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Nicotine and Responding Maintained by Conditioned Reinforcers

Permanent Link: http://ufdc.ufl.edu/UFE0041268/00001

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Title: Nicotine and Responding Maintained by Conditioned Reinforcers Effects of Two Nicotinic Antagonists
Physical Description: 1 online resource (38 p.)
Language: english
Creator: Jones, Jeb
Publisher: University of Florida
Place of Publication: Gainesville, Fla.
Publication Date: 2009

Subjects

Subjects / Keywords: conditioned, hexamethonium, mecamylamine, observing, procedure, rats, reinforcers, response
Psychology -- Dissertations, Academic -- UF
Genre: Psychology thesis, M.S.
bibliography   ( marcgt )
theses   ( marcgt )
government publication (state, provincial, terriorial, dependent)   ( marcgt )
born-digital   ( sobekcm )
Electronic Thesis or Dissertation

Notes

Abstract: Nicotine has been shown to selectively increase responding maintained by conditioned reinforcers as compared to responding maintained by primary reinforcers. In the current study an observing response procedure was employed in order to test the effects of nicotine and two nicotinic antagonists on responding maintained by conditioned and primary reinforcers and extinction responses. Mecamylamine, a central and peripheral nicotinic antagonist, and hexamethonium, a peripheral nicotinic antagonist, were used in order to localize the effect in the nervous system. Nicotine selectively increased responding maintained by conditioned reinforcers and mecamylamine, but not hexamethonium, attenuated this effect. These results suggest that the reinforcer enhancing effect is mediated exclusively in the central nervous system.
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 Jeb Jones.
Thesis: Thesis (M.S.)--University of Florida, 2009.
Local: Adviser: Dallery, Jesse.
Electronic Access: RESTRICTED TO UF STUDENTS, STAFF, FACULTY, AND ON-CAMPUS USE UNTIL 2011-12-31

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Source Institution: UFRGP
Rights Management: Applicable rights reserved.
Classification: lcc - LD1780 2009
System ID: UFE0041268:00001

Permanent Link: http://ufdc.ufl.edu/UFE0041268/00001

Material Information

Title: Nicotine and Responding Maintained by Conditioned Reinforcers Effects of Two Nicotinic Antagonists
Physical Description: 1 online resource (38 p.)
Language: english
Creator: Jones, Jeb
Publisher: University of Florida
Place of Publication: Gainesville, Fla.
Publication Date: 2009

Subjects

Subjects / Keywords: conditioned, hexamethonium, mecamylamine, observing, procedure, rats, reinforcers, response
Psychology -- Dissertations, Academic -- UF
Genre: Psychology thesis, M.S.
bibliography   ( marcgt )
theses   ( marcgt )
government publication (state, provincial, terriorial, dependent)   ( marcgt )
born-digital   ( sobekcm )
Electronic Thesis or Dissertation

Notes

Abstract: Nicotine has been shown to selectively increase responding maintained by conditioned reinforcers as compared to responding maintained by primary reinforcers. In the current study an observing response procedure was employed in order to test the effects of nicotine and two nicotinic antagonists on responding maintained by conditioned and primary reinforcers and extinction responses. Mecamylamine, a central and peripheral nicotinic antagonist, and hexamethonium, a peripheral nicotinic antagonist, were used in order to localize the effect in the nervous system. Nicotine selectively increased responding maintained by conditioned reinforcers and mecamylamine, but not hexamethonium, attenuated this effect. These results suggest that the reinforcer enhancing effect is mediated exclusively in the central nervous system.
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 Jeb Jones.
Thesis: Thesis (M.S.)--University of Florida, 2009.
Local: Adviser: Dallery, Jesse.
Electronic Access: RESTRICTED TO UF STUDENTS, STAFF, FACULTY, AND ON-CAMPUS USE UNTIL 2011-12-31

Record Information

Source Institution: UFRGP
Rights Management: Applicable rights reserved.
Classification: lcc - LD1780 2009
System ID: UFE0041268:00001


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NICOTINE AND RESPONDING MAINTAIN ED BY CONDITIONED REINFORCERS: EFFECTS OF TWO NICO TINIC ANTAGONISTS By JEB JONES A THESIS PRESENTED TO THE GRADUATE SCHOOL OF THE UNIVERSITY OF FLORID A IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF MASTER OF SCIENCE UNIVERSITY OF FLORIDA 2009 1

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2009 Jeb Jones 2

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To my parentswithout whom I never would have made it this farand to Jeffrey for his endless support 3

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ACKNOWLEDGMENTS I thank my parents for always pushing me and supporting me and encouraging me to work harder and persevere. I thank Jeffrey for his constant support and encouragement. I also thank Jesse Daller y who has been a fantastic and supportive mentor the best advisor I could have asked for. Finally I would like to thank my colleagues who assisted in conducting the ex periment and who reviewed drafts of the current paper: Bethany Raiff, Steve Meredi th, Alana Rojewski, Rachel Cassidy, Matthew Weaver, and Ma tthew Capriotti. 4

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TABLE OF CONTENTS page ACKNOWLEDGMENTS .................................................................................................. 4LIST OF TABLES ............................................................................................................ 6LIST OF FIGURES .......................................................................................................... 7ABSTRACT ..................................................................................................................... 8 CHAPTER 1 INTRODUC TION ...................................................................................................... 92 METHOD ................................................................................................................ 14Subjects .................................................................................................................. 14Apparatus and Materials ......................................................................................... 14Procedure ............................................................................................................... 15Drug Administration .......................................................................................... 18Data Analyses .................................................................................................. 193 RESULT S ............................................................................................................... 21Effects of Nicotine ................................................................................................... 21Effects of nAChR Antagonists ................................................................................. 21Mecamylamine ................................................................................................. 21Hexamethonium ............................................................................................... 224 DISCUSSI ON ......................................................................................................... 29LIST OF REFERENCES ............................................................................................... 34BIOGRAPHICAL SKETCH ............................................................................................ 38 5

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LIST OF TABLES Table page 2-1 Dose order by group ........................................................................................... 203-1 Rates ( standard deviation) for each dose combination .................................... 23 6

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LIST OF FIGURES Figure page 3-1 Effects of nicotine. .............................................................................................. 24 3-2 Group graphs of mecamylamine and hexamethonium ....................................... 25 3-3 Individual graphs of mecamylamine: Observing responses. ............................... 26 3-4 Individual graphs of mecamylamine: Food responses. ....................................... 27 3-5 Individual graphs of meca mylamine: Extinction responses. ............................... 28 7

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8 Abstract of Thesis Pres ented to the Graduate School of the University of Florida in Partial Fulf illment of the Requirements for t he Degree of Master of Science NICOTINE AND RESPONDING MAINTAIN ED BY CONDITIONED REINFORCERS: EFFECTS OF TWO NICO TINIC ANTAGONISTS By Jeb Jones December 2009 Chair: Jesse Dallery Major: Psychology Nicotine has been shown to selectively increase responding maintained by conditioned reinforcers as compared to re sponding maintained by primary reinforcers. In the current study an observing response pr ocedure was employed in order to test the effects of nicotine and two nicotinic antagonists on responding maintained by conditioned and primary reinforcers and exti nction responses. Mecamylamine, a central and peripheral nicotinic antagonist, and hex amethonium, a peripheral nicotinic antagonist, were used in order to localize the effect in the nervous system. Nicotine selectively increased responding mainta ined by conditioned reinforcers and mecamylamine, but not hexamethonium, attenuat ed this effect. These results suggest that the reinforcer enhancing effect is m ediated exclusively in the central nervous system.

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CHAPTER 1 INTRODUCTION Cigarette smoking provides numerous opportunities for establishing conditioned reinforcers from the olfactor y, gustatory, and tactile stim ulation directly associated with nicotine administration to the environmental contexts an d activities associated with smoking over time. Nicotine, the putative unconditioned stimulus not only plays a role in establishing these stimuli as conditioned re inforcers, it may also enhance responding maintained by them (e.g., Chaudhri, Caggiula, Donny, Booth et al., 2006; Chaudhri, Caggiula, Donny, Palmatier et al., 2006; Donny et al., 2003). Indeed, enhanced responding for conditioned reinforcers following ni cotine administration may be partially responsible for the maintenance of cigare tte smoking (Caggiula et al., 2001; Rose, 2006) Understanding why people smoke re quires a systematic and thorough analysis of nicotines effects on responding maintain ed by conditioned reinforcers (Clarke, 1991). In the current study we examined the effect s of nicotine and two nicotinic acetylcholine receptor (nAChR) antagonists on responses maintained by conditioned reinforcers. Experiments with humans have provided some evidence for the role of conditioned reinforcement in the maintenance of smoking. One method of examining the conditioned reinforcers present in smoking is by using de-nicotinized cigarettes, which provide similar stimuli involved in smoking except for nicotine (Rose, 2006). Shahan et al. (1999), for example, found similar br eak points for subjec ts responding for nicotinized and de-nicotinized cigarettes on a pr ogressive ratio schedule. Indeed, levels of consumption were similar across both types of cigarettes at each unit price, indicating that subjects worked just as hard to consume both types of cigarettes. 9

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In a similar study, Donny, Houtsmuller, and Stitzer (2007) demonstrated prolonged maintenance of smoking during eleven days in a residential setting in subjects smoking both de-nicotinized and normal cigarettes. Furthermore, those smoking de-nicotinized cigarettes continued to report suppression of cr aving throughout the study. This finding is consistent with the noti on that smoking generates c onditioned reinforcers which contribute to the reinforcing efficacy of cigarettes apart from nicotines primary reinforcing effects. This stipulation is not without its caveats, however. Eleven days of explicit unpairing of nicoti ne and stimuli associated with sm oking ought to be sufficient time to extinguish the purported conditioned reinforcers. Thus, it is possible that some of the stimuli experienced while smoking de-ni cotinized cigarettes were actually serving as primary reinforcers, which may partly explain why extinction of the conditioned reinforcers was not observed in the Donny et al. study. Neverthel ess, the results of these two studies, and others (e.g., Perkins et al., 2001; Shahan, Bickel, Badger, & Giordano, 2001), suggest that conditioned reinforc ers play a role in the maintenance of smoking. Evidence of the role of conditioned reinforc ers in nicotine self-administration (SA) has also been found in the animal laborator y (Caggiula et al., 2001). Presentation of nicotine-paired visual stimuli (e.g., combinat ion of cue lights and house lights) results in increased responding for nicotine (Donny et al., 2003). Further, it has been shown that the presentation of nicoti ne-paired stimuli results in increased SA responding throughout extinction (Donny et al., 1999). Rats first acquired nicotine SA on a progressive ratio schedule, and then the SA response was placed on extinction either by pretreatment with mecamylamine or substi tuting saline for the nicotine. During this 10

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exctinction phase subjects responded at higher rates when nicotine-paired stimuli were present versus when they were not presen t. Nicotine also increases responding for the stimuli with which it has been paired, and this has been shown to be a dose-dependent effect, with greater effects at higher doses (Palmatier et al., 2008). Palmatier et al. paired a neutral stimulus with nicotine infu sions and subsequently made presentation of the paired stimulus contingent on a novel response. Rats that had received higher doses of nicotine emitted the novel response at higher rates than those that received lower doses. One problem in nicotine SA experiments is separating the effects of nicotine SA from the behavioral effects of nico tine. That is, it is difficult to differentiate these effects because nicotine administration results in direct effects on behavior and, additionally, participates in conditioning novel stimuli as reinforcers. Thus, Raiff and Dallery (2006) employed an observing response procedure (W yckoff, 1952) to assess the effects of presession nicotine on responding for pr imary and conditioned reinforcers and responding during periods of extinction. In an observing response procedure, a rat can respond on either of two levers. One lever (i.e., the food-extinc tion lever) provides alternating access to a primary reinforcer or extinction. The other le ver (i.e., observing lever) provides access to a stimulus which in dicates whether the primary reinforcer is available or whether extinction is in effect. The stimulus displayed contingent on responses on the observing lever has eit her been explicitly paired with primary reinforcer availability (S+; e.g., solid houselight) or extinction (S-; e.g., blinking houselight). 11

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The observing response procedure has been used to test for conditioned reinforcement (e.g., Dinsmoor, 1985), and o ffers advantages over other procedures (e.g., the conditioning-a-new-response proc edure) in that it allows testing for conditioned reinforcement over long durations because the conditioned reinforcer does not undergo extinction, as in conditioning a new response procedures. The observing response procedure allowed Raiff & Dallery to demonstrate that nicotine increases responding for conditioned reinforcers but not responding for primary reinforcers or responding during periods of extinction. Note that in the observi ng response procedure, a period of extinction simply means that food reinforcers ar e not available, it does not mean that the S+ is undergoing extinction. The S+ is always associated with the availability of food. The current study expanded on the result s of Raiff and Dallery in order to determine the effects of mecamylamine and hexamethonium, two nAChR antagonists, on responding for conditioned reinforcer s. Mecamylamine and hexamethonium have different sites of action in the nervous system. Mecamylamine is a centrally and peripherally active nicotinic antagonist whereas hexamethonium is only active peripherally (Goodman, Gilman, Brunton, Lazo, & Parker 2006). Thus, differential effects of these two antagonists on responding for conditioned reinforcers can help to delineate the neurophysiological locus of nicotines effects on such responses. Mecamylamine, along with other nA ChR antagonists (e.g., dihydro-erythroidine) has been used to demonstrate that many of ni cotines behavioral e ffects are centrally mediated. Liu et al. (2007) demonstrated that central nicotinic antagonists result in decreased responding for a moderately reinforc ing stimulus. Further, nicotine blocks the 12

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13 reinstatement of responding fo r nicotine-paired stimuli followin g extinction (Liu et al., 2006). Nicotinic antagonists also result in decreased SA. DeNoble & Mele (2006) found that presession injections of mecamylami ne resulted in decreased nicotine SA in rats, whereas hexamethonium did not have an e ffect. Pre-cigarette administration of mecamylamine in humans results in self -reported increases in craving and negative affect (McClernon & Rose, 2005) and reduced satisfaction of smoking and oral stimulation (Rose et al., 1994). The effect of nicotinic antagonists on ni cotine-induced increases in responding maintained by conditioned reinforcers has not been examined using the observing response procedure. In the current study we employed the observing response procedure and administered mecamylamine and he xamethonium in conjunction with 0.3 mg/kg nicotine. First, we replicated previ ous studies by demonstrating that nicotine induced a selective increase in responding for conditioned reinforcers, but not for primary reinforcers or extinction responses (Donny et al., 2003; Raiff & Dallery, 2006, 2008). Second, we tested the effects of mecamylamine and hexamethonium on these three responses. If the increase in responding for conditioned reinforcers is centrally mediated then mecamylamine, but not hexamet honium, should result in a decrease in responding for conditioned reinforcers.

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CHAPTER 2 METHOD Subjects Subjects were eight experimentally naive male Long-Evans rats (Harlan; Indianapolis, IN). The rats were approxim ately 150 days old at the beginning of the experiment. They were individually housed in hanging polycarbonate cages with bedding, in a room t hat was temperature and humidity controlled. Subjects had free access to water and were maintained at appr oximately 85% of their 150 day old ad libitum weights, via post-session feeding (Lab Diet Rodent Diet, Formula 5001; PMI Nutrition International, LLC; Brentwood, MO). The colony room was on a 12:12 hr light dark cycle (lights on from 8am-8 pm). Apparatus and Materials Four Med Associates extra tall oper ant conditioning chambers (Model ENV 007; 30.48 cm L x 24.13 cm W x 29.21 cm H) were used to conduct experimental sessions. Chambers were contained in la rge sound attenuating boxes equipped with fans for ventilation and to ma sk experimental noise. Each intelligence panel contained a food receptacle (5 cm x 5 cm x 3 cm) that was equidistant between two levers (requiring approximately 0.31 N force), each of which measured 4.5 cm x 2 cm and were located 22 cm from the chamber ceiling. Seven cm above each lever were three light-emitting diodes (LED; red, yellow, green; 0.8 cm in diameter, 0.7 cm apart from each other). On the wall parallel to the intelligence panel was a house light (28 volt), centered left to right and 1.5 cm from the ceiling. Purified Rod ent Tablets (45 mg sucrose food pellets; TestDiet, Richmand, IN) were located outsi de of the chamber, but inside the sound 14

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attenuating box. Experimental events and data collection took place on a computer in the same room, using Med-PC softw are and hardware (MED Associates). Drugs. Nicotine ([-]-Nicotine Hydrogen Tartrate Salt; Sigma, St. Louis, MO) was dissolved in potassium phosphate for all s ubcutaneous injections. Doses of 0.3 mg/kg were injected immediately prior to session. Nicotine vehicle injections consisted of potassium phosphate in isolation. Mecamy lamine and hexamethonium were dissolved in saline. Doses of 1 and 5 mg/kg of mecamylamine hydrochloride and doses of 1 and 5 mg/kg of hexamethonium bromide (Sigma, St. Louis, MO) were injected subcutaneously 20 min before nicotine injections (Araki et al., 2004; Ise, Narita, Nagase, & Suzuki, 2000; Olausson, Jentsch, & Taylor, 2004a; Palm atier, Peterson, Wilkinson, & Bevins, 2004). Mecamylamine and hexamethonium vehicl e injections consisted of saline in isolation (1mL/kg). Procedure All sessions were conducted on separat e days, seven days per week, at approximately the same time each day. Lever training Research assistants used 45 mg sucrose pellets to reinforce successive approximations of the rats pre ssing the right and left levers. These initial lever training sessions ended after 30 min or after 20 responses on each lever. One response resulted in a food pellet, with the exception that after three consecutive responses on the same lever food could onl y be earned by pressing the other lever. Lever training continued for up to three additional sessions, as needed. Once lever pressing was acquired, subjects continued to earn food for pressing levers but were required to strictly alternate between the two levers such that the second consecutive response on one lever did not result in food. These alternation sessions lasted for a 15

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maximum of 30 min or until 30 responses had been made on each lever, on seven separate days. The houselight was continuous ly illuminated during all lever training sessions. Discrimination training After subjects were trained to press both levers, the Discrimination Training condition began. During the last minute of the blackout period, all three LEDs above each lever were illuminated to signal the beginning of the session. The LEDs turned off after 1 min and the hous elight was simultaneo usly illuminated, either blinking or continuous (the first co mponent type was determined randomly at the beginning of each session). This LED signal was in effect for t he remainder of the experiment. Components alternated between a continuously illuminated houselight (S+) which signaled periods when food was availabl e for pressing the left, food-extinction, lever (i.e., food components) and a blinki ng houselight (S-; 0.2 sec light-dark alternation) which signaled periods when f ood was not available for pressing the foodextinction lever (i.e., extinc tion components). Initially, a va riable-interval (VI) 15 sec schedule was in effect on the food-extinction lever when the houselight was continuously illuminated. After seven sessions, this value was increased to a VI 20 sec schedule of food delivery. VI distributions were based on the Fleshler-Hoffman distribution (Fleshler & Hoffman, 1962) and were composed of 15 interval values. Components lasted an average of 60 sec (rect angular distribution ranging from 10 to 110 sec); however, if the extinction co mponent was scheduled to change to a food component, it would not change until 5 sec el apsed without a response on either lever (i.e., differential reinforcement of other behavior [DRO] 5 sec). The DRO procedure was implemented to prevent adventitious pai rings between responding during extinction 16

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components and subsequent transitions to f ood components. Aside from the DRO contingency, responses on the right, observing, lever did not have any additional programmed consequences duri ng Discrimination Training. Performance during the Di scrimination Training phase was evaluated using the discrimination index (DI) equal to the rate of responding in the S+ divided by the combined rate of responding in the S+ and S. Discrimination Training lasted a minimum of 65 days and until all but one subject di splayed a DI of 0.75 or higher. Observing response procedure The DRO contingency was discontinued when the observing response procedure began. At the beginning of the session, the computer randomly determined whether a VI 20 sec food or extinction component would be in effect; however, the stimulus correspondi ng to the selected component was only shown contingent on a response to the right, observing lever. Initially, only one response on the observing lever was required to illuminate the schedule correlated stimulus for 10 sec (i.e., fixed-ratio [FR] 1). If a component was scheduled to end during the 10 sec stimulus presentation, the component co ntinued until the stimulus tur ned off. Immediately after the stimulus turned off the schedule changed. For example, if after 5 sec of S+ stimulus presentation the food component was scheduled to switch to extinction, the S+ and food schedule would remain in effect for the final 5 sec of the stimul us presentation and the component immediately changed to extinction when the stimulus turned off. For the first five sessions of the observing procedure, the first five observing responses resulted in the S+ stimulus being present ed. If the extinction component was in effect when one of the first five responses occurred, the co mponent switched to VI 20 sec food (Shahan, 17

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2002). Otherwise, components alternated ev ery 60 sec on average as described for Discrimination Training. The presence or absence of schedule-correlated stimuli did not affect the probability of food deliveries duri ng VI components. In other wo rds, if the VI 20 food timer elapsed, the next response on the foodextinction lever during the VI component resulted in a food delivery, regardless of whether the schedule-corre lated stimuli were on or off. Furthermore, the presence of schedule-correlated stimuli during the VI component did not ensure that the next response on the f ood-extinction lever would result in food this only occurred if the VI timer had elapsed. If the VI timer elapsed, but a food-extinction response did not occur du ring the VI component, the arranged food delivery was saved for t he next VI component. After 11 sessions under the conditions described above, the VI 20 sec food schedule was increased to a VI 30 sec food schedule. Ten sessions later the observing response requirement was increased from FR1 to VI 5 sec. Thus, the terminal parameters of t he observing response procedure c onsisted of a VI 30 sec food schedule alternating with extinction approx imately every 60 sec, and stimuli were presented for 10 sec on a VI 5 sec schedule. A ll sessions from this point forward were arranged according to these terminal par ameters and were 30 min in duration. Drug Administration Establishing increases with nicotine Drug administration began after a minimum of 65 sessions on the observing response procedure. The first 14 drug sessions were the antagonist vehicle (i.e., saline) 20 minutes presession and 0.3 mg/kg nicotine immediately presession. These doses were administered in order to demonstrate that nicotine reliably and select ively increased rates of the observing 18

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response. Injections were administered every other day and occasionally every fourth day. Sessions were always conducted during the intervening days. Antagonist administration Drug administration contin ued to occur every other day. As stated above injections of antagonist occurred 20 minutes prior to session and injections of nicotine occurred immediately prio r to the start of the session. The subjects were randomly divided into two groups and received a counterbalanced order of antagonist drug. Group 1 received me camylamine first and Group 2 received hexamethonium first. The order of doses is shown in Table 2-1. The antagonists were given in descending order of dose (i.e., 5. 0 then 1.0 mg/kg). The complete series of probe injections was administered two times. Data Analyses Paired samples t-tests were conducted to evaluate the effects of nicotine on observing, food, and extinction responses as compared to vehicle. Repeated measures analysis of variance, with Huynh-Feldt correct ion, were performed to evaluate whether there were significant differences across the different dose combinations for each type of response (i.e., observing, food, and extinction) as well as to test for effects based on order of administration of the antagonists. Bonferroni post-hoc analyses were performed to make direct comparisons of the effe cts of each dose on each response type. Alpha was set to 0.05 for all analyses. 19

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20 Table 2-1. Dose order by group Group 1 Group 2 20 min presession Immediately presession 20 min presession Immediately presession Saline 0.3 Nicotine Saline 0.3 Nicotine Saline KPO4 Saline KPO4 Mecamylamine 5.0 0.3 Nicotine He xamethonium 5.0 0.3 Nicotine Mecamylamine 1.0 0.3 Nicotine He xamethonium 1.0 0.3 Nicotine Hexamethonium 5.0 0.3 Nicotine Mecamylamine 5.0 0.3 Nicotine Hexamethonium 1.0 0.3 Nicotine Mecamylamine 1.0 0.3 Nicotine Mecamylamine 5.0 KPO4 Hexamethonium 5.0 KPO4 Mecamylamine 1.0 KPO4 Hexamethonium 1.0 KPO4 Hexamethonium 5.0 KPO4 Mecamylamine 5.0 KPO4 Hexamethonium 1.0 KPO4 Mecamylamine 1.0 KPO4 Order of probe doses presented to both groups Probes were administered every other day. This order of doses was presented twice.

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CHAPTER 3 RESULTS Rates of responding for each of the thr ee response types (observing, food, and extinction) are presented in Table 3-1 for each dose combination. All statistical analyses below were calculated using the percentage of vehicle re sponding for the relevant conditions. Effects of Nicotine Prior to administering the nAChR antagoni sts, we examined the effects of nicotine alone on observing, food, and exti nction responses. Figure 3-1 shows observing, food, and extinction responses plott ed as percent of vehicle following vehicle and nicotine injections. Paired samples t -tests showed that nicotine selectively increased observing responses ( t (15) = -3.868, p < .01), but not food or extinction responses compared to vehicle. Effects of n AChR Antagonists There were no main effects of order of antagonist administration on observing or food responses. There was, however, a main effect of order on extinction responses, F (1, 14) = 17.571, p < .01. Extinction responding was consistently lower in the group that received mecamylamine first. Mecamylamine Figure 3-2 (left panels) shows the aggregated effects of both doses of mecamylamine on observing, food, and extinction responses when administered with vehicle and with nicotine. Mecamylamine resulted in a statistically significant reduction of observing responses when administered with vehicle, F (2, 30) = 23.61, p < .0001, and nicotine, F (2, 30) = 36.5, p < .0001. Mecamylamine also resulted in statistically 21

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significant reductions in food respons es when administered with vehicle, F (2, 30) = 20.51, p < .0001, and nicotine, F (2, 30) = 19.59, p < .0001. Mecamylamine did not have a statistically significant effect on extincti on responses. Graphs of the individual subject data are presented for observing, food, and extinction responses in Figures 3-3, 3-4, and 3-5, respectively. Individual data were generally representative of the observed group effects. Post hoc analyses revealed that only the 5.0 mg/kg dose of mecamylamine, and not the 1.0 mg/kg dose, reduced observing and food respons es when administered with vehicle, suggesting a general rate reduci ng effect of this higher dose. When administered with nicotine, 5.0 mg/kg meca mylamine reduced both observing and food responses. However, only the 1.0 mg/kg dose resulted in a reduction in nicotineinduced increases of observing responses. This lower dose had no effect on observing or food responses when adminis tered with vehicle, nor did it have an effect on food responses when paired with nicotine. Effe cts of mecamylamine on both observing and food responses were dose dependent. Hexamethonium Figure 3-2 (right panels) shows the effects of both doses of hexamethonium on observing, food, and extinction responses when administered with vehicle and with nicotine. Hexamethonium did not result in statistically significant changes in any of the three different response types. Individual data were generally r epresentative of the observed group effects. 22

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Table 3-1. Rates ( standard deviation) for each dose combination Nicotinic Antagonist 20 min presession Vehicle (Saline) Mecamylamine 5.0 Mecamylamine 1.0 Hexamethonium 5.0 Hexamethonium 1.0 Nicotine Immediately presession Observing Responses Vehicle (KPO4) 1.92 + 0.95 1.14 + 0.81 1.72 + 0.94 1.70 + 0.86 1.76 + 0.84 0.3 Nicotine 3.27 + 1.17 1.03 + 0.57 1.73 + 0.86 2.81 + 1.69 2.84 + 1.14 Food Responses Vehicle (KPO4) 11.89 + 6.45 7.50 + 4.26 12.05 + 6.12 10.84 + 4.84 10.97 + 5.12 0.3 Nicotine 12.95 + 4.95 6.75 + 4.01 12.20 + 5.83 12.69 + 4.76 11.77 + 3.48 Extinction Responses Vehicle (KPO4) 7.83 + 4.04 8.51 + 3.83 9.57 + 5.37 7.56 + 3.48 7.33 + 3.19 0.3 Nicotine 8.60 + 2.76 7.49 + 3.72 9.39 + 4.36 9.67 + 4.03 8.24 + 2.63 23

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Observing Responses SalineKP O4 Sali n e-0.3mg /kg Nic o tin e 0 100 200 300Percent of Vehicle Food Responses Sal in e-KPO4 S aline0 .3mg /k g Nic o t ine 0 100 200 300 EXT Responses Sa l ine KP O 4 S aline-0.3mg/kg Nicotine 0 100 200 300 Figure 3-1. Effects of nicotine versus v ehicle on observing (first panel), food (second panel), and extinction (third panel) res ponses. Error bars represent standard deviations. 24

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Observing Responses 0 100 200 300 400 Observing Responses 0 100 200 300 400 Food Responses 0 100 200 300 400 Food Responses 0 100 200 300 400 Extinction Responses S a l ine KP O4 5 0 M e c KP O4 1 0 Mec KPO4 S al in e 0. 3 N i c 5 0 Mec 0.3 N ic 1.0 Mec 0. 3 Nic 0 100 200 300 400 Extinction Responses Saline KPO4 5 0 H e x KP O 4 1 0 He x KP O4 Sa li ne 0.3 N i c 5.0 H ex 0.3 Nic 1 .0 H e x 0 .3 N i c 0 100 200 300 400 Percent of Vehicle Responding Figure 3-2. Effects of mecamylamine (le ft panels) and hexametho nium (right panels) on observing (top panels), food (middle panels), and extinction responses (bottom panels) as percent of vehi cle responding. Bars represent group means and closed circles are individual data points. 25

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281 0 50 100 150 200 250 300 350 400 282 0 50 100 150 200 283 0 50 100 150 200 250 300 350 400 284 0 50 100 150 200 285 0 50 100 150 200 286 0 50 100 150 200 250 300 350 400 287 Sal KPO4 5 0 Me c KPO4 1 0 Mec KPO4 Sal Nic 5 0 Mec Nic 1 0 Mec Ni c 0 50 100 150 200 288 Sal KPO4 5 0 Mec KPO4 1 0 Mec KPO4 Sa l Nic 5 0 Mec Nic 1 0 Mec Nic 0 50 100 150 200Percent of Vehicle RespondingObserving Responses Figure 3-3. Effects of bot h doses of mecamylamine on observing responses for each subject plotted as percent of vehicle responding. Error bars represent the range. 26

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281 0 100 200 300 282 0 50 100 150 200 283 0 50 100 150 200 284 0 50 100 150 200 285 0 50 100 150 200 286 0 50 100 150 200 287 Sal K PO 4 5.0 M ec KPO 4 1.0 Mec KPO4 Sal N ic 5.0 Mec N ic 1.0 Mec N ic 0 50 100 150 200 288 Sal KPO 4 5.0 Mec KPO4 1.0 M ec K P O4 S a l N ic 5.0 Mec N ic 1.0 Mec Nic 0 50 100 150 200Percent of Vehicle RespondingFood Responses Figure 3-4. Effects of both doses of mecamylamine on food responses for each subject plotted as percent of vehicle respondi ng. Error bars represent the range. 27

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28 281 0 50 100 150 200 282 0 50 100 150 200 283 0 50 100 150 200 284 0 50 100 150 200 285 0 100 200 300 400 286 0 50 100 150 200 287 S al KPO 4 5 0 Me c K PO4 1.0 Me c KP O 4 Sal Nic 5.0 Me c Nic 1.0 Mec N i c 0 50 100 150 200 288 Sal K PO4 5.0 Me c K PO4 1 0 Me c K PO4 S a l N i c 5.0 Mec Nic 1.0 Me c Nic 0 50 100 150 200Percent of Vehicle RespondingExtinction Responses Figure 3-5. Effects of bot h doses of mecamylamine on extinction responses for each subject plotted as percent of vehicle responding. Error bars represent the range.

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CHAPTER 4 DISCUSSION The results of the current study add to the growing corpus of data suggesting that nicotine has a selective, enhancing effect on responding maintained by conditioned reinforcers. We demonstrated 1) that nicotine selectively increased responding maintained by conditioned reinforcers, and 2) that mecamylamine, but not hexamethonium, antagonized this effect. Be cause mecamylamine readily crosses the blood-brain barrier and hexameth onium does not, these result s suggest that nicotines effect on responding maintained by conditioned reinforcers is mediated via nAChRs in the central nervous system. Further, by using the observing response procedure we were able to conduct a rigorous, extended test of conditioned reinforcement. This procedure also allowed us to compare responding maintained by conditioned reinforcers to responding maintained by primary reinforcers and responding in extinction. It has previously been demonstrated that t he S+ is responsible for maintaining responding for the observing stimulus (Din smoor, Browne, & Lawrence, 1972). When presented in isolation, Dinsmoor et al found that only the S+, and not the S-, maintained levels of responding similar to when the two stimuli we re both available. Thus, it is not information per se that maintains responding on the observing lever, rather it is the conditioned reinforcer aspects of the stimulus that has in the past been paired with primary reinforcer delivery. Indeed responding is higher when only an S+ is available as compared to when an S+ and Sare available, as in the current study. It has been suggested that the increas es in responding observed following nicotine administration ar e due to a general behavioral activation as opposed to a 29

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reinforcer-enhancing effect (Frenk & Dar, 2004). However, it should be noted that the behavioral activation explanation does not acc ount for the selectivity of response increases in the current study and others (e.g ., Raiff & Dallery, 2008). That is, a general behavioral activation should increase res ponding across the board; however we demonstrated that nicotine selectively incr eases responding maintained by conditioned reinforcers, but not responding maintained by primary reinforcers or responses under extinction. The effects engendered by nicotine might be characterized as rate-dependent, particularly the food responses. In a compar ison of rates following administration of vehicle versus nicotine, Pearsons r for observing, food, and extinction responses was 0.65, -0.84, and -0.69, respectively. Thus, pa rticularly for food responses the effects appear to be correlated with the rate of vehi cle responding. It should be noted, however, that rate-dependency is merely descriptive of the relationship between vehicle and drug responding and does not account for why the rela tionship exists (Poling & Byrne, 2000). Specifically, it does not account for the dis parity in increases across response types nor for the effects of the nAChR anagonists. Nicotinic interaction with nAChRs result s in wide ranging effects on nicotine SA and other responses influenced by nicotine across species. Mecamylamine attenuates nicotine SA (DeNoble & Mele, 2006; Donny et al., 1999) or increases preference for higher doses of nicotine (Glick, Visker, & Maisonnneuve, 1996) in rats. Mecamylamine also blocks reinstatement of nicotine SA brou ght on by nicotine-paired stimuli (Liu et al., 2006; Liu, Caggiula et al., 2007). It has also been noted that the 2 subunit of nAChRs plays a vital role in the reinforcing pr operties of nicotine (Wannacott, Sidhpura, & 30

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Balfour, 2005). Because it is known to be active on these nAChR subtypes (Papke, Sanberg, & Shytle, 2001), some of mecamylami nes behavioral effects might likely be mediated through 2 receptor subtypes. In humans, contrary to its effect on rats, mecamylamine results in increased nicotine SA, whether via smoking (Rose & Corrigall, 1997) or intravenous injection (Rose, Behm, Westman, & Ba tes, 2003). Rose and Corrigall su ggest that the disparate effects between rats and humans might be due to the fact that hum an study participants are nicotine dependent but rats are not. Thus humans respond more for nicotine following mecamylamine administration in order to overcome the nAChR antagonizing effect of the drug. Even still, mecamylamine does result in reduced smoking satisfaction (Rose et al., 1994). Nicotine also effects behavior in ways whic h may be indirectly related to SA. It has been shown to have a reinforcer-enhanci ng effect in rats (Chaudhri, Caggiula, Donny, Palmatier et al., 2006; Olausson et al., 2004a; Olausson, Jentsch, & Taylor, 2004b; Raiff & Dallery, 2008). Olausson et al demonstrated that nicotine selectively increases responding for conditioned reinfo rcers and that mecamylamine, a nAChR antagonist, offsets this effect. Nicotine di d not, however, increase responding for other stimuli suggesting that t he increase in responding was dependent on the conditioned reinforcing aspects of the stimulus and was not due to a general undifferentiated increase in responding. Additionall y, this effect is present whether nicotine delivery is response-dependent or respons e-independent (Chaudhri, Caggi ula, Donny, Booth et al., 2006). 31

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Activation of nAChRs in the central ner vous system results in widespread neural effects involving many neurotransmitter sys tems including dopamine glutamate, and aminobutyric acid. Indeed, complex interactions over time result in different effects on dopaminergic systems in acute versus chronic dosing (Laviolette & van der Kooy, 2004). For this reason it woul d be beneficial to replicate the current study under a chronic dosing regimen to determine if the re sults are disparate wit h the current data. However, it is important to note that Lavio lette and van der Kooy report that mesolimbic dopamine signaling might serve to signal stimu li which predict reward and that this effect might be similar in both acute and chronic dosing. Activation of dopaminergic tracts in t he nucleus accumbens is also widely implicated in as one factor influencing reward, and thus abuse liability, of drugs of abuse (Di Chiara et al., 2004). Indeed, nicotine elicit s a similar increase in dopamine release in the nucleus accumbens as cocaine and am phetamine, albeit to a lesser extent. Furthermore, it has been noted that the tw o subunits of the nucleus accumbens, the core and the shell, have different behavioral e ffects (Balfour, 2004). It is beyond the scope of the current study to tease apart t he effects of these antagonists on accumbal dopamine expression, particularl y due to mecamylamines lack of specificity. However, it would be beneficial for future studies to examine the role of more specific nicotinic antagonists on sensitivity to conditioned reinforcer s, as well as to nicotine in acquisition and maintenance of nicotine self-administration. Balfour (2004) has also argued for a specific role of extracellular dopamine in the medial shell of the nucleus accumbens. His hypothesis is that behavior that is accompanied by an increase in extracellula r dopamine is reinforced. Thus, any and all 32

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behavior occurring in conjunction with nico tine-induced increases in extracellular nicotine should increase in rate. However, as the current study indica tes, it is not all behavior that is increased, but rather only behavior maintained by specific types of consequences, namely conditioned reinforcers. The current study suffered from a few limit ations. In order to make comparisons across subjects, each subject received the sa me dose of nicotine (0.3 mg/kg). Although this dose has frequently been the most behaviora lly active in previous experiments in our lab, testing for the dose of nicotine t hat resulted in the greatest increases in responding maintained by conditioned reinforcer s might have resulted in clearer effects of the two different antagonists. Further, there were only two tests of each antagonist dose. More replications would have been desi rable. Future studies should conduct more extend investigations of these drugs as well as more spec ific nAChR antagonists (e.g., dihydro-erythroidine [DHBE] or varenicline). Ev en still, the results of the current study strongly implicate central, but not peripheral, nAChRs in the mediation of nicotines effects on responding maintained by conditioned reinforcers. 33

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LIST OF REFERENCES Araki, H., Kawakami, K.-y., Ji n, C., Suemaru, K., Kitamura, Y., Nagata, M., et al. (2004). Nicotine attenuates place aversion induced by naloxone in single-dose, morphinetreated rats. Psychopharmacology, 171 (4), 398-404. Balfour, D. J. (2004). The neurobiology of tobacco dependence: A preclinical perspective on the role of the dopam ine projections to the nucleus. Nicotine & Tobacco Research, 6 (6), 899-912. Caggiula, A. R., Donny, E. C., White, A. R., Chaudhri, N., Boot h, S., Gharib, M. A., et al. (2001). Cue dependency of nicotine se lf-administration and smoking. Pharmacology, Biochemistry and Behavior, 70 (4), 515-530. Chaudhri, N., Caggiula, A. R., Donny, E. C., Booth, S., Gharib, M., Craven, L., et al. (2006). Operant responding for conditioned and unconditioned reinforcers in rats is differentially enhanced by the primary reinforcing and reinforcement-enhancing effects of nicotine. Psychopharmacology, 189 (1), 27-36. Chaudhri, N., Caggiula, A. R., Donny, E. C., Palmatier, M. I., Liu, X., & Sved, A. F. (2006). Complex interactions between nicotine and nonpharmacological stimuli reveal multiple roles for nicotine in reinforcement. Psychopharmacology, 184(3), 353-366. Clarke, P. B. (1991). Nicotin ic receptor blockade therapy and smoking cessation. British Journal of Addiction, 86 (5), 501-505. DeNoble, V. J., & Mele, P. C. (2006). Intravenous nicotine self-administration in rats: effects of mecamylamine, hexamethonium, and naloxone. Psychopharmacology, 184 (3-4), 266-272. Di Chiara, G., Bassareo, V., Fenu, S., De Luc a, M. A., Spina, L ., Cadoni, C., et al. (2004). Dopamine and drug addi ction: the nucleus accumbens shell connection. Neuropharmacology, 47 (Suppl1), 227-241. Dinsmoor, J. A. (1985). The ro le of observing and attention in establishing stimulus control. Journal of the Experimenta l Analysis of Behavior, 43 (3), 365-381. Dinsmoor, J. A., Browne, M. P., & Lawrence, C. E. (19 72). A test of the negative discriminative stimulus as a reinforcer of observing. Journal of the Experimental Analysis of Behavior, 18 (1), 79-85. Donny, E. C., Caggiula, A. R., Mielke, M. M., Booth, S., G harib, M., Hoffman, A., et al. (1999). Nicotine self-administration in rats on a progressive ratio schedule of reinforcement. Psychopharmacology, 147(2), 135-142. 34

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Donny, E. C., Chaudhri, N., Caggiula, A. R., Evans-Martin, F. F., Booth, S., Gharib, M. A., et al. (2003). Operant res ponding for a visual reinforcer in rats is enhanced by noncontingent nicotine: implications for nicotine self-administration and reinforcement. Psychopharmacology, 169(1), 68-76. Donny, E. C., Houtsmuller, E., & Stitzer, M. L. (2007). Smoking in the absence of nicotine: Behavioral, subjective and physiological effects over 11 days. Addiction, 102 (2), 324-334. Fleshler, M., & Hoffman, H. S. (1962). A progression fo r generating variable interval schedules. J. exp. Anal. Behav., 5 529-530. Frenk, H., & Dar, R. (2004). Reward potentiation or behavioral activation? A comment on Donny et al. Psychopharmacology, 171(4), 472-473. Glick, S. D., Visker, K. E., & Maisonnneuve, I. M. (1996). An oral self-administration model of nicotine preference in rats: Effects of mecamylamine. Psychopharmacology, 128(4), 426-431. Goodman, L. S., Gilman, A., Brunton, L. L., Lazo, J. S., & Parker, K. L. (2006). Goodmand & Gilman's The Pharmacological Basis of Therapeutics (11th ed.). New York: McGraw-Hill. Ise, Y., Narita, M., Nagase, H., & Suzuki, T. (2000). Modulat ion of opioidergic system on mecamylamine-precipitated nicoti ne-withdrawal aversion in rats. Psychopharmacology, 151(1), 49-54. Kumar, R., Reavill, C., & Stol erman, I. P. (1987). Nicotine c ue in rats: effects of central administration of ganglion-blocking drugs. British Journal of Pharmacology, 90 (1), 239-246. Laviolette, S. R., & van der Kooy, D. (2004) The neurobiology of nicotine addiction: bridging the gap from molecules to behaviour. Nat Rev Neurosci, 5 (1), 55-65. Liu, X., Caggiula, A. R., Yee, S. K., Nobuta, H., Poland, R. E., & Pechnick, R. N. (2006). Reinstatement of nicotine-seeking behav ior by drug-associated stimuli after extinction in rats. Psychopharmacology, 184 (3), 417-425. Liu, X., Caggiula, A. R., Yee, S. K., Nobuta, H., Sved, A. F., Pechnick, R. N., et al. (2007). Mecamylamine Attenuates CueInduced Reinstatem ent of NicotineSeeking Behavior in Rats. Neuropsychopharmacology, 32(3), 710-718. Liu, X., Palmatier, M. I ., Caggiula, A. R., Bonny, E. C., & Sved, A. F. (2007). Reinforcement enhancing effect of nico tine and its attenuation by nicotinic antagonists in rats. Psychopharmacology, 194(4), 463-473. McClernon, F. J., & Rose, J. E. (2005). Mecamylami ne moderates cue-induced emotional responses in smokers. Addictive Behaviors, 30(4), 741-753. 35

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Olausson, P., Jentsch, J. D., & Taylor, J. R. (2004a). Nicotine enhances responding with conditioned reinforcement. Psychopharmacology, 171(2), 173-178. Olausson, P., Jentsch, J. D., & Taylor, J. R. (2004b). Repeated nicotine exposure enhances responding with conditioned reinforcement. Psychopharmacology, 173 (1), 98-104. Palmatier, M. I., Coddington, S. B., Liu, X., Donny, E. C., C aggiula, A. R., & Sved, A. F. (2008). The motivation to obtain nico tine-conditioned reinforcers depends on nicotine dose. Neuropharmacology, 55 (8), 1425-1430. Palmatier, M. I., Peterson, J. L., Wilkinson, J. L., & Bevins R. A. (2004). Nicotine serves as a feature-positive modulator of Pavl ovian appetitive conditioning in rats. Behavioural Pharmacology, 15 (3), 183-194. Papke, R. L., Sanberg, P. R., & Shytle, R. D. (2001). Analysis of mecamylamine stereoisomers on human nicotinic receptor subtypes. The Journal of Pharmacology and Experimental Therapeutics, 297 (2), 646-656. Perkins, K. A., Gerlach, D., Vender, J., Gr obe, J., Meeker, J., & Hutchison, S. (2001). Sex differences in the subjective and reinforcing effects of visual and olfactory cigarette smoke stimuli. Nicotine & Tobacco Research, 3(2), 141-150. Poling, A., & Byrne, T. (Eds.). (2000). Introduction to Behavioral Pharmacology Reno, Nevada: Context Press. Raiff, B. R., & Dallery, J. (2006). Effects of Acute and Chronic Nicotine on Responses Maintained by Primary and Conditioned Reinforcers in Rats. Experimental and Clinical Psychopharmacology, 14 (3), 296-305. Raiff, B. R., & Dallery, J. (2008). The generality of nicotine as a reinforcer enhancer in rats: effects on responding maintained by primary and conditioned reinforcers and resistance to extinction. Psychopharmacology, 201 (2), 305-314. Rose, J. E. (2006). Nicotine and nonnicoti ne factors in cigarette addiction. Psychopharmacology, 184(3-4), 274-285. Rose, J. E., Behm, F. M., We stman, E. C., & Bates, J. E. (2003). Mecamylamine acutely increases human intravenous ni cotine self-administration. Pharmacology, Biochemistry and Behavior, 76 (2), 307-313. Rose, J. E., Behm, F. M., Westm an, E. C., Levin, E. D., Stei n, R. M., Lane, J. D., et al. (1994). Combined effects of nicotine and mecamylamine in attenuating smoking satisfaction. Experimental and Clinical Psychopharmacology, 2(4), 328-344. Rose, J. E., & Corrigall, W. A. (1997). Nic otine self-administration in animals and humans: Similarities and differences. Psychopharmacology, 130(1), 28-40. 36

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Shahan, T. A. (2002). The observing-response procedure : A novel method to study drug-associated conditioned reinforcement. Experimental and Clinical Psychopharmacology, 10 (1), 3-9. Shahan, T. A., Bickel, W. K. Badger, G. J., & Giordano, L. A. (2001). Sensitivity of nicotine-containing and de-nicotinized cigarette consumption to alternative nondrug reinforcement: A behavioral economic analysis. Behavioural Pharmacology, 12(4), 277-284. Shahan, T. A., Bickel, W. K., Madden, G. J., & Badger, G. J. (1999). Comparing the reinforcing efficacy of nicotine contai ning and de-nicotinized cigarettes: a behavioral economic analysis. Psychopharmacology, 147(2), 210-216. Wannacott, S., Sidhpura, N., & Balfour, D. J. (2005). Nicotine: from molecular mechanisms to behaviour. Current Opinion in Pharmacology, 5 (1), 53-59. Wyckoff, L. B., Jr. (1952). The role of obs erving responses in di scrimination learning. Part I. Psychological Review, 59 (6), 431-442. 37

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38 BIOGRAPHICAL SKETCH Jeb Jones received his Bachelor of Sci ence with High Honor in applied psychology from the Georgia Instit ute of Technology in May of 2005. Subsequently he worked at the Marcus Institute, a research and treatment facility for children and adolescents with developmental disabilities and severe behavio r problems, eventually being promoted to serve as a primary therapist and assist in the development of tr eatment and research protocols. He was accepted for admissi on to the behavior analysis program in the Department of Psychology at the University of Florida for the fall semester of 2007 to study under the leadership of Dr. Jesse Dallery. There he conducted the current experiment as well as assisted in numerous other experiments with animals and humans. He earned his Master of Science degree from the University of Florida in the fall of 2009.