of free feeding [ D = 11] on choice. Figure 3-6 shows the effects of free-feed ing on response latency for each of the 4 surviving rats. Each panel shows average res ponse latency during the fi nal 20 sessions of the food-restricted diet (C) and dur ing the final 20 sessions of the free-feeding condition (F). Acute effects of nicotine from Fi gure 3-1 are also shown for conve nience. With the exception of Rat 140, for which free-feeding had little effect on latency, response latencies were substantially higher under free-feeding than under any but the highe st (1.0 mg/kg) dose of nicotine. Friedman 41

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ANOVA indicated a sig nificant effect of dose and free-feeding on latency [ F = 23.58, P = 0.0013]. Dunns multiple comparison test indicated a significant effect of only 0.3 mg/kg relative to 1.0 mg/kg and free-feeding [ D = -27, -23; P < 0.05]. Discussion The present experiment was the first to comb ine a risky choice task with an impulsive choice task by adding different am ounts to a delay-based risky c hoice procedure. Subjects were initially indifferent between 1 pellet delivered after a variable (MT 10 s) delay and 3 pellets delivered after about 35 s. Acute injections of nicotine produced dosedependent increases in preference for the smaller, more variable option ove r the larger, less variab le option. Under the most effective doses of nicotine (0.3 mg/kg and 1.0 mg/kg), rats were indifferent between 1 pellet after a variable delay a nd 3 pellets after about 15 s. Why did nicotine increase preference for the sma ller, more variable alternative? As with nicotine-induced increases in impulsive choice (Dallery & Locey, 2005), Experiment 2 results could be accounted for by either an increase in delay discounting or a decrease in magnitude sensitivity. By using different magnitudes with the delay-based ri sky choice procedure, either of these two behavioral mechanisms could be affect ed by nicotine. However, given that the same procedure (with some of the same subjects) pro duced no increases in dela y-based risky choice in Experiment 1, it is reasonable to conclude that the acute effects of ni cotine on both impulsive choice and in this case, riskpulsive choice (a hybrid risky choice impulsive choice procedure), are due to a decrea se in magnitude sensitivity rather than delay sensitivity. A comparison of dose effect curves from Dallery & Locey (2005) and Experiment 2 (Figure 3-4) reveals very sim ilar effects on proportion of choices for the large alternative. Although the procedures used in these two experiments were very similar, the present, riskychoice procedure did use a faster titrating delay (10%/t rial) procedure than was used in the 42

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context of impulsive choice (up to 1 0%/6 trials). As such, it is difficult to precisely compare the magnitude of effects across these studies. Howe ver, the minimal and inconsistent effects of nicotine in Experiment 1, combined with the si milarity of impulsive a nd riskpulsive functions in Figure 3-4, provide compelling evidence that any acute effect of nicotine on impulsive choice is the result of a decrease in magnitude sensitivity. It is tempting to attribute nicotine effects on magnitude sensitivity to its effects as an appetite-suppressant. Indeed, it may well be th e case that nicotine effects on impulsive choice are limited to situations with food reinforcers. As such, it is imperative before drawing any general conclusions that the pr esent set of experiments (inclu ding Experiments 3 and 4) be replicated with alternat ive reinforcers. However, Figure 3-5 and Figure 3-6 suggest that the present results cannot be accounted for entirely by the appetite-suppr essant effects of nicotine. Figure 3-5 shows that any minimal effect of free-feeding on proportion of choices for the titrated delay was substantially less than the effects of acute nicotine admi nistration of all but the least effective dose (0.03 mg/kg). Th is suggests that free-feeding had less effect than nicotine on magnitude sensitivity. In contrast, Figure 3-6 sh ows that for all but the largest dose of nicotine, free-feeding had a much greater effect on response la tency. Insofar as this increased latency to respond for food typifies an appe tite suppressant effect, these data suggest that free-feeding has much greater appetite-suppressant effects than nicotine, yet much weaker effects on magnitude sensitivity, and thereby on impulsive choice. A more thorough investigation with alternating drug and free-feed conditions may be needed before reaching any definitive conclusions. However, the present results do sugg est that appetite suppr ession is unlikely to account for the decreases in magnitude sensitivity produced by nicotine. 43

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The results from Experiment 1 and 2 pr ovide compelling evidence for a magnitudesensitivity effect by nicotine. However, there ar e a few alternative explanations that might be worth considering for the present findings. First, perhaps nicotine does increase delay discounting, without affecting magnitude sensitiv ity, but it only does so in the presence of different magnitudes. All of the present data (i.e ., Figure 3-4) would be consistent with such an interpretation. Although such an interpretation might seem a b it of a stretch, it cannot be eliminated until a simpler procedure is used whic h involves choices between different reinforcer magnitudes without differences in reinforcer delays. A second limitation of these first two experiments is that the differe nces in preference found in Experiment 1 might be the result of di fferences in baseline performance. Even though the only procedural change between Experiment 1 and Experiment 2 was a change in reinforcer magnitude, this change in reinforcer magnitude also produced a change in indifference delays during the pre-baseline condition. Due to the high ly valuable nature of the MT 10 s option, as a result of the 1 s component of that schedule, the indifference delays in Experiment 1 were typically very close to 1 s upon co mpletion of the pre-baseline condi tion (as shown in Table 2-1). In contrast, the high-magnitude reinforcer available with the titrated delay in Experiment 2 produced much higher indifference delays (media n of 36 s). Similarly, the Dallery & Locey (2005) procedure also found indiffe rence delays much higher than 1 s due to the large magnitude reinforcer available with the titrated delay. As such, it may be the case that nicotine increases aversion to long delays, thus shif ting preference away from the va riable delay in Experiment 1 because of the 19 s component and away from the titrating delay in Expe riment 2 (and Dallery & Locey, 2005) because of the larger titrated de lay and the beginning of the session. This interpretation is supported by the increased ris ky choice found with Rat 136 whose pre-baseline 44

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indifference delay was one of the highest. Howe ver, this interpretation is not supported by Rats 139 and 140, the two other rats with pre-baseline indifference delays substantially higher than 1 s. Furtherm ore, insofar as an aversion to long delays is synonymous with an increase in delay discounting, as explained in th e introduction, an increase in delay discounting should have produced an increase in ris ky choice in Experiment 1. Unfortunately, Experiment 1 might not have b een the best measure of risky choice. As was just mentioned, by using such an extremely valuable variable delay, the indifference delay at the end of the pre-baseline condition in Experiment 1 was frequently close to 1 s (for 6 of the 9 rats). Given a choice between 1 s and the 1 s, 19 s MT schedule, increasing k in Equation 4 should increase preference for the 1 s alternative rather than the va riable alternative. In other words, the lack of an increase in preference for the variable alternative is consistent with a nicotine-induced increase in delay discounting on ce the titrated delay drops to 1 s. However, because of the percentage adjustment, a substa ntial portion of the session would be needed before the titrated delay reached 1 s for all but Ra t 103. In order for the titrated delay to reach 1 s would have required a substantia l preference for the variable delay early in the session, which did not occur. Also, the fact that such sma ll indifference delays were obtained suggests that there was typically a bias for the variable-delay lever (as even an infinitely high k would not predict an indifference delay of 1.0 for Rat 103), and if such a bias was accounted for, then increasing k in Equation 4 should still ha ve increased preference for th e variable-delay lever. Nevertheless, results from the first two experime nts might have been more convincing had a less extreme MT schedule been used (e.g., 3 s and 17 s) to consistently obtain indifference delays more distal to the more immediate element of the MT schedule (e.g., 3s). 45

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A final limitation of the first two experiments is that even if nicotine does decrease sensitivity to reinforcer magnitude, these experiments do not indicate how that happens. For instance, is it the case that (1) smaller magn itude reinforcers become more valuable under nicotine, (2) larger magnitude reinforcers become less valuable under nicotine, or (3) some combination of #1 and #2? Experiments 3 and 4 were designed to address all of the above limitations. 46

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Table 3-1. Num ber of sessions and percentage of choices for th e titrating-delay lever during the last 7 sessions for the pre-baseline and ba seline conditions. Al so, the indifference delay (in seconds) determined fr om the pre-base line condition. aPre-baseline terminated without stability 47

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Average Latency (Seconds) 161 CV0.030.10.31 1 10 100 136 CV0.030.10.31 158 1 10 100 141 1 10 100 159 157 Nicotine Dose (mg/kg) 140 CV0.030.10.31 139 137 Mean CV0.030.10.31 1 10 100 Nicotine Dose (mg/kg) Figure 3-1. Average latency to re spond as a function of nicotine dose. Note logarithmic y-axis. C and V indicate contro l (no injection) and vehi cle (potassium phosphate) injection, respectively. Vertical lines represent standard errors of the mean. 48

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125 CV0.030.10.31 0.1 1 10 119 0.1 1 10 118 0.1 1 10 103 0.1 1 10 100 0.1 1 10 Mean CV0.030.10.31 140 139 137 136 161 CV0.030.10.31 159 158 157 Average Titrated Delay Proportion of VehicleNicotine Dose (mg/kg) 141 Exp 2 Exp 1 Figure 3-2. The session average ti trated delay as a function of nicotine dose for Experiment 1 (closed circles) and Experiment 2 (open circles). Note logarithmic y-axis. C and V indicate control (no injection) and vehicle (potassium phosphate) injection, respectively. Vertical lines repres ent standard errors of the mean. 49

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125 CV0.030.10.31 0.0 0.2 0.4 0.6 0.8 119 0.0 0.2 0.4 0.6 0.8 118 0.0 0.2 0.4 0.6 0.8 103 0.0 0.2 0.4 0.6 0.8 100 0.0 0.2 0.4 0.6 0.8 Mean CV0.030.10.31 140 139 137 136 161 CV0.030.10.31 159 158 157 Proportion of Choices for Titrated DelayNicotine Dose (mg/kg) 141 Exp 2 Exp 1 Figure 3-3. The proportion of choice s for the titrated delay in Expe riment 1 (closed circles) and Experiment 2 (open circles) as a function of nicotine dose. 50

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Proportion of Choices for the Titrated Delay Mean CV0.030.10.31 0.0 0.2 0.4 0.6 0.8 1.0 Nicotine Dose (mg/kg) Exp 1 (n=9) Exp 2 (n=9) Imp. Choice (n=5) Figure 3-4. The mean proportion of c hoices for the titrated delay as a function of nicotine dose in Experiment 1 (closed circles), Experiment 2 (open circles), and the Dallery & Locey (2005) impulsive choice experiment. Proportion of Choices for Titrated Delay 136 CF0.030.10.31 0.0 0.2 0.4 0.6 0.8 141 0.0 0.2 0.4 0.6 0.8 Nicotine Dose (mg/kg) 140 CF0.030.10.31 139 Mean CF0.030.10.31 0.0 0.2 0.4 0.6 0.8 Nicotine Dose (mg/kg) Figure 3-5. The proportion of choices for the titr ated delay during acute dosing, during the 20 sessions prior to free-feeding (control, C ), and during the final 20 sessions under free-feeding (F). Vertical lines re present standard errors of the mean. 51

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Average Latency (Seconds) 136 CF0.030.10.31 1 10 100 141 1 10 100 Nicotine Dose (mg/kg) 140 CF0.030.10.31 139 Mean CF0.030.10.31 1 10 100 Nicotine Dose (mg/kg) Figure 3-6. Average latency to respo nd during acute dosing, during the 20 se ssions prior to freefeeding (control, C), and duri ng the final 20 sessions under free-f eeding (F). Vertical lines represent standard errors of the mean. 52

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CHAP TER 4 EXPERIMENT 3: EFFECTS OF NICOTINE ON CONCURRENT PROGRESSIVE RATIOS WITH DIFFERENT REINFORCER MAGNITUDES Introduction Progressive ratio (PR) schedul es were first described by Findley (1958). These schedules are essentially a series of fixed-ratio (FR) schedules schedules that arrange reinforcement after a fixed number of responses in which the ratio value increases over succe ssive reinforcements. Whereas the most prominent feature of an FR is the ratio requirement, the most prominent feature of a PR is the step size. As such FR 50 indicates 50 responses are required for reinforcement whereas PR 50 indicates that th e ratio requirement will increase by 50 after each reinforcement. PR schedules were initially us ed by Findley (1958) as an effective means to establish switching between concurrent ratio schedules schedules that would otherwise typically engender exclusive prefer ence for the lower ratio schedule. Hodos (1961) proposed the use of single-alternative PR schedules as a means of measuring reinforcer value (or in his words, reward stre ngth). Under a properly arranged PR schedule, a subject will eventually stop responding once th e ratio requirement becomes too large. Presumably this breakpoint would always be th e same for any particular reinforcer under the same motivational conditions (e.g., similarly food-deprived). Also the breakpoint would presumably be higher for higher-valued reinforcers (i.e., higher-value reinforcers should be able to support more behavior under such a schedul e), thus making the PR breakpoint a sensitive measure of reinforcer value. Given that the focus of the present set of e xperiments is to explore how nicotine impacts reinforcer value, PR schedules might be a usef ul tool in that explor ation. Results from Experiments 1 and 2 suggest that nicotine decrea ses magnitude sensitivity. This might be accomplished by decreasing the apparent magnitude of larger reinforcers or increasing the 53

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m agnitude of smaller reinforcers. If it is the ca se that nicotine decreases the apparent magnitude of large reinforcers, then nicotine should produce a reduc tion in a PR breakpoint with large magnitude reinforcers. If, however, nicotine increases the apparent magnitude of small reinforcers, then nicotine should produce an in crease in a PR breakpoint with small magnitude reinforcers. Alternatively, both effects might occur if the decrease in reinforcer magnitude sensitivity arises as a combina tion of both decreasing the apparent magnitude of large reinforcers and increasing the apparent magnitude of small reinforcers. One potential drawback in ar ranging single-alternative PR sc hedules to assess relative changes in reinforcer value between small and la rge magnitude reinforcers is the aforementioned caveat with respect to identical motivational co nditions. As the disparity between small and large reinforcers increases, so too does the disp arity in motivational conditions. For example, the PR breakpoint with respect to a gallon of ice cream would likely be lower than the PR breakpoint for a spoonful of ice cream (assuming no means of storing un-consumed ice cream). This ice cream example has been supported experimental ly by Hodos & Kalman (1963), who found PR 5 breakpoints to be an inverted-U (or V) -shaped function of re inforcer volume (sweetened condensed milk mixed with tap water) with rats. He conclude d that the down-turn in the breakpoint function was the resu lt of increased satiation with higher reinforcer volumes. Although this effect was only found with relatively small step si zes (e.g., PR 5), it indicates a potentially serious problem for any interpretation of changes in single-alternative breakpoints. If nicotine decreased a single-alternative PR breakpoint, it would be impossible to determine if that decrease was the result of d ecreasing the reinforcer value (thus decreasing the amount of behavior that reinforcer could maintain) or the result of increasing the reinforcer value (but increasing satiation in the process). 54

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D espite this potentially serious flaw in singl e-alternative PR schedul es, they have been extensively used in behavioral pharmacology, pa rticularly in drug self -administration studies (see Stafford, LeSage, & Glowa, 1998 for review). Nevertheless, the use of a single-alternative PR schedule in the context of comparing breakpo ints for different magnitude reinforcers seems particularly problematic given the potential confound of differences in satiation. Furthermore, if the effects observed in Experiment 2 were the result of a magnitude sensitivity effect, that effect was only observed in a choice context. It may be the case that nicotine decreases magnitude sensitivity without increasing the value of small reinforcers, per se, or decreasing the value of large reinforcers, per se. Instead it may be that nicotine simply decreases the difference in value between different magnitude reinforcers. If that were the case, there might be little effect of nicotine on reinforcer magnitude when only one re inforcer is present (as may essentially be the case in a single-alternative sche dule). Whether or not nicotine effects on magnitude sensitivity are unique to choice contexts might certainly prove to be a worthwhile area of research. However, it would seem prudent to first verify the existence of such an effect before attempting a thorough exploration of its boundary conditions. Experiment 3 was thus designed to maintain the focus on a choice context in addressing whether or not the previously observed eff ects of nicotine (in Dallery & Locey, 2005 and Experiment 2) were due to an effect on magnitude sensitivity. As such, Experiment 3 used a concurrent progressive ratio schedule in which one PR alternative produced large magnitude reinforcers and the other PR alternative produced small magnitude reinforcers. Unlike the original concurrent PRs arrang ed by Findley (1958), ratio requi rements were not reset after completing a ratio on the other alternative (Findley was interested in arra nging ratio schedules in which pigeons would switch rather than exclus ively prefer one option; whereas the present 55

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experim ent is designed to assess di fferences in reinforcer value be tween the two reinforcers). By arranging these schedules conc urrently, the motivational cond itions (i.e., economic contexts) were held constant across the two alternatives any increases in satiation were the same for both the small and large magnitude reinforcer PRs. Method Subjects Six experimentally nave Long-Evans hooded male rats (Harlan, Indianapolis, IN) were housed in separate cages under a 12:12 hr light/dar k cycle with continuous access to water. Each rat was maintained at 85% of its free-feeding weight as determined at postnatal day 150. Apparatus The Apparatus was the same as described in Chapter 2. Procedure Experimental sessions were conducted 7 days a week at approximately the same time every day during the rats light cycle. Training. All rats were trained under a simplif ied version of the baseline procedure. This involved a concurrent (PR 1, PR 1) sc hedule in which each reinforcer presentation increased the subsequent ratio requirement on th at lever by 1. Rats then experienced over 8 months of concurrent progressive ratio schedu les with occasional manipulations of various parameters. Baseline. A concurrent (PR x1.2 1-pellet, PR x1.2 5-pellet) with starting ratio requirements of FR 5 and a COR 5 (changeover re sponse requirement of 5) was used as the baseline condition. PR x1.2 schedules are FR schedules in which the response requirement increases by 20% after each ratio completion. Ratio completions on one PR (e.g., the 1-pellet PR) had no effect on the response requirement of the other schedule (e.g., the 5-pellet PR). 56

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After the 10-minute blackout, se ssions began with the illumi nation of a green light above one lever and a yellow light above the other. E ach light remained on for 5 s. Each response on one of the two levers reset the duration of the light above that lever for 5 s and designated that lever as active. Responses on an active lever were reinforced with 1 pellet (for responses on the small lever) or 5 pellets (f or responses on the large leve r) based on the current ratio requirement for that lever (i.e., 5, 6, 8, 9, 11, 13, 15, 18, 22, 26, 31, 38, 45, 54, 65, 78, 93, 111, 134, 160). Ratio completion had no immediate eff ect on the stimulus light s except the standard 5 s illumination produced by the terminal response. Ratio completion produced a 4 s feeding period during which responses on either leve r produced no programmed consequences. At the end of the feeding period, both le ver lights were turned on for 5 s but only the most recently active lever was designated as activ e. Responses on an inactive lever turned off the light above the active lever, deactivated that le ver, and initiated the COR 5. Five consecutive responses on an inactive lever (including any initial response while the other lever was active) turned on the light above that lever for 5 s and designated that lever as active. Responses on inactive levers never contributed towards the comp letion of any progressive ratio requirement. Sessions were terminated after 30 minutes or 20 reinforcements (20-100 pellets). The baseline condition continued for a minimum of 40 sessions and until the rate of responding for each alternative was stable for seven consecutive days. Stability was determined based on response rates in each session according to three criteria. First, each of the 7-session response rates had to be within 20% of the av erage of those 7 values. Second, the average response rates for the first three a nd last three of those seven sessi ons were required to be within 10% of the 7-session average. Third, there could be no increasing or decreasing trend in response rates across the final 3 sessions (i.e., three consecutive increas es or decreases in 57

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response rate for either the sm all or large lever). Response rates for all rats were stable within 5 days of the 40-session minimum. Acute Drug Regimen. The same procedure describe d in the baseline was used throughout the drug regimen. Doses were 0.74, 0. 56, 0.3, 0.1, and 0.03 mg/kg nicotine (Sigma Chemical Co., St. Louis, MO). Each rat experien ced two cycles of each dose in either ascending or descending order (counterbalanced acro ss rats) with each cycle preceded by a vehicle injection. Results Figure 4-1 shows total session responses as a proportion of mean session responses on that lever under vehicle. Respons es for the large (open circles) a nd small (closed circles) levers are shown as a function of nicotin e dose. C and V indicate c ontrol (no injection) and vehicle (potassium phosphate) injection, re spectively. The 0.56 mg/kg dose is not labeled. Vertical lines represent standard errors of the mean. For example, Rat 205 responded 75% more (proportion = 1.75) on the small lever and 45% less (proportion = 0.55) on the large le ver under the 0.56 mg/kg dose than under vehicle. There were substantial indivi dual differences in performance under nicotine. For 3 of the six rats (203, 205, and 206), there was increas ed responding on the sma ll lever and decreased responding on the large lever at all do ses of nicotine. This was also the case for Rat 202 with the exception of 0.3 mg/kg nicotine which had the op posite effect. Rat 204 showed the same effect at the largest doses (0.56 mg/kg and 0.74 mg/kg) but the opposite effect (increased responding for the large, decreased responding for the small) at the smaller doses (0.1 mg/kg and 0.3 mg/kg). During nicotine-administration sessions, Rat 207 exhibited only minor and inconsistent deviations from performance under vehicle injections. 58

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Response rates for the mean data showed a dose-dependent increase in responding for the small lever and a dose-dependent decrease in resp onding for the large. Only the largest doses (0.56 mg/kg and 0.74 mg/kg) produced response rate s that were substantia lly higher (for the small lever) or lower (for the large lever) than rates during control (no injection) sessions. Friedman ANOVA indicated a si gnificant effect of dose on responses for the small and large levers [ F = 16.86, 17.11, P = 0.0098, 0.0089]. Dunns multiple comparison test indicated a significant effect of only 0.74 mg/kg relative to vehicle for the small and large levers [ D = -25, 26; P < 0.05]. Discussion If nicotine decreases sensitivity to reinforcer magnitude, then there should have been a separation in the two data paths in Figure 4-1. Specifically, if nicotine increases the value of the small reinforcer, Figure 4-1 should show a dosedependent increase in small (1-pellet) lever responses as a function of nicotin e dose. Alternativel y, if nicotine decrea ses the value of the large reinforcer, Figure 4-1 should show a dosedependent decrease in large (5-pellet) lever responses as a function of nico tine dose. Both effects are apparent for Rat 205, 206 and the mean. However, neither effect is seen consistently across most of the rats. On the group level, the pres ent findings offer general suppo rt to the interpretation that nicotine increases impulsive choice via a decreas e in magnitude sensitivity rather than an increase in delay sensitivity. The concurrent pr ogressive ratio procedure does have the apparent virtue of being able to indicate whether a decrease in magnitude sensitivity is due to an increase in preference for the small, a decrease in preference for the large, or both. The latter seems to be the case in the mean data of Figure 4-1, as indi cated by the divergent data paths for the large and small levers. However there are a host of limita tions of the present experimental design and its findings. 59

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First, the concurrent progressive ratio proce dure fails to separate magnitude and delay. Because lever presses require a considerable duration to complete, any increase in response requirement for reinforcement also entails a pr oportional increase in delay requirement for reinforcement. As such the present study fails where both Dallery and Locey (2005) and Experiment 2 failed. That is, all three failed to separate reinforcer delay and reinforcer magnitude. Second, the current procedure was not desi gned to obtain breakpoints. Due to the diminishing effect of drug over time, maximum session durations were severely limited in the present study. Because of the large number of pellets earned on the large lever, sessions were restricted in number of ratios that could be completed. By th e end of the baseline condition, sessions never reached the maximum time duration sessions always terminated due to the ratio completion limit of 20, often within 5 minutes. While the concurrent natu re of the schedule does seem to allow inferences into relative reinforcer value, it is difficult to determine what relation preference under these conditions would have to true breakpoints. And indeed, because sessions were terminated after 20 total ratio completions, it is likely unreasonable to make any inferences from the present data with respect to whether nicotine increases the value of the large or decreases the value of the small because a ny increase or decrease in ratio completions on one alternative would necessarily entail a corresponding decrease or increase on the other. As such, it is unclear that the present design offe rs any real advantages over Experiment 1 and Experiment 2 except for the greate r expediency of the procedure. Third, the lack of a consistent dose-depende nt effect on choice across rats (e.g., Figure 41) limits what general conclusions can be drawn from the data. Furthermore, even for those few rats that did show a consiste nt dose-dependent effect of ni cotine (e.g., Rat 206), alternative 60

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interpretations abound. For instance, unlike Expe rim ent 1 and 2, the present procedure did not establish indifference under ba seline performance. As such any decreased difference in performance between the two levers could be the result of a dose-dependent breakdown in simple stimulus control rather than an effect on magnitude sensitivity, per se. Perhaps related, any effect observed in Figure 4-1 might easily be dismissed as a simple rate-dependent effect nicotine might simply be increasing low res ponse rates and decreasing high response rates independent of the consequences on each lever. In summary, the present experiment offers, at best, weak support for the interpretation that nicotine decreases sensitivity to reinforcer magnitude. What is needed is a more conclusive experiment that addresses all of the limitations of Experiments 1-3. Such an experiment must do the following: Separate amount and delay so that any effect of nicotine on choice can be attributed to sensitivity to one or the other. Provide a comparable baseline for the amount-sensitivity test and the delay-sensitivity test (to avoid the alternative explan ation from Experiments 1 and 2 that differences in baseline indifference delays were responsible for differences in drug effects). Provide a sensitive baseline that clearly shows whether nicotine increases or decreases delay sensitivity and whether nicotine incr eases or decreases magnitude sensitivity. Indicate whether any decrease in magnitude sensitivity is produced by increasing the apparent magnitude of the small reinforcer or decreasing the apparent magnitude of the large reinforcer. Provide adequate controls to rule out alternative explanations such as a breakdown in stimulus control or a simple rate -dependent effect of nicotine. The final experiment in the present study E xperiment 4 was designed to address all of the above limitations. 61

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Responses as Proportion of Vehicle 205 CV0.030.10.30.74 0.0 0.5 1.0 1.5 2.0 2.5 202 0.0 0.5 1.0 1.5 2.0 2.5 206 CV0.030.10.30.74 203 Nicotine Dose (mg/kg) 207 CV0.030.10.30.74 204 MeanNicotine Dose (mg/kg) CV0.030.10.30.74Responses as Proportion of Vehicle 0.0 0.5 1.0 1.5 2.0 Figure 4-1. Total session responses for small (closed) and large (open) levers as a proportion of responses for that lever under vehicle. C and V indicate control (no in jection) and vehicle (potassium phosphate) in jection, respectively. Vertical lines represent standard errors of the mean. 62

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63 CHAPTER 5 EXPERIMENT 4: EFFECTS OF NICOTINE ON CONCURRENT-CHAINS PERFORMANCE WITH DIFFERENT REINFORCER MAGNITUDES AND DELAYS Introduction Results from Dallery & Locey (2005), Experime nt 1, and Experiment 2 are all consistent with a nicotine-induced decrease in magnitude sensitivity and little, if any, effect on delay sensitivity. All of those procedures, however, are re latively complicated involving alternatives that differ along at least 2 dimensions: reinforcer magnitude and delay (Dallery & Locey, 2005); reinforcer delay and probability of delay (Experi ment 1); and reinforcer magnitude, delay, and probability of delay (Experiment 2). If one is in terested in determining what effect nicotine has on sensitivity to reinforcer magnitude, it seems simpler to arrange simple choices between alternatives that differ only in magnitude. Afte r obtaining a stable base line of preference under such a preparation, nicotine c ould then be administered to as sess its effects. Similarly if interested in nicotine effects on sensitivity to reinforcer delay, why not arrange simple choices between different delays and then measure the e ffects of nicotine on such choices? The simple answer to that question is: it would not work. If given a choice between tw o FRs (e.g., FR 1 with 3 pelle ts vs. FR 1 with 1 pellet), exclusive preference would quickly emerge for th e higher rate of reinforcement (e.g., Findley, 1958). As such, the only way that nicotine would ha ve an effect on preference in such a situation would be if sensitivity to reinforcer magn itude was not only decreased, but completely eliminated by nicotine something that is not suggested by the present da ta. Even if magnitude sensitivity were completely eliminated (produc ing complete indifference between 1 pellet and 3 pellets), exclusive preference fo r the 3-pellet alternative might still be found because no particular pattern of responses is predicte d between two equally-valued FR schedules.

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One possible solution to this problem would be to arrange progressive, rather than fix ed, ratio schedules to measure relative preference fo r each alternative. This was the approach in Experiment 3 which led to limited success. A nother possible solution would be to arrange a concurrent-chains procedure with equal-interval VIs in the initial links. A chained schedule is a schedule in which two or more reinforcement sc hedules are arranged successively with each component schedule comprising a link in the chain (see Skinner, 1958 for diagram). The completion of each link produces a stimulus change and only completion of the final link results in primary reinforcement (e.g., food). A concur rent-chains procedure involves two (or more) chained schedules in which the initial links are available simultaneously. Autor (1960) was the first to use equal-interval VI initial links to assess relative preference between reinforcement schedule A (initiated upon completing the VI on the left key) and reinforcement schedule B (initiated upon completing the VI on the right key). Early findings with such procedures (e.g., Herrnstein 1964a, 1964b) indicated th at relative preference during th e initial links was directly proportional to the relative value of the terminal link schedules. Further research (see Mazur, 2006 for review) has found that degree of preference depends somewhat on the exact schedule parameters used (e.g., duration of initial-link VIs). Nevertheless, the concurrent-chains procedur e remains an effective and sensitive method for comparing the relative value of two terminal links. The present experiment sought to take advantage of that by arranging conc urrent chains with different re inforcer delays (for the delay group) and different reinforcer magnitudes (for th e magnitude group) in th e terminal links. If nicotine decreases magnitude sensitivity but ha s no effect on delay sens itivity, this should be revealed by dose-dependent decreases in relative preference for the large magnitude terminal link 64

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(for the m agnitude group) and no dose-dependent changes in relative preference for the short delay terminal link (for the delay group). Method Subjects Twelve experimentally nave Long-Evans hooded male rats (Harlan, Indianapolis, IN) were housed in separate cages under a 12:12 hr li ght/dark cycle with continuous access to water. Each rat was maintained at 85% of its free-feed ing weight as determined at postnatal day 150. Apparatus The Apparatus was the same as described in Chapter 2. Procedure Experimental sessions were conducted 7 days a week at approximately the same time every day during the rats light cycle. Training. Lever pressing was initially trained on an alternative (FR 1, RT 100) schedule of reinforcement (see Sk inner, 1958 for diagram). A fi ve minute pre-session blackout was followed by the illumination of the houselight a nd all six lever lights. The houselight remained on for the duration of each training sess ion. The six lever lights flashed on a 0.5 s onoff cycle. In the initial trial, both levers we re active so that a single response on either lever resulted in immediate delivery of 1 food pellet and the termination of all si x lever lights. After a 2 s feeding period, the lights we re illuminated and a new trial began. After two consecutive presses of one lever, that lever was deactivated until the other lever was pressed. Lights above deactivated levers were never illuminated and presses on those levers had no programmed consequences. The RT schedule was initiated at th e beginning of each trial so that a single pellet was delivered, response-independently, approximate ly every 100 s (0.01% chance every 0.01 s). After a total of 60 food deliverie s, the session was terminated. Training sessions were conducted 65

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for 10 days, at the end of which all response rates were above 10 pe r m inute. Initially, rats were exposed to a multiple schedule (a schedule of re inforcement in which different components are differentially signaled) in whic h the different delays and magn itudes were experienced within each session. The multiple schedule was suspended after approximately 135 sessions due to apparent cross-component interference. Concurrent-Chains Baseline. Rats were randomly assigned to either the magnitude (n=6) or delay (n=6) group. In the magnitude gro up, choices resulted in either 1 pellet (if the small lever was chosen) or 3 pellets (if the l arge lever was chosen). In the delay group choices resulted in 2 pellets afte r a 1 s delay (short lever) or a 9 s delay (long lever). For both groups, after a 10-minute blackout, sessions began with the illumination of the houselight, a yellow light above the left lever, and a red light above the right lever. The houselight remained on for the duration of each session. Each trial co nsisted of a concurrent-chains schedule with a concurrent (VI 20 s, VI 20 s) schedule in the in itial links. During the initial links the two lever lights flashed on a synchronized 0. 5 s on-off cycle. The VI sche dules were 20-element FleshlerHoffman distributions (Fleshler & Hoffman, 1962) from which intervals were selected without replacement to ensure greater daily consistency in reinforcement rate. For the magnitude group, one lever was the small lever and one was the l arge lever (counterbalan ced across rats). For the delay group, one lever was the short lever and one was the long lever. Completing the initial link on the small or large lever resulte d in both lever lights be ing turned off and an immediate delivery of 1 food pellet (small lever) or 3 food pellets (large lever). For the delay group, completing the initial link on the short or long lever produced an FT 1 s (short lever) or FT 9 s (long lever) terminal link. During term inal links, the lever light above the not-chosen lever was turned off and the light above the chos en lever remained on for the duration of the FT 66

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schedule. T he FT schedules ended with the delive ry of 2 food pellets regardless of which lever had been chosen. For both groups, a new trial bega n with the onset of both lever lights 35 s after each initial-link completion. VI timers were only active during the initial links. New trials began with a new interval for the previously chosen lever and a continuation of the active in terval on the not-chosen lever. Sessions were terminated after 20 minutes (about 30 total trials). After 80 sessions the initial links were ch anged to a concurrent (VI 30 s, VI 30 s) schedule and remained so for the remainder of the experiment. The baseline condition continued for 75 sessions after this change. Acute Drug Regimen. The same procedure describe d in the baseline was used throughout the drug regimen. Rats were administered nicotine doses of 0.74, 0.56, 0.3, 0.1, and 0.03 mg/kg nicotine (Sigma Chemi cal Co., St. Louis, MO). Injec tions occurred twice per week (Wednesday and Saturday). Each rat experien ced two cycles of each dose in descending order with each cycle preceded by a vehicle injection. Results Figure 5-1 shows the proportion of responses fo r the large alternative (for the magnitude group) during the final 10 sessions of the baselin e condition for each rat and for the group mean. Figure 5-2 shows the proportion of responses for th e short delay alternativ e (for the delay group) during the final 10 sessions of the baseline condi tion for each rat and for the group mean. Note the y-axis begins at 0.5 as se ssion preference was never for the small or long delay for any rat (nor would it have been expected to be). Although there is some variability across rats (e.g., Rat 184), in general preferences were very high (80% or more for most rats) and thus very similar between the two groups. 67

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Figure 5-3 shows the proportion of responses fo r the large alternative (for the magnitude group) as a function of nicotine dose during th e acute drug regimen. Figure 5-4 shows the proportion of responses for the short delay altern ative (for the delay gr oup) as a function of nicotine dose during the acute dr ug regimen. C and V indicat e control (no injection) and vehicle (potassium phosphate) injection, respectivel y. The unlabeled tick mark (between 0.3 and 0.74) indicates 0.56 ml/kg nicotine. Again, note the y-axis begins at about 0.4 (0.5 for the mean) given that 0.5 would indicate complete indiffe rence between the two alternatives. For the magnitude group, several rats approached (Rat 180 and 185) or dropped below (Rat 182 and 184) the 0.5 indifference point. Regardless of diffe rences in preference under vehicle and no-drug conditions, nicotine produced similar dose-dependent decreases in proportion of responses for the large lever across all rats in the magnitude group. Friedman ANOVA indicated a significant effect of dose on choice proporti ons in the magnitude group [ F = 30.71, P < 0.0001]. Dunns multiple comparison test indicated a significant e ffect of 0.56 mg/kg and 0.74 mg/kg relative to vehicle [ D = 30, 27; P < 0.05]. For the delay group, ther e seems to be a slight decrease in preference for two rats (Rat 186 and 189) as a func tion of dose. For the other 4 rats there is either a slight increase or no effect of dose. Friedman ANOVA indicated no significant effect of dose on choice proportions in the delay group [ F = 3.5, P = .744]. Dunns multiple comparison test indicated no si gnificant effects of any dos e relative to vehicle (P < 0.05). Figure 5-5 shows mean response data for the magnitude group. Both panels show responses for the large lever (ope n circles) and small lever (clo sed circles) as a function of nicotine dose during the acute drug regimen. The left panel show s responses as a proportion of responses under vehicle administration. The ri ght panel shows responses as a proportion of responses on the large lever under vehicle administra tion. Both panels show that moderate doses 68

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of nicotine (0.1 m g/kg and 0.3 mg/kg) increased responding on the small lever and had little effect on large-lever responding. Large doses of nicotine (0.56 mg/kg and 0.74 mg/kg), however, reduced responding on both levers. As can be seen in the right panel, that reduction was much greater, proportionally, on the large lever than on the small. As such, the effects seen in Figure 5-3 seem to be the result of two distin ct processes: increases in responding on the small lever at moderate doses and extreme decreases in responding on the large lever at high doses. Discussion Unlike Experiment 1 and 2, baseline pref erence was fairly extreme in both groups as shown in Figures 5-1 and 5-2. This can also be seen for control and vehicle sessions in Figures 5-3 and 5-4. For both the magnitude and delay groups, preference during ve hicle sessions was at or above 90% for 4 of the 6 rats. As such, th e present procedure was not ideal for detecting increases in magnitude or dela y sensitivity which could only in crease preference by 10% or less for most of the rats. That being the case, the pr esent procedure should be used with caution with drugs that are expected to increase delay discoun ting (or magnitude sensitivity). However, given the findings from Experiments 1-3, the present procedure might have been ideal for assessing the reductive effects of nicoti ne on magnitude sensitivity. Across all rats in the magnitude group, nicotine produced a substantial decrease in preference for the large a lternative. If the maximum possible reduction in magnitude sensitivity would result in indifference between the two options (0.5 proporti on of responses for the large), several rats experienced nearly the maximum possible reduction. When the peak effect for each rat is calculated as a proporti on of the maximum possible reduc tion (reduction to 0.5 in Figure 53), magnitude sensitivity reduction was 49%, 52%, 77%, 88%, 105%, and 147% (out of a maximum 100%). In contrast, the peak eff ect for each rat in the delay group was a delay sensitivity reduction of -37%, -9%, 19%, 21%, 42%, and 57%, with a re duction of 16% in the 69

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m ean performance (which might have been less if not for the ceiling effect on increases in preference for the short delay). It is interest ing to note that the two rats which showed an apparent bias for the lever assigned to the sm all magnitude (rat 182 and 184 which showed much lower preferences during baseline than all the others), ultimately preferred the small (1-pellet) lever under the most effective dose of nicoti ne (0.56 ml/kg for Rat 182 and 0.74 ml/kg for Rat 184). The slight decrease in pref erence for the short delay under so me doses of nicotine for 1/3 of the rats (Rat 186 and 189; Figur e 5-4) is consistent with the slight decrease in preference for the variable delay observed for 1/3 of the rats (R at 100, 103, and 118; Figure 2-3) in Experiment 1. Collectively, these data suggest that nicotine might produce minor decreases in delay sensitivity for some rats. It is unclear what w ould be responsible for this effect in only 33% of observed rats. Nevertheless, it is possible that this uncommon e ffect might result in nicotine producing decreases in impulsive choice rather than increases, under some preparations. Or perhaps such an effect could cancel out the magn itude sensitivity effect to produce no apparent effect under some preparations for some rats (e .g., Rats 204 and 207 in Figure 4-2). However, under the preparations used in Experiments 2 and 4, nicotines decreasing effect on magnitude sensitivity seems to be much more powerful, consistent, and ubiquitous than any effect (increasing or decreasing) on delay sensitivity. It is also worth noting that despite the expected lack of effect for the delay group, that group proved to be an essential control in the pres ent experiment. Because the concurrent chains procedure used a baseline of extreme preference for the large magnitude reinforcer (an average of about 85% under vehicle and control in Figure 5-3), any observed change in preference might have been the result of a decrease in stimul us control rather than a decrease in magnitude 70

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sensitivity. However, if that were the case, th ere should have been a comparable decrease for the delay group, but there was not. Si m ilar alternative explan ations, such as a simple rate-dependent effect, are also ruled out due to the similarity of the delay group baseline and dissimilarity in the effects of nicotine between these two groups. As such, the present experiment provides substantial support for th e interpretation that nicotine incr eases impulsive choice by decreasing sensitivity to reinforcer magnitude. Nevertheless, it is important to note that th e concurrent-chains pro cedure used in this experiment does have its limitations. Due to the performance ceiling produced by the extreme baseline preference, the present procedure w ould not be ideal for assessing pharmacological manipulations that produce an increase in either magnitude sensitivity or delay discounting. Also, because of the need for a control group to rule out alternative explanations (as described above), the present procedure would also not be ideal for assessing pharmacological manipulations that produce decreases in both magnitude and delay sensitivity. However, for drugs which primarily affect impulsive choi ce by decreasing delay discounting alone or magnitude sensitivity alone, as seems to be the case with nicotine, the present concurrent-chains procedure might be a useful choice. Given that Figure 5-3 (in c onjunction with Figure 5-4) de monstrates that nicotine decreases magnitude sensitivity, the question remains as to how this is accomplished. Is it the case that nicotine increases the apparent magnitude of small reinforcers or decreases the apparent magnitude of large reinforcers? The answer app ears to be: yes, it does both. Figure 5-5 shows that under moderate doses (0.1 mg/kg and 0.3 mg /kg) nicotine increases responses on the small lever while having no effect on the large lever. However, at the larges t doses (0.56 mg/kg and 0.74 mg/kg) nicotine decreases re sponses for both; but that decrease is much less on the small 71

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lever than o n the large. Again, such effects might be interprete d as having nothing to do with magnitude sensitivity at all but being the by-prod uct of moderate doses simply increasing lower response rates. Similarly, the right panel shows that response rates converge on the largest doses of nicotine, an effect that would be predicted if those doses were eliminating stimulus control. However, such interpretations are not consistent with the lack of similar effects for the delay group. Certainly, some complex explanation is po ssible as to why such an effect was blocked in the delay group (e.g., perhaps the differences in signaled delays somehow enhanced stimulus control in subsequent trials much more than the different amounts of food pellets). Nevertheless, insofar as such explanations do not reduce to de scriptions of lower-lev el mechanisms of how magnitude sensitivity is reduced, the more parsim onious explanation would currently seem to be that (1) nicotine increases impul sive choice in rats by decreasi ng sensitivity to reinforcer magnitude and (2) that decrease in reinforcer magnitude sensitivity is accomplished by both an increase in apparent magnitude of smaller reinforcers at mode rate doses of nicotine and a decrease in apparent magnitude of larger re inforcers at larger doses of nicotine. 72

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0.5 0.6 0.7 0.8 0.9 1 66676869707172737475Baseline SessionsProportion of Responses for the Large 180 181 182 183 184 185 Mean Figure 5-1. Proportion of responses for the large (3-pellet) le ver during the final 10 sessions of the baseline condition for all rats in the magnitude group. Note truncated y-axis. 0.5 0.6 0.7 0.8 0.9 1 66676869707172737475 Baseline SessionsProportion of Responses for the Short Dela y 186 187 188 189 190 191 Mean Figure 5-2. Proportion of responses for the short delay (1 s) lever during th e final 10 sessions of the baseline condition for all rats in the delay group. Note truncated y-axis. 73

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Proportion of Responses for the Large 183 CV0.030.10.30.74 0.4 0.5 0.6 0.7 0.8 0.9 180 0.4 0.5 0.6 0.7 0.8 0.9 184 CV0.030.10.30.74 181 Nicotine Dose (mg/kg) 185 CV0.030.10.30.74 182 MeanNicotine Dose (mg/kg) CV0.030.10.30.74Proportion of Responses for the Large 0.5 0.6 0.7 0.8 0.9 Figure 5-3. Proportion of responses for the large (3-pellet) leve r as a function of nicotine dose. C and V indicate contro l (no injection) and vehi cle (potassium phosphate) injection, respectively. Vertical lines represent standard errors of the mean. Note truncated y-axis. 74

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Proportion of Responses for the Short Delay 189 CV0.030.10.30.74 0.4 0.5 0.6 0.7 0.8 0.9 186 0.4 0.5 0.6 0.7 0.8 0.9 190 CV0.030.10.30.74 187 Nicotine Dose (mg/kg) 191 CV0.030.10.30.74 188 MeanNicotine Dose (mg/kg) CV0.030.10.30.74Proportion of Responses for the Short Delay 0.5 0.6 0.7 0.8 0.9 Figure 5-4. Proportion of responses for the short delay (1 s) lever as a f unction of nicotine dose. C and V indicate control (no injection) and vehicle ( potassium phosphate) injection, respectively. Vertical lines represent standard errors of the mean. Note truncated y-axis. 75

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76 MeanNicotine Dose (mg/kg) CV0.030.10.30.74Responses as Proportion of Vehicle 0 1 2 3 MeanNicotine Dose (mg/kg) CV0.030.10.30.74Responses as Proportion of Large 0 1 Figure 5-5. Responses for the large (3-p ellet, open circles) and sm all (1-pe llet, closed circles) levers as a proportion of responses on that lever under vehicle (left pa nel) or as a proportion of responses on the large lever under vehicle (right panel) for each nicotine dose. Vertical lines represent standard erro rs of the mean. Note the different y-axis in each panel.

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CHAP TER 6 GENERAL DISCUSSION Summary of Findings Previous research with smokers (Bickel, Odum, & Madden, 1999) and rats (Dallery & Locey, 2005) suggested that nicotine increases impulsive choice pref erence for a smaller, sooner reinforcer over a larger, later reinforcer. The present set of four experiments were designed with two basic aims: (1) to more caref ully examine the behavioral mechanisms of action responsible for nicotine eff ects on impulsive choice, and (2) to evaluate Equation 1-4, and the likelihood that it accurately describes how reinforcer magn itude and delay contribute to reinforcer value. Equation 1-4 is reproduced here for convenience: kD M V 1 (1-4) Experiment 1 used a risky choice procedure to isolate the effects of nicotine on delay sensitivity. The procedure attempted to identify the titrated delay that was equally preferred to the variable delay. This indiffe rence point was then used as the initial titrating delay in all subsequent sessions to provide a sensitive baseline of indifference by which any change in preference could be easily detected As it turned out, there was very little effect of nicotine on risky choice. Given that an increase in delay discounting should have increased preference for the variable delay, these results suggested that the effects of nicotine on impulsive choice are not due to any effect on delay discounting. Experiment 2 was a systematic replication of Experiment 1. The only change in the procedure was a modification of the reinforcer magnitude available on the titrating alternative. Instead of 1-pellet on each alternative, the titra ting delay was followed by a 3-pellet reinforcer. Under this preparation, nicotine produced increas es in riskpulsive choice very similar to the 77

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dose-dependent increases in im pulsive choice pr eviously found by Dallery and Locey (2005). This effect could have been produced by an in crease in delay discount ing or a decrease in magnitude sensitivity. Given the findings fr om Experiment 1, a decrease in magnitude sensitivity was the most parsimonious explanation. Experiment 3 was a test of the magnitude sensitivity effect. Concurrent PRs were established to assess allocation of response effort when one PR re sulted in 1 pellet and the other resulted in 5 pellets. Nicotine effects were inconsistent across rats. However, average performance showed a dose-dependent decrease in relative difference between ratios completed on the two alternatives, as would be expected if nicotine decrease d magnitude sensitivity. That decrease in relative differen ce between ratios completed was accomplished by both an increase in small-reinforcer ratio completions and a decr ease in large-reinforcer ratio completions. However, due to procedural lim itations (fixed total number of ratio completions per session), such data were not informative of any lower-lev el behavioral mechanisms driving the apparent decrease in magnitude sensitivity. Experiment 4 used a concurrent-chains procedure to assess nicotine effects on choice between different magnitudes and different delays. A fairly extreme preference was initially found between a large reinforcer magnitude (3 pellets) and a small reinforcer magnitude (1 pellet) for one group of rats and between a short delay (1 second) and a long delay (9 seconds) for another group of rats. Nicotine produced a shift towards indiffere nce for the magnitude group, suggesting a decrease in magnitude sensiti vity, but had no effect on preference for the delay group, suggesting that the effect observed in the amount gr oup was not the result of some other behavioral mechanism (e.g., a decrease in stimulus control, a simple rate-dependent effect, etc.). The shift towards indifference in th e magnitude group was produced by an increase in 78

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responses for the sm all reinforcer under moderate doses of nicotine and an extreme decrease in responses for the large reinforcer under large doses of nicotine. Collectively, these experiments indicated that (a) nicotine increases impulsive choice by decreasing magnitude sensitivity and (b) any complete account of how delay and magnitude contribute to reinforcer value needs a magnitude sensitivity parameter. Implications for Interpretations of Drug Action Nicotine Effects Statements about changes in impulsive c hoice are frequently considered synonymous with statements about changes in delay discounting. This is potentially because of the previous prodigious success of Equation 1-4. If Equation 1-4 is a comple te account of how reinforcer delay and reinforcer magnitude contribute to rein forcer value, then any change in value while those parameters are held constant must necessarily be due to a change in k the delay discounting parameter. As such, when Bickel et al. (1999) discussed the correlation between smoking and impulsive choice, it was discussed in terms of a correlation between smoking and delay discounting. When Dallery and Locey (20 05) concluded that nicotine increased impulsive choice, they concluded that nicotine increased delay discounting. Working within the framework of Equation 1-4, such conclusions were inevitab le. However, the present set of experiments suggests that the framework was flawed and that the inevitable conclusions were wrong. The possibility of an alternative mechanism cha nges in magnitude sensitivity became apparent from the results of Experiment 1. The likely reality of that alternative mechanism, at least in the case of nicotine effects on impulsive c hoice, was confirmed by Experiments 2-4. Given that nicotine increases magnitude sens itivity, rather than delay discounting, what are the implications of this for smokers? Considering that most smokers maintain only low to moderate doses of nicotine in their body at a ny given time, nicotine is likely increasing the 79

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apparent m agnitude (and thus va lue) of small reinforcers rather than decreasing the apparent magnitude (and thus value) of large reinforcers. This suggests that the widespread smoking of cigarettes is not simply due to the direct eff ects of nicotine (e.g., the sensation produced by the drug) but also (or perhaps even exclusively) due to the indirect effect of increasing the value of other small reinforcers (i.e., making the world more enjoyable). Indeed, this might help to explain why nicotine self-administration is difficu lt to obtain in rats unless visual stimuli (small reinforcers) are associated with the nicotine delivery (Caggiula et al., 2001, 2002; Donny et al., 2003). Further evidence in support of the small-reinforcer-enhancement hypothesis has recently emerged from research on nicotine and conditioned reinforcement. In an experiment by Raiff & Dallery (2006), nicotine enhanced responding maintained by stim ulus lights (presumably small conditioned reinforcers) in a dos e-dependent manner very similar to the effects observed in the present set of experiments. Of course, much more research is needed to determine exactly what small reinforcers are enhanced by nicotine. For instance, is the absolu te magnitude of the rein forcer relevant or the value relative to other available reinforcers? Is the reinforcer-enhancement effect limited to sucrose pellets and stimulus lights, some broad class of reinforcers, or all reinforcers in general? The latter possibility seems to be contradicted by the self-administr ation findings in which nicotine-producing responses are not maintained by the enhancemen t of grooming, sniffing, etc. in these studies, but a pparently only by enhancing the more obtrusive presentation of stimulus lights. Nevertheless, if the rein forcer-enhancing effects of nicotin e are responsible for the effect on impulsive choice observed in Bickel et al. (1999) with hypothetical monetary rewards, it would seem that the scope of the present findings go well bey ond sucrose and stimulus lights 80

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with ra ts. A relatively virginal area of research awaits further explorati on to effectively address these issues. Treatment Implications What about implications for treatment? If the prevalence of smoking is primarily the result of a small-reinforcer-enhancing effect of nicotine, what does that suggest about treatment options? First, it suggests that nicotine replacemen t therapy (NRT) is not ideal. At least insofar as cigarette puffs are themselves small reinforcer s (which presumably they are, even if only as secondary, rather than primary reinforcers), th en any nicotine administration (e.g., nicotine patches) should increase the value of cigarette puffs as reinforcers (thus increasing the likelihood of engaging in cigarette-puff-seeking behavior). Such increases might be responsible for the limited success of NRT (Fiore, Smith, Jorenby, & Baker, 1994) and the finding that nicotine patches have no reductive effect on cigarette cr aving or any other reac tions (e.g., heart rate, negative affect, etc.) to sm oking cues (Tiffany, Cox, & Elash, 2000). Second, the small-reinforcer -enhancing effect suggests a pos sible treatment: altering the proportion of small and large reinforcers in th e smokers environment. Given that low-tomoderate doses of nicotine maintain smoking pr imarily through enhancing the value of small reinforcers, reducing the number of small reinforcers (relative to large) should also reduce the reinforcing efficacy of the drug. Indeed, extr emely heavy smokers (those experiencing large doses of nicotine) should find smoking aversive if exposed to a substa ntial number of large reinforcers rather than small (as the value of th e large reinforcers would be decreased). Although a potentially effective treatment in theory, the expense and logistics i nvolved in filling an environment with primarily large reinforcers w ould likely make such a treatment infeasible (though potentially feasible through the use of so me other drug with prolonged and powerful 81

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direct-reinfo rcing effects but such a treatment would likely have other undesirable side-effects [e.g., abuse of the treatment drug]). Third, the small-reinforcer-enhancing effect suggests that (small-magnitude) voucher reinforcement therapy might be an ideal treatmen t option. If nicotine enhances the value of small, smoking-incompatible reinforcers, then it should increase the likelihood of smoking abstinence. Astute readers may note that such an effect is unlikely give n that abstinence would result in an absence of nicotine and thus, no incr eased value of abstinence-c ontingent reinforcers. However, Dallery & Locey (2005) found that fo llowing chronic nicotin e administration (e.g., daily smoking) and the subsequent termination of any nicotine administration, the nicotineenhancing effect on impulsive choice persisted for months (without any drug on-board). If that persistent drug effect was the result of a small-reinforcer-enhancement effect, then it is reasonable to assume that nicotine might increa se the value of vouchers long after smoking that last cigarette. The current success of voucher reinforcement therapy for smokers (e.g., Dallery, Glenn, & Raiff, 2007; Tidey, ONeill, & Higgi ns, 2002; Wiseman, Williams, & McMillan, 2005) would seem to support this analysis. As woul d the finding that nicotine replacement therapy had no effect on smoking or rates of delay discount ing when combined with small monetary contingencies (i.e., vouchers) for smoking abstinence (Dallery & Raiff, 2007). Effects of Other Drugs It is now unclear whether ch anges in impulsive choice found with opioids (Kirby et al., 1999; Madden et al. 1999; Madde n, et al. 1997), alcohol (Pet ry, 2001; Vuchinich & Simpson, 1998), and cocaine (Coffey et al., 2003) are due to effects on dela y discounting (as is typically inferred) or due to effects on magnitude sensi tivity. The exclusive adherence to impulsive choice procedures procedures that confound differences in rein forcer magnitude and delay makes it impossible to differentiate which behavioral mechanisms are responsible for the 82

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observed ef fects on choice. Clarifying this issue will require the use of alternative procedures, such as those used in the pr esent set of experiments. Implications for an Equation of Reinforcer Value Although the present results may have particular relevance fo r researchers interested in the behavioral effects of nicotine and other drug s, the inability of Equation 1-4 to account for these data has broader implications. The present findings suggest that the currently popular conceptualization of the relationship between re inforcer amount and reinforcer value (e.g., Mazur, 2006) may be incomplete. One likely pos sibility is that a magnitude sensitivity parameter should be added to provide a more accu rate characterization of how amount and delay determine reinforcer value. The need for separate magnitude and delay se nsitivity parameters has been proposed by several researchers. For example, the concat enated generalized matching law (Killeen, 1972; Logue, Rodriguez, Pena-Correal, & Mauro, 1984), useful for the pr ediction and/or description of performance under concurrent interval and concu rrent chain schedules, in cludes a parameter for reinforcer magnitude sensitivity. Pitts & Febbo ( 2004) used a slightly modified version of the concatenated generalized matching law in an at tempt to isolate the behavioral mechanism of action in amphetamine-induced changes in im pulsive choice using a concurrent-chains procedure. Both delay and magnitude sensi tivity exponents were estimated, and amphetamine generally decreased sensitivity to reinforcer delay. Similarly, Kheramin et al. (2002) used an alternative mathematical model proposed by Ho, Mobini, Chiang, Bradshaw, & Szabadi, (1999) in an attempt to separate the relative influen ce of magnitude sensitivity and delay discounting on impulsive choice in orbital prefrontal cortex-les ioned rats. Although this method has potential, it relies upon a number of assumptions about how di fferent variables intera ct to produce the value of a reinforcer. 83

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The presen t set of experiments represents an alternative, experimental approach to separate the relative contributi on of magnitude sensitivity and delay discounting in impulsive choice. By eliminating the differences in reinfo rcer magnitude (as in Experiment 1), the risky choice procedure can assess what, if any, e ffect a particular ma nipulation has on delay discounting. By comparing ris ky choice effects with equal and different reinforcer magnitudes (as in Experiment 2), one can assess what, if any, effect a particular manipulation has on magnitude sensitivity. And by arranging concu rrent chains with di fferent magnitudes and different delays in the terminal links (as in Expe riment 4), one can assess the extent to which a particular manipulation decr eases either magnitude or delay sensitivity. As previously discussed, Equation 1-4 cannot reconcile the findings from the present experiments. The increase in risky choice onl y in the presence of different reinforcer magnitudes, and the preference decreasing effect s in the magnitude group of Experiment 4, imply that some magnitude sensitivity parameter, z is needed. But exactly what relation should it have to magnitude within Equation 1-4? One consideration is whether changes in z should account for preference reversals that is, a shift in preference from the larger, later reinforcer to the smaller, sooner reinforcer as the delay to making a choice decrea ses (see Green & Estle, 2003). With delay discounting, a multiplicative relation between delay and k is sufficient such that changes in k can produce preference reversals (e.g., Mazur, 1987). For example, given a choice between 1 pellet delayed 1 second and 3 pe llets delayed 5 seconds, Equation 1-4 predicts that changing k from less than 1 to greater than 1 woul d produce a shift in preference from the 3 pellet option to the 1 pellet option. However, a multiplicative relation between magnitude and a sensitivity parameter would be incapable of pr oducing such preference reversals. Whether z was 84

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0.009 or 900, the relative values of the two al ternatives would rem ain constant. As such, z should most likely hold an exponential relations hip to amount as per Equation 6-1: kD M Vz 1 (6-1) Using this equation with the previous exam ple (1 pellet delayed 1 second vs. 3 pellets delayed 5 seconds) and holding k constant at 1, a change in z from less than 1 to greater than 1 would produce a shift in preference from the 1 pe llet option to the 3 pellet option. Unlike Equation 1-4, Equation 6-1 is cap able of accounting for both the pr esent data and the Dallery and Locey (2005) data. A nicotine-induced decrease in z would increase impulsive choice (Dallery & Locey, 2005) and riskpulsive choice (Experiment 2) without having any effect on risky choice with equal magnitudes (Experiment 1). Similarly, a decrease in z would decrease preference for a large reinforcer relative to a small reinforcer (Experiment 3 and 4) without having any effect on preference with equal magnitudes (Experiment 4 delay group). Although Equation 6-1 can account for the dos e-dependent decrease in magnitude sensitivity, it has several problems. (1) It ca nnot account for the reinforcement enhancing effect of small reinforcers suggested by Experiment 4 (a decrease in z would increase preference for the small reinforcer by decreasing the value of bo th but decreasing the la rge reinforcer by more than the small). (2) It yields substantially di fferent predictions when different units are used (e.g., decreasing z from 1 to 0.5 would decrease the valu e of a 500 ml solution but increase the value of a 0.5 L solution). (3) The equation is not balanced in terms of measurement units (the left side of the equation [value] is reported in magnitude units but the right side reduces to magnitude units per unit of time). (4) Reinfor cers, as stimuli without temporal components, should not have values determined by delay or de grees of delay discounting. (5) Insofar as the equation applies to the value/efficacy of a reinfor cer, any operation that changes the value of any 85

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of its param eters (including delay and delay discounting) would const itute an establishing operation. Problems 1 5, and corresponding solu tions, are described in more detail in the appendix. All five problems can be solved by consideri ng the genesis of Equation 1-4. The value of option A was initially established in relation to the value of option B in Equation 1-3. What the present set of problems suggests is that it is u ltimately impossible to do ot herwise. All of these problems completely vanish if Equation 61 is abandoned in favor of Equation 6-2: )1/( )1/( B Z B A Z A AkDM kDM P (6-2) Ultimately we are left with preferen ce for A is equal to the reinforce ment on A (rather than the reinforc er value of A) divided by the reinforcemen t on B. Reinforcement is shown as reinforcer magnitude raised to the power of ma gnitude sensitivity divide d by the sum of 1 plus reinforcement delay multiplied by delay discounting. It should not be lost on the reader that Equation 6-2 may be much closer to contempor ary models of choice designed for concurrent chains procedures (e.g., Pitts & Febbo, 2004; see Mazur, 2006 for a review of others) than to Equation 1-4. Perhaps it will ultimately prove more fruitful to use one of those models as a starting point than to use Equati on 6-2. It might well be worth reiterating that Equation 6-2 has not been thoroughly tested, by any means particularly, it remains to be seen what the ideal combination of parameters will be to capture eff ects on magnitude sensitivity be they effects of nicotine, some other drug, or any other environmental manipulation. Whatever magnitude sensitivity parameter or alternative mathematical model proves most useful in accounting for the present and futu re data, the present results certainly seem to refute the assumption that nicotine-induced increas es in impulsive choice reflect increases in delay discounting. In so doing, these results also challenge the common assumption of identity 86

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between im pulsive choice effects an d delay discounting effects. Fo r instance, several researchers have reported a magnitude effect in humans, such that increasing reinforcer magnitude decreases k (e.g., Green, Myerson, & McFadden, 1997; Kirby, 1997; Raineri & Rachlin, 1993). Perhaps it does. But at present, research only indicates that increasing reinforcer magnitude decreases impulsive choice. There is currently no evidence that this decrease in impulsive choice is due to a decrease in k rather than an increase in magnitude sensitivity. Equation 1-4 and similar mathematical models of choice have been very effective in the description and prediction of c hoice, both within behavioral pha rmacology and the experimental analysis of behavior in general. The present results suggest that it may be useful to consider additional behavioral mechanisms, such as chan ges in magnitude sensitivity, to account for druginduced changes in inter-temporal choice. Further work is needed to establish the generality of this conclusion. Such work should avoid excl usive reliance on procedures that conflate differences in reinforcer amount and delay, su ch as impulsive choice procedures. A critical complement will be procedures that isolate th e relative contributions of delay discounting and magnitude sensitivity on choice. The value of such procedures, whether we call them impulsive, risky, ris kpulsive, concurrent chai ns, or something else, should ultimately be judged by their capacity to identify functional relations betw een amount, delay, and choice. 87

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APPENDIX: DERIVAT ION1 OF EQUATION 6-2 FROM EQUATION 6-1 kD M Vz 1 (6-1) Although Equation 6-1 can account for the dos e-dependent decrease in magnitude sensitivity, can it account for the lower-level mechanisms res ponsible for those decreases? Results from Experiment 4 (Figur e 5-5) suggested that nicotine increased the value of the small reinforcer at moderate doses and decreased the va lue of the large reinforcer at larger doses. Equation 6-1 can certainly account for the effect observed with larger doses. Decreases in z would decrease the value of both small and large reinforcers, with the relative decrease in the value of larger reinforcers being much greater than the decrease in the value of smaller reinforcers. This was exactly the effect obs erved with the large doses (0.56 ml/kg and 0.74 ml/kg) in Figure 5-5. However, assuming both fr ee parameters maintain consistent value across all reinforcement alternatives, increases in the value of small reinforcers can only be accomplished by decreases in k or increases in z (assuming magnitude and delay are held constant). Any such changes would produce either no change in the relative value of the small reinforcer (if k decreased while delay was held constant across alternatives) or a decrease in value relative to the large (if z increased). In other words, Equation 6-1 cannot account for the apparent value-enhancing effects of ni cotine indicated in Figure 5-5. In order to produce both absolute increases in the value of small reinforcers and increases relative to large reinforcers, somethi ng like Equation A-1 may be needed where e is sensitivity to the absolute magnitude of the reinforcer and z is sensitivity to changes (or differences) in magnitude. kD eM Vz 1 (A-1) Under normal conditions both e and z can likely be set equal to 1 (although all current impulsive choice data would be consistent with any value of e greater than 0 because changes in e would have no effect on relative preference). If th at is the case, then a change in sensitivity to absolute reinforcer magnitude ( e ) to 100 and a change in relative reinforcer magnitude sensitivity ( z ) to 0.2 would produce the 250% increase in value for 1-pellet and no change in reinforcer value for 3-pellets that was observed for the 0.3 mg/kg dose in Figure 5-5. The precise determination of values in this manner is not en tirely appropriate given the procedure used in Experiment 4 (the arrangement of VI 30 s initial links produced greater than 300% preference for the large under baseline conditi ons). Nevertheless, the dosedependent decrease in relative preference shown in Figure 5-3 would i ndicate a dose-dependent decrease in z whereas the dosedependent increase in responses on the small lever at moderate doses in Figure 5-5 would indicate a dose-dependent increase in e within that tightly constrained range of doses. Although all the data from the present set of experiments and previous experiments interpreted in the context of E quation 1-4 are consistent with Equation A-1, further research is needed with parametric analyses of magnitudes and delays to determine the function that best describes the relation between reinforcer magnitude, reinforcer delay, and reinforcer value. However, even without knowing the best possible equation to describe this relation, there are a few concerns that might be raised with respec t to the general notion of a relative magnitude sensitivity parameter, such as z in Equations 6-1 and A-1. Consider a choice between (A ) $2 now or (B) $1 now plus $1 now. It seems reasonable to assume that anyone would be indifferent betw een these two options gi ven that they both are 88

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equivalent in both m agnitude and delay. And yet, with a magnitude sensitivity parameter ( z in Equation 6-1) of 0.5, option A would be valued at $20.5 = $1.4 and option B would be valued at $10.5 + $10.5 = $2. Conversely, with a magnitude sensit ivity parameter of 2, A (V = $4) would be preferred to B (V = $2). But does the present set of experiments s uggest that nicotine is actually going to shift preference one way or the other between the options A and B? Probably not. One solution to the above problem is to simp ly point out that $1 now plus $1 now is not really possible. If such a thing happened it w ould actually be $2 now. Bu t that solution does not help too much because what about $1 now a nd $1 delayed .00001 s vs. $2 now? The better solution would be to recognize th at value cannot be calculated by simple addition. In other words, if $1 now has a value of $1, that does no t imply that adding another will result in a combined value of $2. The implication of the magnitude sensitivity parameter is that value does not accumulate in such a manner when the magnitude sensitivity parameter is something other than 1. So if z = 2, then the effective value of that s econd $1, will be $3 (because the value of $2 would be $4). A more serious problem for Equation A-1 might seem to be the problem of inconsistent predictions across different units of measurement. For instance, what if liquid reinforcers were used in the Experiment 4 and nico tine reduced magnitude sensitivity ( z ) by 50%, from 1.0 to 0.5? If the reinforcer was 500 ml of sucrose solu tion, the value would plummet to 22.4 ml (5000.5 ml = 22.4 ml). However, if the reinforcer was 0. 5 liters of sucrose solution, the value would increase to 0.71 liters (0.50.5 L = 0.71 L). Something would seem to be seriously wrong when such disparate predictions result simply fr om using different units of measurement. However, the problem of units is not unique to the magnitude sensitivity parameter ( z ). Consider a choice between (A) $1 in 1 day or (B) $3 in 4 days. If your k is greater than 2, youll prefer A, if it is less than 2 youll prefer B. Now consider a choice between $1 in 24 hours or $3 in 96 hours. It is the exact same choice; and yet when presented in te rms of hours instead of days, the k that would generate indifference is 0.083 in stead of 2. It would seem that both the relative magnitude sensitivity parameter and th e delay discounting parame ter have potentially serious problems with respect to units of measurement. While on the topic of problems with units, cons ider the units in Equations 1-4 and A-1. If value is reported in terms of magnitude units (e.g., pellets), then what happens to the time units in the denominator of the equation? One solution would be to contend that k has time-1 units which cancel out the time units from whatever delay is present. With this solution k -values should be reported as x /second or x /day rather than x Although this has its appeal in that it would draw attention to the fa r different implications of k when different units of measurement are involved, and help with solv ing the previously discussed probl em of measurement units, such a solution ignores the root of the problem. The root of the problem seems to be the use of Equations 1-4 and A1 without respect for their origins namely: Equations 1-1 1-3. Equation 1-4 is derived directly from the proposition that preference for option A is a function of reinforcement rate on option A relative to reinforcement rate on option B. Certainly a few modifications are ma de between Equation 1-1 and 1-4, but in essence, the value of option A is its reinforcement rate (Equation 1-4 is taken from the numerator of Equation 1-3). As such, why try to convert value to magnitude units at all? Why divorce it from the temporal component that is clearly essential in its determination? It should be fairly clear from its etymology that the value of a reinforcer must be in magnitude units per unit of time. 89

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A term inological problem becomes apparent at this point (if it had not already) in that reinforcers are typically defined as stimuli that increase some dimension of an operant response class in virtue of being conti ngent on that operant (paraphras ed from Catania, 1998). So if Equations 1-4 and A-1 describe the value of a s timulus, why would a stim ulus have a temporal component? For example, if someone asks me what the value of my car is, it would be inappropriate to include any temporal component in the assessment of that value. I was not asked for the value of th e car if it arrives in a week, I was as ked about the value the car itself: a stimulus without any temporal component. A related terminological issue involves the relation between Equations 1-4 and A-1 and establishing operations that is, operations that change the efficacy of a reinforcer (Catania, 1998). Given that changes in magnitude, delay, delay discounting, and magnitude sensitivity change the value (and thus efficacy) of a reinforcer all of these effects (or to be more precise: the operations that bring about these effects) must necessarily be establishing operations. Although this is not necessarily a problem per se, the usefulness of the term establishing operation would seem to become e ssentially useless if this line of reasoning was followed to its natural conclusion because esse ntially any operation that aff ects behavior would be an establishing operation. The answer to both terminological issues would seem to be the same: Equations 1-4 and A-1 do not indicate the value of a reinforcer, but instead indicate the value of a reinforcement that is, the value of a reinforcer delivery Clearly, the temporal parameters ( D and k ) in these equations relate to the delivery of the reinforcer rather than to the stimulus itself. Conversely, the magnitude parameters ( M z and e ) clearly relate to the stimul us itself and therefore might more reasonably be included in discussions of establishing operations. As such, the common interpretation of impulsive c hoice changes as change s in delay discounting would not suggest that nicotine administration is an establishi ng operation. However, the present set of experiments, which indicate that nicotine decrea ses magnitude sensitivit y, does suggest that nicotine administration is an establishing operation. Accepting that Equations 1-4 and A-1 refer to value of reinforcement in terms of magnitude/time units rather than magnitude unit s solves many of our problems, but what about the inconsistent predictions across units? To answer this question, perhaps we should consider what is meant by reinforcement value? If I say that a particular reinforcement has a value of 3 pellets per minute, what does that imply? It would seem to imply virtually nothing in isolation. The usefulness of a reinforcement value measure only seems to come from relating it to some other reinforcement value (e.g., the reinforcement of option A at 3 pellets per minute is half as valuable as that of option B at 6 pellets per mi nute) or to the amount of behavior it can sustain (e.g., the reinforcement of option A at 3 pellet s per minute is able to maintain up to 100 responses per reinforcer). However, the amount of behavior that a particular reinforcement can maintain will almost certainly depend upon the reinforcement context in which it occurs (e.g., the response rate maintained by 3 pellets per minute on option A will depend upon the reinforcement rate on option B). As such, except fo r the rare instances in which we are trying to identify how much behavior a pa rticular reinforcement can maintain in complete isolation from other reinforcement, it might be a pointless endea vor to talk about the value of reinforcement A independent of the value of reinforcement B. In other words, the problem of inconsistent predictions across units can be solved by once again considering the orig ins of Equation 1-4. The value of option A was initially established in relation to the value of option B in Equation 1-3. What the present discussion suggests is that it 90

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is ultim ately impossible to do otherwise. The pr oblem inconsistent predictions with changes in measurement units completely vanishes if Equa tion A-1 is abandoned in favor of Equation 6-2: )1/( )1/( B Z B A Z A AkDM kDM P (6-2) Ultimately we are left with preference for A is equal to the reinforcement on A divided by the reinforcement on B. Reinforcement is shown as magnitude raised to the power of relative magnitude sensitivity divided by the sum of 1 plus delay multiplied by delay discounting. Note that absolute magnitude sensitivity ( e in Equation A-1) is unnecessary in Equation 6-2 because absolute magnitude sensitivity on A cancels out ab solute magnitude sensitivity on B. In other words, preference is determined by relative va lue, so any effect th at produces proportional increases in the value of all altern atives will have no impact on choice. Notes 1. Derivation is used here in the lay sense (i .e., Equation 6-1 is the or igin from which Equation 6-2 is obtained) not in the mathematical sense (i.e., Equation 6-2 is not mathematically or logically necessary given that Equation 6-1 is true). 91

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92 LIST OF REFERENCES Autor, S. M. (1960). The strength of conditioned reinforcers as a f unction of frequency and probability of reinforcement. Unpublished do ctoral dissertation, Harvard University. Baker, F., Johnson, M.W., & Bickel, W.K. (2003). Delay discounting in cu rrent and never-before cigarette smokers: Similarities and differen ces across commodity, sign, and magnitude. Journal of Abnormal Psychology, 112 382-392. Bateson, M. & Kacelnik, A. (1995). Preferences for fixed and variable food sources: Variability in amount and delay. Journal of the Experimental Analysis of Behavior, 63 313-329. Baum, W. M. & Rachlin, H. (1969) Choice as time allocation. Journal of the Experimental Analysis of Behavior, 12, 861-874. Bekesy, G.V. (1947). A new audiometer. Acta Oto-laryngol., 35, 411-422. Bickel, W.K., Odum, A.L., & Madden, G.J. ( 1999). Impulsivity and cigarette smoking: Delay discounting in current, never, and ex-smokers. Psychopharmacology, 146, 447-454. Blough, D.S. (1958). A method for obtaining ps ychophysical thresholds from the pigeon. Journal of the Experimental Analysis of Behavior, 1 31-43. Catania, A. C. (1998). Learning (fourth ed .). Prentice Hall, Upper Saddle River, NJ. Caggiula, A. R., Donny, E. C., White, A. R., Chaudhri, N., Booth, S., Gharib, M. A., et al. (2001). Cue dependency of nicotine self-administration and smoking. Pharmacology Biochemistry and Behavior, 70, 515. Caggiula, A. R., Donny, E. C., White, A. R., Chaudhri, N., Booth, S., Gharib, M. A., et al. (2002). Environmental stimuli promote acquisitio n of nicotine self-adm inistration in rats. Psychopharmacology, 163, 230. Cardinal, R.N., Daw, N., Robbins, T.W., & Everitt, B.J. (2002). Local anal ysis of behaviour in the adjusting-delay task for assessing choice of delayed reinforcement. Neural Networks, 15, 617-634. Cicerone, R.A. (1976). Preference for mixed vers us constant delay of reinforcement. Journal of the Experimental Analysis of Behavior, 25 257-261. Coffey, S.F., Gudleski, G.D., Saladin, M.E., & Brady, K.T. (2003). Impulsivity and rapid discounting of delayed hypothetical rewards in cocaine -dependent individuals. Experimental and Clinical Psychopharmacology, 11 18-25. Dallery, J., Glenn, I.M., & Raiff, B.R. (2007). An internet-based abstinence reinforcement treatment for cigarette smoking. Drug and Alcohol Dependence, 86, 230-238.

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Dallery, J. & Locey, M.L. (2005). Effects of Acute and Chronic Nicotine on Im pulsive Choice in Rats. Behavioural Pharmacology, 16 15-23. Dallery, J. & Raiff, B.R. (2007). Delay disco unting predicts cigarette smoking in a laboratory model of abstinence reinforcement. Psychopharmacology, 190, 485-496. Donny, E. C., Chaudhri, N., Caggiula, A. R., Evan s-Martin, F. F., Booth, S., Gharib, S., et al. (2003). Operant responding for a visual reinfo rcer in rats is enhanced by noncontingent nicotine: Implications for nicotine self-administration and reinforcement. Psychopharmacology, 169, 68. Findley, J. D. (1958). Preference and switching under concurrent scheduling. Journal of the Experimental Analysis of Behavior, 1, 123. Fiore, M. C., Smith, S. S., Jorenby, D. E., & Baker, T.B. (1994). The effectiveness of the nicotine patch for smoking cessation: A meta-analysis. The Journal of the American Medical Association, 271, 1940-1947. Fleshler, M. & Hoffman, H. S. (1962). A progression for generati ng variable-interval schedules. Journal of the Experimental Analysis of Behavior, 5, 529. Frederick, S., Lowenstein, G., & ODonoghue T. (2002). Time discounting and time preference: A critical review. Journal of Economic Literature 40, 351-401. Green, L. & Estle, S. (2003). Preference revers als with food and water reinforcers in rats. Journal of the Experimental Analysis of Behavior, 79, 233-242. Green, L. & Myerson, J. (2004). A discounti ng framework for choice with delayed and probabilistic rewards. Psychological bulletin, 130, 769-792. Green, L., Myerson, J., & McFadden, E. (1997). Ra te of temporal discounting decreases with amount of reward. Memory & Cognition, 25, 715. Herrnstein, R. J. (1964a). Aperi odicity as a factor in choice. Journal of the Experimental Analysis of Behavior, 7, 179-182. Herrnstein, R. J. (1964b). Secondary reinforc ement and rate of primary reinforcement. Journal of the Experimental An alysis of Behavior, 7, 27-36. Ho, M. Y., AlZahrani, S. S. A., AlRuwaitea, A. S. A., Bradshaw, C. M., & Szabadi, E. (1998). 5Hydroxytryptamine and impulse control: Prospects for a behavioural analysis. Journal of Psychopharmacology, 12(1) 68-78. Ho, M.-Y., Mobini, S., Chiang, T.J., Bradshaw C.M., & Szabadi, E. (1999). Theory and method in the quantitative analysis of im pulsive choice behaviour: implications for Psychopharmacology. Psychopharmacology, 146, 362-372. Hodos, W. (1961). Progressive ratio as a measure of reward strength. Science, 134, 943. 93

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Hodos, W ., & Kalman, G. (1963). Effects of increment size and reinforcer volume on progressive ratio performance. Journal of the Experimental Analysis of Behavior, 6, 387 392. Johnson, M.W. & Bickel, W.K. (2002). Within -subject comparison of real and hypothetical money rewards in delay discounting. Journal of the Experimental Analysis of Behavior, 77, 129-146. Kheramin, S., Body, S., Mobini, S., Ho, M.-Y ., Velazquez-Martinez, D.N., Bradshaw, C.M., Szabadi, E., Deakin, J.F.W., & Anderson, I.M. (2002). Effects of quinolinic acid-induced lesions of the orbital prefrontal cortex on inter-temporal choice: A quantitative analysis. Psychopharmacology, 165(1) 9-17. Killeen, P. (1972). The matching law. Journal of the Experimental Analysis of Behavior, 17 489-495. Kirby, K. N. (1997). Bidding on the future: Ev idence against normative discounting of delayed rewards. Journal of Experimental Psychology: General, 126 54. Kirby, K.N., Petry, N.M., & Bickel, W.K. (1999). Heroin addicts have higher discount rates for delayed rewards than no n-drug-using controls. Journal of Experimental Psychology: General, 128 78-87. Logue, A. W. Rodriguez, M. L. Pena-Correal, T. E. & Mauro, B. C. (1984). Choice in a selfcontrol paradigm: Quantification of experienced-based differences. Journal of the Experimental Analysis of Behavior, 41 53-67. Madden, G.J., Petry, N.M., Badger, G.J., & Bi ckel, W.K. (1997). Impulsive and self-control choices in opioid-dependent patients and non-drug-using controls participants: Drug and monetary rewards. Experimental and Clinical Psychopharmacology, 5 256-262. Madden, G.J., Bickel, W.K., & Jacobs, E.A. ( 1999). Discounting of delayed rewards in opioiddependent outpatients: Exponential or hyperbolic discounting functions. Experimental and Clinical Psychopharmacology, 7 284-293. Mazur, J.E. (1984). Tests of an equivalence rule for fixed and variable reinforcer delays. Journal of Experimental Psychology: Animal Behavior Processes, 10, 426-436. Mazur, J.E. (1986). Fixed and vari able ratios and delays : Further tests of an equivalence rule. Journal of Experimental Psychology : Animal Behavior Processes, 12, 116-124. Mazur, J.E. (1987). An adjusting procedure fo r studying delayed reinforcement. In M. L. Commons, J. E. Mazur, J. A. Nevin, & H. Rachlin (Eds.), Quantitative analyses of behavior: The effects of delay and of in tervening events on reinforcement value. (pp. 5573). Erlbaum, Hillsdale, N. J. Mazur, J. E. (1997). Choice, delay, pr obability, and conditioned reinforcement. Animal Learning & Behavior, 25 131. 94

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Mazur, J.E. (2006). Mathem atical models a nd the experimental anal ysis of behavior. Journal of the Experimental Analysis of Behavior, 85 275-291. Mitchell, S.H. (1999). Measures of impulsiv ity in cigarette smokers and non-smokers. Psychopharmacology, 146, 455-464. Navarick, D.J. (2004). Discounting of delaye d reinforcers: Measurement by questionnaires versus operant choice procedures. The Psychological Record, 54, 85-94. Petry, N.M. (2001). Delay discounting of mone y and alcohol in activ ely using alcoholics, currently abstinent alcoholics, and controls. Psychopharmacology, 154, 243-250. Pitts, R.C. & Febbo, S.M. (2004). Quantitative an alyses of methamphetamine's effects on selfcontrol choices: Implications for elucidati ng behavioral mechanisms of drug action. Behavioural Processes, 66, 213-233. Pubols, B.H. (1958). Delay of reinforcement, response perseveration, and discrimination reversal. Journal of Experimental Psychology, 56 32-39. Rachlin, H., & Green, L. (1972). Co mmitment, choice and self-control. Journal of the Experimental Analysis of Behavior, 17 15-22. Rachlin, H., Raineri, A., & Cross, D. ( 1991). Subjective probability and delay. Journal of the Experimental Analysis of Behavior, 55 233-244. Raiff, B. R. & Dallery, J. (2006). Effects of acu te and chronic nicotine on responses maintained by primary and conditioned reinforcers in rats. Experimental and Clinical Psychopharmacology, 14, 296. Raineri, A., & Rachlin, H. (1993). The effect of temporal constr aints on the value of money and other commodities. Journal of Behavioral Decision Making, 6, 77. Sidman, M. (1960). Tactics of Scientific Research New York: Basic Books. Skinner, B. F. (1958). Diagramming Schedules of Reinforcement. Journal of the Experimental Analysis of Behavior, 1, 67-68. Stafford, D., LeSage, M. G., & Glowa, J. R. ( 1998). Progressive-ratio schedules of drug delivery in the analysis of drug self-administration: a review. Psychopharmacology, 139 169-184. Tidey, J. W., ONeill, S. C., & Higgins, S. T. (2002). Contingent monetary reinforcement of smoking reductions, with and without transd ermal nicotine, in outpatients with schizophrenia. Experimental and Clinical Psychopharmacology, 10 241. Tiffany, S. T., Cox L. S., & Elash, C. A. (2000). Effects of transdermal nicotine patches on abstinence induced and cue-elicited craving in cigarette smokers. Journal of Consulting and Clinical Psychology, 68, 233. 95

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97 BIOGRAPHICAL SKETCH Matthew Locey has been dedicated to the scie ntific approach of environment-behavior relations since his freshman year in 1996 when he was introduced to the field of behavior analysis by Dr. H.S. Pennypacker, Jr .. He began his graduate studies in behavior analysis at the University of Florida in 2000, under the supervision of Dr. Jesse Dallery. Matts research interests center around th e development and application of precise quantitative models of choice. During his grad uate career, Matt has conducted a broad range of experiments within this genera l framework of quantitative mode ling. Those experiments have ranged from human modeling of risk-sensitive foraging in anim als to animal modeling of impulsive choice in humans. He is currently studying the relationship be tween delay and social discounting, the interac tion of molar and molecular control ling variables, a nd the predictive validity of measures of impulsive choice and delay discounting. After graduation, Matt began his postdoctoral fellowship under the guidance of Dr. Howard Rachlin at the State University of New Yo rk at Stony Brook. From there he will seek a position allowing him to contribute through research, teaching, and clinical application to the dissemination of an analytical approach to the prediction and control of behavior.