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Tolerance to Cocaine following Chronic Administration of a Behaviorally Inactive Dose

Permanent Link: http://ufdc.ufl.edu/UFE0045440/00001

Material Information

Title: Tolerance to Cocaine following Chronic Administration of a Behaviorally Inactive Dose
Physical Description: 1 online resource (65 p.)
Language: english
Creator: Minervini, Vanessa
Publisher: University of Florida
Place of Publication: Gainesville, Fla.
Publication Date: 2013

Subjects

Subjects / Keywords: acute -- chronic -- cocaine -- operant -- pause -- pigeons -- rate -- tolerance
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: A procedure often used to demonstrate the development of tolerance is chronic(i.e., repeated) pre-session drug administration.  The magnitude of the dose selected for repeated administration is of critical importance to researchers.  Tolerance typically does not develop to a cocaine dose if the acute (i.e., initial) effects of that dose eliminate responding; therefore, the dose that researchers have often selected for chronic administration is the largest dose that disrupts and reduces, but does not abolish, responding.  Some evidence suggests that tolerance may develop after chronic administration of relatively smaller doses, however.  The purpose of the present experiment was to assess systematically effects of pre-session chronic(i.e., daily) administration of a behaviorally-inactive dose.  Specifically, response rates and post-reinforcement pauses of five pigeons key pecking under a three-component multiple fixed-ratio schedule of food reinforcement were observed under chronic cocaine administration.  After baseline responding was established, we evaluated the effects of a range of doses during acute (i.e., drug administrations spaced by at least 5 days) administration.  The largest dose that failed to alter responding acutely was administered chronically. After 30 consecutive sessions of chronic administration smaller and larger doses occasionally were substituted for the chronic dose. After assessments of the during-chronic dose-effect curves were completed, pigeons received pre-session saline (drug vehicle) administration for 30 consecutive sessions (i.e., a withdrawal phase), and then the effects of the series of doses on responding were re-determined.  All subjects developed tolerance to doses of cocaine that had initially caused large decreases in rate, with the magnitude of the effects varying across components of the multiple schedule and subjects.  Specifically, tolerance generally was greatest in the components with smaller ratios. Following a withdrawal phase, tolerance was usually diminished.  Overall, the results demonstrate that under these conditions, repeated experience with deleterious effects of cocaine on food-maintained responding is not a necessary factor in the development of tolerance.
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 Vanessa Minervini.
Thesis: Thesis (M.S.)--University of Florida, 2013.
Local: Adviser: Branch, Marc N.

Record Information

Source Institution: UFRGP
Rights Management: Applicable rights reserved.
Classification: lcc - LD1780 2013
System ID: UFE0045440:00001

Permanent Link: http://ufdc.ufl.edu/UFE0045440/00001

Material Information

Title: Tolerance to Cocaine following Chronic Administration of a Behaviorally Inactive Dose
Physical Description: 1 online resource (65 p.)
Language: english
Creator: Minervini, Vanessa
Publisher: University of Florida
Place of Publication: Gainesville, Fla.
Publication Date: 2013

Subjects

Subjects / Keywords: acute -- chronic -- cocaine -- operant -- pause -- pigeons -- rate -- tolerance
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: A procedure often used to demonstrate the development of tolerance is chronic(i.e., repeated) pre-session drug administration.  The magnitude of the dose selected for repeated administration is of critical importance to researchers.  Tolerance typically does not develop to a cocaine dose if the acute (i.e., initial) effects of that dose eliminate responding; therefore, the dose that researchers have often selected for chronic administration is the largest dose that disrupts and reduces, but does not abolish, responding.  Some evidence suggests that tolerance may develop after chronic administration of relatively smaller doses, however.  The purpose of the present experiment was to assess systematically effects of pre-session chronic(i.e., daily) administration of a behaviorally-inactive dose.  Specifically, response rates and post-reinforcement pauses of five pigeons key pecking under a three-component multiple fixed-ratio schedule of food reinforcement were observed under chronic cocaine administration.  After baseline responding was established, we evaluated the effects of a range of doses during acute (i.e., drug administrations spaced by at least 5 days) administration.  The largest dose that failed to alter responding acutely was administered chronically. After 30 consecutive sessions of chronic administration smaller and larger doses occasionally were substituted for the chronic dose. After assessments of the during-chronic dose-effect curves were completed, pigeons received pre-session saline (drug vehicle) administration for 30 consecutive sessions (i.e., a withdrawal phase), and then the effects of the series of doses on responding were re-determined.  All subjects developed tolerance to doses of cocaine that had initially caused large decreases in rate, with the magnitude of the effects varying across components of the multiple schedule and subjects.  Specifically, tolerance generally was greatest in the components with smaller ratios. Following a withdrawal phase, tolerance was usually diminished.  Overall, the results demonstrate that under these conditions, repeated experience with deleterious effects of cocaine on food-maintained responding is not a necessary factor in the development of tolerance.
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 Vanessa Minervini.
Thesis: Thesis (M.S.)--University of Florida, 2013.
Local: Adviser: Branch, Marc N.

Record Information

Source Institution: UFRGP
Rights Management: Applicable rights reserved.
Classification: lcc - LD1780 2013
System ID: UFE0045440:00001


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1 T OLERANCE TO COCAINE FOLLOWING CHRONIC ADMINISTRATION OF A BEHAVIORALLY INACTIVE DOSE By VANESSA MINERVINI A THESIS PRESENTED TO THE GRADUATE SCHOOL OF THE UNIVERSITY OF FLORIDA IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF MASTER OF SCIENCE UNIVERSITY OF FLORIDA 201 3

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2 201 3 Vanessa Minervini

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3 To my family

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4 ACKNOWLEDGMENTS This research was supported by National Institute of Drug Abuse (NIDA) grant No. DA004074. I would like to thank the members of my committee, Drs. Marc Branch, Jesse Dallery, and Drake Morgan, for their helpful comments and suggestions during the defense meeting. I am extremely grateful to Marc Branch, who served as both the committee chair and invaluable. I would also like to thank my former labmates David Maguire, Anne Macaskill, and Brian Kangas. Brain Kangas was instrumental in providing conceptual contributions at the conception of this project. David Maguire spent many hours teaching me EC Basic language and programming skills. Anne Macaskill helped me write Excel macros, which made for extremely efficient data analysis. I acknowledge and thank each of them for effectively sh aping my behavior. Linda Flunker, our former lab technician, deserves recognition for assistance with data collection and general animal husbandry. Last but not least, I would like to recognize my undergraduate research assistants, Lee Griffith, Luis Oter o Valles, and Yi Yang, for their assistance with this project.

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5 TABLE OF CONTENTS page ACKNOWLEDGMENTS ................................ ................................ ................................ .. 4 LIST OF TABLES ................................ ................................ ................................ ............ 6 LIST OF FIGURES ................................ ................................ ................................ .......... 7 ABSTRACT ................................ ................................ ................................ ..................... 8 CHAPTER 1 INTRODUCTION ................................ ................................ ................................ ........ 10 2 METHOD ................................ ................................ ................................ .................... 18 Subjects ................................ ................................ ................................ ..................... 18 Apparatus ................................ ................................ ................................ ................... 18 Procedure ................................ ................................ ................................ ................... 19 Training ................................ ................................ ................................ ............ 19 General P rocedure ................................ ................................ ........................... 19 Baseline ................................ ................................ ................................ ............ 20 General Pharmacological P rocedure ................................ ................................ 20 Acute Administration and A ssessment ................................ ............................. 21 Chronic A dministration ................................ ................................ ..................... 21 During chronic A ssessment ................................ ................................ .............. 22 Withdrawal and During withdrawal A ssessment ................................ ............... 22 3 RESULTS ................................ ................................ ................................ ................... 24 4 DISCUSSION ................................ ................................ ................................ ............. 51 LIST OF REFERENC ES ................................ ................................ ............................... 59 BIOGRAPHICAL SKETCH ................................ ................................ ............................ 65

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6 LIST OF TABLES Table page 2 1 T he number of determinations f or each probe dose across phases ................... 23 3 1 Variance a ccounted for (R2 values) for response rate and pause dose effect functions ................................ ................................ ................................ ............. 39

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7 LIST OF FIGURES Figure page 3 1 Response rate and pause as a function of cocaine dose for Pigeon 1082 ......... 40 3 2 Response rate and pause as a function of cocaine dose for Pigeon 1163 ......... 41 3 3 Response rate and pause as a function of cocaine dose for Pigeon 1166 ......... 42 3 4 Response rate and pause as a function of cocaine dose for Pigeon 1186 ......... 43 3 5 Response rateand pause as a function of co caine dose for Pigeon 1859 .......... 44 3 6 Dose effect functions fit to the mean response r ate data for individual pigeons ................................ ................................ ................................ ............... 45 3 7 ED 50 values obtained from the fitted dose eff ect functions for response rate ..... 46 3 8 Dose effect functions fit to the mean post reinforcement pause data for individual pigeons ................................ ................................ ............................... 47 3 9 ED 50 values obtained from the fitted dose effect functions for pausing ............... 48 3 10 Number reinforcers as a function of cocaine dose for in dividual pigeons. .......... 49 3 11 Response rate and pause as a function of successive ratios under 5.6 mg/kg probes for Pigeon 1859 ................................ ................................ ...................... 50

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8 Abstract of Thesis Presented to the Graduate School of the University of Florida in Partial Fulfillment of the Requirements for the Degree of Ma s ter of Science T OLERANCE TO COCAINE FOLLOWING CHRONIC ADMINISTRATION OF A BEHAVIORALLY INACTIVE DOSE By Vanessa Minervini Ma y 201 3 Chair: Marc N. Branch Major: Psychology A procedure often used to demonstrate the development of tolerance is chronic (i.e., repeated) pre session drug administration. The magnitude of the dose selected for repeated administration is of critical importance to researchers. Tolerance typically d oes not develop to a cocaine dose if the acute (i.e., initial) effects of that dose eliminate responding; therefore, the dose that researchers have often selected for chronic administration is the largest dose that disrupts and reduces, but does not abolis h, responding. Some evidence suggests that tolerance may develop after chronic administration of relatively smaller doses, however. The purpose of the present experiment was to assess systematically effects of pre session chronic (i.e., daily) administra tion of a behaviorally inactive dose. Specifically, response rates and post reinforcement pauses of five pigeons key pecking under a three component multiple fixed ratio schedule of food reinforcement were observed under chronic cocaine administration. A fter baseline responding was established, we evaluated the effects of a range of doses during acute (i.e., drug administrations spaced by at least 5 days) administration. The largest dose that failed to alter responding acutely was

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9 administered chronicall y. After 30 consecutive sessions of chronic administration smaller and larger doses occasionally were substituted for the chronic dose. After assessments of the during chronic dose effect curves were completed, pigeons received pre session saline (drug veh icle) administration for 30 consecutive sessions (i.e., a withdrawal phase), and then the effects of the series of doses on responding were re determined. All subjects developed tolerance to doses of cocaine that had initially caused large decreases in ra te, with the magnitude of the effects varying across components of the multiple schedule and subjects. Specifically, tolerance generally was greatest in the components with smaller ratios. Following a withdrawal phase, tolerance was usually diminished. Overall, the results demonstrate that under these conditions, repeated experience with deleterious effects of cocaine on food maintained responding is not a necessary factor in the development of tolerance.

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10 CHAPTER 1 INTRODUCTION Classified as a central nervous system stimulant, cocaine exerts its effects principally by blocking dopamine reuptake in the brain. Some physiological effects of cocaine include increased heart rate, body temperature, and blood pressure. Additionally, t he blood vessels constrict and the pupils dilate (National Institute on Drug Abuse, 2010). A complete understanding of the effects of cocaine, however, includes not only its physiological action but also its behavioral action. Research conducted in the field of behavioral pharmacology, an interdisciplinary field incorporating the research methodology of the experimental analysis of behavior with pharmacology, has long standing findings demonstrating interactions between drugs and behavior where the goal is to determine behavioral mechanisms of drug action. the environment. In an operant conditioning paradigm, the environment includes the prevailing schedule of reinforceme nt. Under schedules of reinforcement that engender low baseline response rates, acute administration of psychostimulants usually elevates responding, and under schedules of reinforcement that engender high baseline response rates, acute administration of p sychostimulants generally slows responding. Therefore, environmental factors like the schedule of reinforcement can cause an interaction between the drug and behavior, largely determining the effects that a drug exerts on behavior, rather than its effects depending solely on known pharmacological properties (Barrett, 1976; Dews, 1955, 1958; Gonzales & Goldberg, 1977; Kelleher & Morse, 1964, 1968). For example, cocaine can produce dose dependent rate decreasing effects on responding maintained by fixed rat io (FR) food reinforcement and

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11 dose dependent rate increasing effects on responding maintained by fixed interval (FI) food reinforcement. The acute effects of cocaine will determine what type of changes in behavior can be considered as tolerance. In gen eral, tolerance is defined as a decreased sensitivity to drug effects after repeated dosing (i.e., chronic administration). A large dose that formerly produced an effect no longer may be effective, or a larger dose may be needed to produce effects compara rate increasing effects would mean that during chronic administration rates decrease, decreasing effects would mean that rates increase. Unde r an FR schedule, typical control levels are characterized by a ratio schedules engender performance that consists of a pause (i.e., a period of nonresponding) at the start of a ratio followed by rapid respondin under an FR arrangement are that pausing increases and rates decrease (MacPhail & increasing and rate decreasing effects would be characterized by a decline in pausing and recovery of response rates. It has been demonstrated that number of environmental and behavioral factors modulate whether and the degree to which behavioral tolerance develops. Some of these varia bles include repeated administration (Branch & Dearing, 1982; Branch, Walker, & Brodkorb, 1999; Schama & Branch, 1994; Woolverton, Kandel, & Schuster, 1978a), whether the dose is administered pre or post session (Marusich & Branch, 2009; Pinkston & Branch 2004, 2010; Weaver, Dallery, & Branch, 2010; Woolverton,

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12 Kandel, & Schuster, 1978b), the reinforcement schedule type and context (e.g., Barrett, 1976; Kelleher & Morse, 1964; 1968; Gonzales & Goldberg, 1977; Smith, 1986; Schuster, Dockens, & Woods, 1966; Waller, 1961), the degree of stimulus control (e.g., (e.g., Hughes, Pitts, & Branch, 1996; Ross & Schaal, 2002; Schaal & Branch, 1992; Schaal, Miller, & Odum, 1995), the reinforcer magnitude (Durgin, Porter, Bradley, Laraway, & Poling, 2009; Ginsburg, Pinkston, & Lamb, 2011; Pinkston, Ginsburg, & Lamb, 2009), the response effort (e.g., Hughes, Sigmon, Pitts, & Dykstra, 2005; Makhay, Alling, & Poling, 1994), and the reinfor cement schedule parameter (e.g., Hoffman, Branch, Sizemore, 1987; Hughes & Branch, 1991; McMillan, 1969; Nickel, Alling, & Poling, 1993; Van Haaren & Anderson,1994; Yoon & Branch, 2004). Though exactly how environmental variables function contributing to t olerance or lack thereof remains to be elucidated, the reinforcement loss hypothesis proposed by Schuster et al. (1966) has accumulated much empirical support and has endured as an viable explanation. According to the reinforcement loss hypothesis, tolera nce is thought result in a decreased rate of reinforcement. If an organism experiences the prevailing contingencies of a schedule in the presence of behaviorally deleter ious drug effects (i.e., behavior is disrupted severely enough such that reinforcement is markedly reduced or not obtained), it can learn to adjust its behavior accordingly to compensate for the cost associated with drug induced losses. Schuster et al. (1966) demonstrated that amphetamine tolerance developed in the differential reinforcement of low rates (DRL ) component, but not in the fixed interval (FI)

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13 component, in a multiple schedule. Physiological mechanisms of tolerance, such as changes in metab olism or neurotransmitter receptor sites, cannot fully explain the increased responding in both components, thereby diminishing reinforcement rates in the DRL context but not in the FI context, which led Schuster et al. to suggest that behavioral tolerance occurs only when the effect of the drug is such that behavior becomes incompatible wit h the contextual contingencies, and contact with reinforcement decreases. Sinc e the inception of the reinforcement loss hypothesis as an explanation of tolerance, differential tolerance has been demonstrated across drugs, species, and responses in a multitude of studies (Bowen, Fowler, & Kallman, 1993; Carlton & Wolgin, 1971; Demell week & Goudie, 1982; Emmett Oglesby & Taylor, 1981; Foltin & Schuster, 1982; Galbicka, Kautz, Ritch, Wolgin & Wade, 1995; Hughes, Popi, & Wolgin, 1998; Nickel, Alling, Kleiner, & Poling, 1993; Poling & Nickel, 1993; Salisburry & Wolgin, 1985; Schuster et a l., 1966; Schuster & Zimmerman, 1961; Smith 1986, 1990; Wolgin, 2000; Wolgin & Wade,1995). The finding that the reinforcement schedule modulates tolerance is interesting because the multiple schedule arrangement reveals that the presence and absence of to lerance can occur within a single session, thus indicating that simple, general pharmacological effects cannot be a complete account. Such an effect even has been extended to schedule parameter dependent tolerance to the disruptive effects of cocaine. Ho ffman et al. (1987) trained three pigeons to respond under a three component multiple FR schedule with food reinforcement. When cocaine was administered acutely, it produced dose dependent, rate decreasing effects in all three

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14 components. Following chron ic administration of a dose that suppressed but did not entirely eliminate responding, tolerance developed in the small and medium ratio components. Little to no tolerance developed in the large ratio component. These results somewhat were consistent w ith the reinforcement loss hypothesis in that response rates recovered during chronic administration and subjects were able to adjust behavior to achieve reinforcement. The results were inconsistent with the reinforcement loss hypothesis, however, because tolerance failed to occur in the large ratio component even though reinforcement loss occurred in that component. Follow up studies by Branch (1990) and Schama & Branch (1989) revealed that differences in reinforcement rate across components were not ass ociated with differential development of tolerance. Findings reported by Yoon and Branch (2004) and Hughes et al. (2005) showed that differences in unit price also were not associated with differential development of tolerance. Our present understanding o f the effect obtained by Hoffman et al., therefore, is that the response requirement is the relevant variable that controls the extent to which tolerance develops. Typically, for most drugs of abuse, the acute effects are dose dependent, so it is necessar y to assess the effects of a range of doses on responding. A dose response function, with dose expressed on the x axis and quantifiable behavior expressed on the y for chronic administration. The best dose at which one can observe the development of tolerance during chronic administration is between the effective dose (ED) 25 and the ED 75 (Schuster, 1978). An ED 25 is a dose that alters (i.e., increases or decreases) r esponding by 25% relative to baseline, and an ED 75 would be a dose that alters

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15 responding by 75% relative to baseline (see Method section for a full description of the equation). Thus, for rate decreasing drugs, typically the largest dose that reduces re sponding without eliminating it entirely has been selected for chronic administration. Because previous research on repeated administration of cocaine has indicated that tolerance can develop with relatively lower doses but usually does not develop with hi gher doses that abolish responding (Bowen, Fowler, & Kallman, 1993; Branch, Wilhem, & Pinkston, 2000; Stafford & Branch, 1996), the systematic manipulation and assessment of the chronic dose selection is of critical importance in understanding factors that contribute to the development of tolerance or lack thereof. In the behavioral literature on drug action, surprisingly few studies have attempted to assess the role of the chronic dose when it is administered pre session. Bowen et al. (1993) found that acute cocaine administration dose dependently decreased responding in a milk drinking task in rats. Rats then either received 8.0 mg/kg, 16.0 mg/kg, or 32.0 mg/kg cocaine chronically. They found that dose specific tolerance occurred to the lowest dose te sted (i.e., 8.0 mg/kg), but that tolerance failed to generalize when higher doses were substituted for the chronic dose. Following the moderate dose chronic administration, tolerance was observed across a range of doses tested, and the highest dose tested (32.0 mg/kg) produced hardly any tolerance. Stafford and Branch (1996) decreasing effects under an FR 30 schedule in pigeons. Then, pigeons were divided into three groups: The pigeons eith er received a small, medium, or large chronic dose for 40 consecutive sessions. They found a shift in the dose response function, indicative of tolerance, when the chronic dose was small. Evidence of tolerance to larger doses occurred even

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16 when the chron ic dose was low enough such that its effect on response rate was indistinguishable from that of baseline responding. The combined results from these studies illustrate that the degree of tolerance is affected by the dose selected for chronic administratio n; however, neither study addressed this variable in the context of a multiple schedule, which also has been shown to modulate the degree of tolerance (e.g., Hoffman et al., 1987). decr easing effects in a multiple FR 5 FR 100 schedule following pre session chronic administration of a small dose. For all six pigeon subjects, they found that tolerance developed in the small ratio component but not in the large ratio component. That is, f ollowing chronic administration of a small dose, acute effects (i.e., decreased response rates at high doses) were attenuated. Of particular interest is that the small chronic dose produced no noticeable effect on response rates in the small ratio compone nt, suggesting that tolerance may develop after pre session administration of a behaviorally inactive dose. Unfortunately, one limitation in their study was the criterion session small dose was chosen b ecause in a previous condition of the experiment it was defined as one that did not affect within session responding when administered post session. The problem with the definition is twofold. First, by the end of the post session chronic administration condition, responding had decreased in the large ratio component for 3 of 7 subjects and had decreased in the small ratio component for 1 subject. Second, when the small dose then was administered chronically pre session, it reduced responding, albeit

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17 sli ghtly, in the large action on responding. The purposes of the present experiment were to (a) evaluate the development of tolerance after chronic administration of a dose that failed to red uce responding acutely (i.e., a behaviorally inactive dose) and (b) determine whether the fixed ratio (FR) parameter modulated the degree of tolerance. To do so, we arranged a three ined by access to grain. Once baseline responding had stabilized, an acute dose effect determination was conducted. The largest dose that failed to disrupt responding acutely then was administered chronically. To evaluate whether and the degree to which tolerance developed, we reassessed the effect of a series of doses on responding by conducting a during chronic dose effect determination. The development of tolerance to larger doses of cocaine following pre session chronic administration of a behavioral ly inactive dose not only would confirm findings reported by Bowen et al. (1993), Stafford and Branch (1996), and Pinkston and Branch (2004), but also provide evidence against the reinforcement loss hypothesis in that tolerance need not require learning an d behavioral compensation due to the presence of decreased reinforcement rate under drug effects.

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18 CHAPTER 2 METHOD Subjects Six experimentally nave adult male White Carneau pigeons (numbered 1078, 1082, 1163, 1166, 1186, and 1859) were obtained from from Double T Farms, Glenwood, Iowa. We maintained the pigeons at 85% of their free feeding body weight via post session feedings consisting of mixed grain and pellets (Purina P igeon Chow Checkers) in equal proportions. Outside of daily sessions, the pigeons were individually housed in a temperature and humidity controlled colony room with a 16:8 hr light:dark cycle. In their home cages, the pigeons freely had access to water an d health grit. Due to a beak injury that failed to heal properly, one subject did not complete the experiment. Apparatus The experiment was conducted in two pigeon operant conditioning chambers (interior dimensions 35 x 30 x 35 cm). The front panel of th e chambers contained a houselight positioned 30 cm from the chamber floor, and 7 cm below the houselight were 3 horizontally positioned keys. The keys measured 2.5 cm in diameter and were positioned 8 cm from the walls and 5.5 cm apart. Only the center k ey illuminated white, red, or green was used; its activation required a minimum force of 0.098 N. A 30 ms tone, produced by a Mallory Sonalert device, accompanied each successful response to the key. Located 10 cm directly below the center key and 11 cm from the chamber floor there was a 5 cm by 5.5 cm aperture through which access to a solenoid operated hopper filled with buckwheat, milo, and hempseed could be provided. During reinforcer presentations, the aperture and raised hopper were illuminated, an d all other

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19 lights in the chamber were extinguished. In one of the chambers, an additional 5 cm by 5.5 cm aperture for pellet delivery was located 3.5 cm to the left of the grain aperture, but it served no function in this experiment. White noise at appro ximately 95 dB masked extraneous sounds in the rooms containing the operant chambers. In an adjacent room, computers running EC BASIC software (Palya & Walter, 1993) controlled experimental events and recorded data, and cumulative response recorders provi ded live time data collection. Procedure Training After the pigeons reliably approached and ate from the raised hopper, responses to the center key (illuminated white) were shaped by reinforcing successive approximations. Once key pecking was established the following session consisted of a fixed ratio 1 schedule with the center key illuminated white and lasted until the pigeon earned 60 reinforcers. General p rocedure To arrange a 3 component multiple schedule, we introduced two additional key colors r ed and green. A 5 min blackout occurred at the beginning of all sessions. Each component was selected randomly without replacement and remained in effect until the pigeon earned four reinforcers. If a pigeon failed to earn all four programmed reinforcers within an allotted time limit, then components ended after 90 (white), 300 (red), or 810 (green) s elapsed. The white, red, and green key always signaled the small medium and large ratio components, respectively. A sequence of all components compris ed a block, and sessions ended after 3 blocks.

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20 The FR response requirement in each component was increased gradually across sessions until the target FR in each component was achieved; the targeted terminal schedule was a multiple FR 5 FR 25 FR 125 sched ule. Each FR increase (i.e., 2, 3, 5, 8 12, 20, 25, 30, 36, 47, 55, 65, 75, 85, 95, 105, 125) occurred only if visual inspection of the cumulative response records and overall response rate data revealed that within session responding in all components ap peared stable. Baseline During baseline our aim was to obtain consistent responding in all components with differentially longer post reinforcement pause in the large ratio component. In order to accomplish these outcomes, the details of the procedure were tailored to individual subjects. Pigeons 1082 and 1186 responded under FR 5 FR 25 FR 125 with 3 s access to grain. Pigeon 1166 responded under the same schedule, but his weight was increased from 85% to 98% of his free feeding body weight, and his re inforcer access was increased to 4 s. Pigeon 1163 responded with 3 s access to grain, but his large ratio performance deteriorated beyond FR 80, so this value ultimately was chosen for his large ratio component. In order to maintain responding, pigeon 18 59 required 6 s access to food and a reduction of the response requirements to FR 5, FR 15, and FR 45. The baseline conditions remained in effect until response rate and post reinforcement pause were stable for at least 30 sessions. General pharmacologica l procedure Cocaine hydrochloride obtained from National Institute on Drug Abuse was dissolved in 0.9% saline solution. Doses were delivered in mg/kg, expressed in terms of the salt, and administered intramuscularly (pectoral muscle) immediately prior to a

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21 For example, Pigeon 1859 weighed 682 g and always received a 0.68 ml injection. Acute administration and assessment Doses were administered every fifth session in eith er an ascending (Pigeons 1166 and 1186) or descending (Pigeons 1082, 1163, and 1859) series. The series of doses for Pigeons 1082, 1163, and 1186 included 0.0 mg/kg (i.e., saline), 1.0 mg/kg, 3.0 mg/kg, 5.6 mg/kg, and 10.0 mg/kg. The effects of this seri es of doses on response rate and post reinforcement pause were assessed twice. Pigeon 1859 received the same series of doses, but after the two determinations, we administered an abbreviated series of 0.0 mg/kg, 3.0 mg/kg, and 5.6 mg/kg for two additional determinations of each dose. We altered the series of doses for Pigeon 1166 such that the 1.0 mg/kg was excluded and a 17.0 mg/kg dose also was assessed. For each pigeon, the number of times a dose was administered is shown in Table 2 1 Chronic administ ration Based on visual analysis of the acute dose response functions and corresponding cumulative response records, we selected the largest dose that failed to suppress rates or elevate post reinforcement pause during acute administration. We chose 1.0 m g/kg for Pigeon 1859, 3.0 mg/kg for Pigeons 1163, 1166, and 1186, and 5.6 mg/kg for Pigeon 1082. The dose then was administered immediately prior to 30 consecutive sessions. Rarely, during chronic administration, an apparatus failure prevented us from co nducting a daily session. Under these circumstances, the pigeon still received administration of its chronic dose and was returned to its home cage.

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22 During chronic assessment To determine whether and the extent to which tolerance developed, we reassessed the effect of the series of doses on rate and pause by administering a probe dose from the series every fifth session. On days intervening probes, pigeons received their chronic dose. After two determinations of each dose from the series, we replicated do ses at the critical points in the curve and probed for tolerance to higher doses if necessary. For each pigeon, the number of the number of times a dose was administered is shown in Table 2 1. Withdrawal a nd during withdrawal assessment Pigeons received saline immediately prior to 30 consecutive sessions. To determine whether tolerance was reversible or attenuated, we reassessed the effect of the series of doses a final time by administering a probe from the series every fifth session. On days intervening probes, pigeons received a saline injection. After two determinations of each dose from the series, we replicated doses at the critical points in the curve if necessary. For each pigeon, the number of the number of times a dose was adm inistered is shown in Table 2 1.

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23 Table 2 1. For all pigeons, the number of determinations for each probe dose across phases. See text for details.

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24 CHAPTER 3 RESULTS Figures 3 1 through 3 5 show both of the primary dependent variables overall resp onse rate and post reinforcement pause as a function of cocaine dose in each component of the multiple schedule for individual pigeons. The C and S on the x axis represent Control and Saline, respectively. The control data points are an average of the ef fects from all sessions preceding a probe session in a given phase. All other data points are based on the average of at least 2 determinations per dose, but the exact number of doses that each pigeon received during each phase of probing can be seen in Ta ble 2 1. The circles represent the acute probes, the squares represent the chronic probes, and the triangles represent the withdrawal probes. Error bars represent the range of effects. Figure 3 1 shows data from Pigeon 1082. During acute dosing, 10.0 mg/kg of cocaine eliminated responding and maximized pausing in the medium and large ratio components. In the small ratio component, 10.0 mg/kg of cocaine caused responding to be nearly eliminated and pausing to drastically increase relative to other do ses. Following chronic administration, the effect of 10.0 mg/kg on both rate and pause was greatly attenuated. When 13.0 mg/kg was administered tolerance was evident in the small ratio component for rate and pause, but less so in the medium and large ra tio components. Interestingly, there must have been a small degree of tolerance to 13.0 mg/kg because some responding still occurred at this dose that was larger than the dose that had eliminated responding entirely during acute probing (i.e., 10.0 mg/kg) Following a period of withdrawal, the effects of cocaine appear to be more similar to the

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25 effects during acute than chronic probing, indicating that tolerance mostly was reversible. Figure 3 2 shows data from Pigeon 1163. During acute dosing, 10.0 mg/k g of cocaine eliminated responding and maximized pausing in all components. The range bars are wide at the 5.6 mg/kg dose because responding appeared to be bimodal. That is, for 3 of 6 determinations responding was eliminated, but for 3 of 6 determinatio ns responding was comparable to that at lower doses. The order of the determinations was not predictive of the degree of responding that occurred. After chronic administration, tolerance occurred to the 5.6 mg/kg dose. The range bars at this dose during this phase also were wide, but mean responding shifted in a direction that indicates tolerance had developed. In other words, this pigeon was tolerant to the effects of 5.6 mg/kg more often following chronic administration than he was prior to chronic adm inistration of 3.0 mg/kg. Following a period of withdrawal, however, Pigeon suppressing and pause increasing effects than he was during the acute (i.e., initial) phase. Figure 3 3 shows data from Pige on 1166. During acute dosing, some degree of responding was maintained in the small and medium ratio components even at the largest dose that the IACUC protocol permitted us to administer (i.e., 17.0 mg/kg). Towards this end of the curves, it is diffic ult to ascertain the degree to which tolerance developed in the small ratio component due to the fact that the 17.0 mg/kg dose resulted in only a 50 % reduction in responding relative to control levels. (Note that in order to obtain even this reduction it was necessary to decrease the deprivation such that this pigeon was maintained at 98% of his free feeding weight). All the mean values

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26 from the probes during chronic administration, nevertheless, are above those from acute determinations. In the medium ratio component tolerance developed to the effects of 17.0 mg/kg. That is, response rates were higher and pausing was shorter after chronic administration of 3.0 mg/kg. Some tolerance also is evident at the 10.0 mg/kg dose, but the ranges for the acute a nd chronic effects overlap somewhat. Relative to the medium ratio component, tolerance to the 10.0 mg/kg dose is more evident in the large ratio component. Though the effects on rate and pause sometimes fell in the range of the acute effects, the range a lso extended to levels comparable to responding under control conditions and smaller doses. Tolerance failed to develop at 17.0 mg/kg in the large ratio component. After a withdrawal period, tolerance was not attenuated in the small ratio component, but the effects of the 17.0 mg/kg dose in the medium ratio component provided evidence that tolerance was reversed. Figure 3 4 shows data from Pigeon 1186. For this pigeon, 5.6 mg/kg greatly reduced responding and elevated pausing in all components when admi nistered acutely, but responding recovered entirely at this dose in all components following chronic administration of 3.0 mg/kg. Tolerance to 10.0 mg/kg was most evident in the small ratio component. The range of effects was much smaller relative to the range of effects in the other two components. Tolerance still occurred during some sessions when 10.0 mg/kg was administered because the top of the range for response rate and bottom of the range for pause indicate that responding occasionally was indist inguishable from that under control conditions and smaller doses. When 13.0 mg/kg was administered (a dose that was larger than a dose that eliminated responding entirely during acute dosing), baseline level, some, and no responding was observed in

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27 the sm all medium and large ratio components, respectively. After a period of withdrawal, tolerance was reversed only at the 13.0 mg/kg dose but not at smaller doses. Figure 3 5 shows data from Pigeon 1859. When administered acutely, 10.0 mg/kg either mar kedly reduced or eliminated responding in all three components. The range of effects for 5.6 mg/kg was wide because the effects seemed to be bimodal. Several probe administrations allowed us to conclude that responding either was reduced greatly or not a t all by this dose. After chronic administration of 1.0 mg/kg, the mean and the range of 5.6 mg/kg effects shifted up for response rate and shifted down for pause in both the small and medium ratio components, indicating that some degree of tolerance had developed. Tolerance to 10.0 mg/kg was not evident nor was tolerance observed at any dose in the large ratio component. In the large ratio component the chronic range of effects for both 3.0 mg/kg and 5.6 mg/kg did become narrower relative to the acute range, however. After a period of withdrawal the effects of 5.6 mg/kg tended to shift towards the direction of acute effects, but did not reverse fully for rate and pause in the small component ratio. Effects in the medium ratio component remained at ch ronic levels following withdrawal, and no change across phases seemed to occur in the large ratio component. Figure 3 6 shows the mean response rate data (shown in the left panels of Figures 3 1 through 3 5) fit to monotonic decreasing logistic dose respo nse functions. The following equation was used

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28 where Top and Bottom are the plateaus of the curve in the y axis units. Top was allowed to vary and Bottom was constrained to zero because it is nonsensical for response rates to be negative. ED 50 is the concentration of the dose that yields responding halfway between Bottom and Top In other words, ED 50 estimates the dose that would reduce responding by 50%. HillSlope which was allowed to vary, describes the steepness of the curve. A HillSlope of 1.0 is standard, and anything less (i.e., more negative) than 1.0 would be steeper (GraphPad Prism 5 ). Overall response rate in seconds is on the y axis, a nd cocaine dose in mg/kg is on the x medium and large ratio performance with the individually tailored FR parameter displayed in each panel. The open circles and dashed c urve represent the data from acute dosing. The closed squares and solid curve represent data from the during chronic assessment, and the closed triangles and solid curve represent data from the during withdrawal assessment. If the largest dose in the ser ies failed to eliminate responding entirely in a component, we entered a zero as the response rate data for the next largest dose (1/8 log unit larger) to complete the curve. The goodness of fit, or variance accounted for, was high with R 2 ranging from .9 3 to 1.0. The R 2 values for all curves are reported in Table 3 1 In these graphs, tolerance is indicated by the descending portions of the curve during chronic administration being to the right of that for the acute functions. That is the case in every panel except one (Pigeon 1859 in the large ratio component) for the comparison between acute and chronic functions.

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29 Overall, tolerance tended to develop to larger doses of cocaine after chronic administration of an initially (i.e., acutely) behaviorally i nactive dose. For all pigeons except Pigeon 1166, the chronic dose response function shifted to the right of the acute dose response function in both the small and medium ratio components. Pigeon ratio component were relatively insensitive to suppressing effects even at the largest dose that the IACUC permitted us to administer (i.e., 17.0 mg/kg). Tolerance (i.e., a shift in the chronic dose response curve to the right of the acute dose response curve) was observed in the large ratio component for 4 of 5 pigeons with the exception being Pigeon 1859 whose chronic curve overlays his acute curve. For this pigeon, following a period of cocaine withdrawal, a left shift of the downward portion of the curve re lative to the chronic curve indicates that tolerance either was erased entirely or at least attenuated in the small ratio component. In the medium ratio component, the withdrawal curve more closely approximates the chronic curve, rather than the acute curv e, indicating that tolerance was not attenuated. In the large ratio component, despite the nonoccurrence of decreasing effects following a period of withdrawal were more pronounced than in either the acute or chronic phases. To quantify and compare the degree to which tolerance developed across conditions and as a function of the FR parameter, Figure 3 7 shows the ED 50 values obtained from the dose response curves for each FR parameter across conditions. The white, dark, and shaded bars represent the acute, chronic, and withdrawal phases, respectively. F or all pigeons the chronic ED 50 was greater than the acute ED 50 in most components For P igeon 1166, we did not ascertain tolerance in the small ratio

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30 component because response rates were relatively insensitive to cocaine's rate suppressing effects even at the largest dose that the IACUC protocol permit ted us to administer (i.e., 17.0) across phases For Pigeon 1859, the acute ED 50 and chronic ED 50 in the large ratio component were equivalent, indicating that tolerance failed to develop. The degree of tolerance as indicated by the change in ED 50 values, did not appear to be modulated by the FR schedule parameter and seemed comparable across components for Pigeon 1163 For Pigeon 1082, the difference in ED 50 values between the acute and chronic phases was slightly greater in the small ratio component relative to the medium and large ratio component, in which comparable tolerance levels were observed. For 1166, 1186, and 1859, the magnitude of tolerance diminished as FR value increased. This effect was most evident for Pigeon 1186 (small ratio tolerance compared to medium and large ratio tolerance), Pigeon 1166 (medium ratio tolerance compared to la rge ratio tolerance), and Pigeon 1859 (small and medium ratio tolerance compared to no tolerance in the large ratio component). The chronic ED 50 values tended to be greater than the withdrawal ED 50 values indicating that the development of tolerance un der these conditions appeared either to be reversible or attenuated. The FR schedule parameter was not predictive of the degree of reversibility, and individual differences were observed. Interestingly, P igeon ED 50 values were larger than the withdrawal ED 50 values, suggesting increased sensitivity to cocaine's rate suppressing effects after chronic administration and a period of withdrawal Tolerance was not reversed in only two cases: Pigeon medium ratio responding.

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31 Figure 3 8 shows the mean pause data (shown in the right panels of Figures 1 5) fit to monotonic increasing logistic dose response functions. The same equation that was used for response rate curves in Figure 3 6 also was used for these pause curves. Top and Bottom are still the plateaus of the curve in the y axis units, and HillSlope which was allowed to vary, still describes the steepness of the curve. For the pause data Bottom was allowed to vary (but had t o yield a value greater than 0), and Top was constrained to 300, 900, and 2430 for the small medium and large ratio components, respectively. These values were chosen because they were the maximum time that a given component could be in effect each s ession if a pigeon failed to make any responses; no responses would reflect maximal pausing. If a dose failed to eliminate responding entirely (i.e., induce maximal pausing) in a component, we entered 300, 900, or 2430 as the pause data for the next larges t dose (1/8 log unit larger) to complete the curve. ED 50 is the concentration of the dose that yields responding halfway between Bottom and Top In other words, ED 50 estimates the dose that would increase pausing by 50%. Post reinforcement pause in s econds is on the y axis, which extends beyond zero such that all data points are visible. Cocaine dose in log mg/kg is on the x axis. medium and large ratio performance with the individua lly tailored FR parameter displayed in each panel. The open circles and dashed curve represent the data from acute dosing. The closed square and solid curve represent data from the during chronic assessment, and the closed triangles and solid curve repres ent data from the during withdrawal assessment.

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32 The goodness of fit, or variance accounted for, was high with R 2 ranging from 87 to 1.0. The R 2 values for al l curves are reported in Table 3 1 A shift of the chronic curve down and to the right of the a cute curve indicates that increasing effects occurred for most pigeons in at least one of the three components, but there was much more individual variability in the pause data relative to the rate data. Pigeon 1082 developed tolerance in all three components, with the degree of tolerance being greater as the FR requirement increased. For this pigeon, tolerance was reversible in the small and large ratio components, and it wa s diminished in the medium ratio component after a period of withdrawal. Pigeon 1163 also developed tolerance in all three components, but the degree of tolerance in the large ratio component was much smaller than that in the small and medium ratio comp onents. Tolerance was not only reversed for this pigeon but also its pausing became more Pigeon 1166 was relatively insensitive to the pause increasing effects in the small ratio component. During acute administration the amount of time spent pausing during the small ratio component of the session was already so low that we observed a floor effect the chronic curve could not shift to the right given the dose range assessed. In the medium ratio component, the curves fell on top of each other, which indicates that examination of pausing at 17.0 mg/kg, however, reveals that a small degree of tolerance developed and then was reverse d: The chronic data point is below the acute data point, which in turn is below the withdrawal data point. Some tolerance also

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33 developed in the large ratio component. Despite a shift in sensitivity at lower doses, at higher doses pausing was not maximal after chronic administration. Pausing at 17.0 mg/kg then returned to the maximum level following withdrawal. Pigeon 1186 developed marked and comparable tolerance across the components, but after withdrawal, tolerance was not reversible or even noticeably diminished in any component. Pigeon 1859 developed the least amount of tolerance relative to the other pigeons. In fact, whether tolerance developed is, at worst, arguable and, at best, negligible. In the small and medium ratio components, the chronic curved appeared to shift slightly downward at lower doses, but overlapped the acute curve at higher doses. In these components the most convincing evidence for tolerance can be seen at 5.6 mg/kg where the chronic data point falls below the acute data poi nt (note that the dose effect equation underestimates the obtained acute data). In the large ratio component there is a downward shift in the curve at higher doses, but again, the change in pausing is minimal. Evidence for tolerance seems to exist at 5.6 mg/kg (the chronic data point falls below the acute data point) and at 10.0 mg/kg. Acute administration of 10.0 mg/kg maximized pausing, but after chronic administration of 1.0 mg/kg, some responding occurred in the large ratio component, resulting in so mewhat decreased pausing. When the dose effect functions were reassessed after a period of withdrawal, no changes in the functions occurred for either the small or medium ratio components; however, pausing in the large ratio component, appeared to be mor e sensitive to increasing effects relative to pausing observed during the acute and chronic phases.

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34 In addition to the visual analysis of the curve shifts, changes in pausing across phases can be quantified by obtaining ED 50 values from th e dose response functions. Figure 3 ED 50 values based on the pause data for each FR parameter across conditions. The white, dark, and shaded bars represent the acute, chronic, and withdrawal phases, respectively. Three pigeons (1082, 1163, and 1186) had chronic ED 50 values that were greater than acute ED 50 values in all three increasing effects. For Pigeon 1082, the degree to which tolerance developed after chronic administration and the extent to which it was attenuated after withdrawal was simi lar across components. For Pigeons 1163 and 1186, the degree of tolerance was greater in the small and medium ratio components relative to the large ratio component. For example, the difference between the acute and chronic ED 50 ratio co mponent is much smaller than the difference between the acute and chronic ED 50 in his small ratio tolerance was reversed for this pigeon was inversely related to the degree to which tolerance was modulated by the FR parameter. That is, the difference between the withdrawal ED 50 and both the acute ED 50 and chronic ED 50 was much greater in the small ratio component relative to the other two components. Though tolerance also was related to the FR parameter for Pigeon 1186, its reversibility was not. In fact, tolerance was hardly reduced in the small and medium ratio components and not at all reduced in the large ratio component. For Pigeons 1166 and 1859, tolerance was not o bserved in either the small or medium ratio components, and the ED 50 values across phases were approximately

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35 equal. For both of these pigeons, a hint of tolerance in the large ratio component was evident with the chronic ED 50 being a bit greater than th e acute ED 50 The small amount of tolerance that developed was not reversible, however, for Pigeon 1166 but was for Pigeon 1859. Figure 3 10 displays an analysis that shows consumption, the number of reinforcers earned out of 12 available, as a function o decreasing and pause increasing effects resulted in decreased consumption due to the time limit contingency in each component. Data from individual pigeons are shown in each row, and the FR parameter displayed in each panel denotes the component. Closed circles, open squares, and closed triangles represent data obtained from the acute, chronic, and withdrawal phases, respectively. Each data point represents the mean number of reinforcers earned of at least two determination s at each dose. Some doses were probed more than twice, and the exact number of probes each pigeon received in each phase is reported in Table 2 1. Errors bars represent the range. When administered acutely, 10.0 mg/kg was a large enough dose to either r educe markedly or eradicate consumption in all components for three pigeons (1082, 1163, and 1186). For these pigeons tolerance to cocaine after chronic administration is evidenced by increased consumption. The greatest degree of tolerance occurred at th e smallest FR requirement. For Pigeons 1082 and 1186, tolerance in the small ratio component was substantial they never failed to earn an available reinforcer even at a dose that was higher than a dose that interrupted consumption acutely. A ceiling eff ect occurred for Pigeon 1166 in the small ratio component. Even the largest dose of cocaine did not interrupt consumption acutely; therefore we were unable

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36 to examine any increases in consumption after chronic administration. Tolerance to 17.0 mg/kg in t he medium ratio component was extreme, and all 12 reinforcers were earned after chronic administration of 3.0 mg/kg compared to only 9 earned during acute administration. Some tolerance also is evident in the large ratio component, but to a lesser extent than that observed in the medium ratio component, therefore showing schedule parameter specificity similar to that of Pigeons 1082, 1163, and 1186 For Pigeon 1859, tolerance occurred to effects of 5.6 mg/kg in the small and medium ratio components and to 3.0 mg/kg in the large ratio component. At these doses, the number of reinforcers earned was always high after chronic administration. During acute administration the range of consumption at these doses was much wider. Although mean consumption at c hronic 10.0 mg/kg is lower than mean consumption at acute 10.0 mg/kg in the small and medium ratio components, the range of chronic effects extends beyond the mean of acute effects. In the large ratio component both the acute and chronic range of effect at 5.6 mg/kg are wide. Acutely, the bottom of the range reaches zero, but Pigeon 1859 always earned at least some reinforcers and sometimes earned all reinforcers at 5.6 mg/kg after chronic administration of 1.0 mg/kg. Additionally, there seemed to be a hint of tolerance in the large ratio component even at after chronic administration he earned a reinforcer. For Pigeon 1859, the combined analyses seem to suggest (albeit, we akly) that perhaps some tolerance developed to the 5.6 mg/kg dose. Figure 3 11, therefore, provides a more detailed, reinforcer by reinforcer analysis of the effects of 5.6 mg/kg following chronic administration of 1.0 mg/kg. Response rate and pause are shown on

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37 the y axes for the left panels and right panels, respectively, across successive ratios for the 5.6 mg/kg dose. Recall that each session consisted of 12 possible reinforcement opportunities for each component type, so points between the gaps in t he data paths represent individual sessions prior to which a 5.6 mg/kg probe was administered. Also recall that if a pigeon failed to earn all of the programmed reinforcers within the designated time limit, a component ended. Thus, data paths with fewer than twelve data points indicate that not all of the possible ratios were completed. Phase change lines separate acute dosing from during chronic dosing as well as during chronic dosing from during withdrawal dosing. Additionally, the circle, square, an d triangle data points represent acute, chronic, and withdrawal data, respectively. The FR parameter for each component is displayed in the upper left cor ner of the response rate panels. In the small ratio component, the acute effects of 5.6 mg/kg cocaine decreased response rate in an individual ratio to 1 peck per second or less for more ratios (7 vs. 1) than did that dose after chronic administration. A similar, but less dramatic, pattern also occurred in the small ratio component analysis of pausing. T hat is, there are more instances of long pausing in the acute phase relative to the chronic phase. Given that the withdrawal observations tend to be distributed between the range of acute and chronic effects, tolerance appeared to have been slightly atten uated following a period of drug withdrawal. In the medium ratio component, though responding only sometimes was disrupted or eliminated in the acute phase, response rates never were eliminated by 5.6 mg/kg during chronic probing. Pause increases induced by 5.6 mg/kg also tended to be more variable and longer in duration in the acute phase relative to pausing observed in the chronic phase. After withdrawal, tolerance was attenuated for the rate

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38 measure, yet not for the pause measure. In the large ratio c omponent, tolerance failed to develop to either rate decreasing or pause increasing effects of 5.6 mg/kg. Curiously, following withdrawal, rate and pausing were more sensitive to the effects of 5.6 mg/kg relative to both the acute and chronic phases durin g the first probe determination and less sensitive during the second probe determination. The overall impression from this analysis is that modest tolerance was evident in the two smaller ratio components, but not in the large ratio component.

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39 Ta ble 3 1 pause dose effect functions shown in Figures 3 6 and 3 8.

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40 Figure 3 1. Response rate, expressed as pecks per second, and pause, expressed in seconds, as a function of cocaine dose for Pigeon 1082 for each FR parameter in the multiple schedule. The maximum value on the Y axes for pause data indicate the arbitrary maximum possible average pause value for a component. Each data poin t is the mean of at least two probe determinations, and error bars denote the range of effects. Circles, squares, and triangles represent data obtained in the acute, chronic, and withdrawal phase, respectively.

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41 Figure 3 2. Response rate, expressed as pecks per second, and pause, expressed in seconds, as a function of cocaine dose for Pigeon 1163 for each FR parameter in the multiple schedule. Details are the same as those for Figure 3 1.

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42 Figure 3 3. Respon se rate, expressed as pecks per second, and pause, expressed in seconds, as a function of cocaine dose for Pigeon 1166 for each FR parameter in the multiple schedule. Details are the same as those in Figure 3 1.

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43 Figure 3 4. Response rate, expressed as pecks per second, and pause, expressed in seconds, as a function of cocaine dose for Pigeon 1186 for each FR parameter in the multiple schedule. Details are the same as those in Figure 3 1.

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44 Figure 3 5. Response rate, expressed as pecks per second, and pause, expressed in seconds, as a function of cocaine dose for Pigeon 1859 for each FR parameter in the multiple schedule. Details are the same as those in Figure 3 1.

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45 Figure 3 6. Dose effect functions fit to the mean response rate data for indi vidual details about fitting. Open circles and dashed curves represent acute data. Closed squares and solid curves represent chronic data. Closed triangles and solid curves represent withdrawal data.

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46 Figure 3 7. ED 50 values obtained from the fitted dose effect functions for response rate. Each panel represents an individual pigeon. White, black, and grey bars represent acute, chronic, and withdrawal phases, respectively.

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47 Figure 3 8. Dose effect functions fit to the mean post reinforcement pause data for circles and dashed curves represent acute data. Closed squares and solid curves represent chro nic data. Closed triangles and solid curves represent withdrawal data.

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48 Figure 3 9. ED 50 values obtained from the fitted dose effect functions for pausing. Each panel represents an individual pigeon. White, black, and grey bars represent acute, chr onic, and withdrawal phases, respectively.

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49 Figure 3 10. The number reinforcers earned out of the 12 possible as a function of by column). Each data point is the mean of at l east two probe determinations, and error bars denote the range of effects. Filled circles represent data obtained in the acute phase, open squares represent data obtained in the chronic phase, and filled triangles represent data obtained in the withdrawal phase.

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50 Figure 3 11. Response rate, expressed in pecks per second, and post reinforcement pause, expressed in seconds, as a function of successive ratios under 5.6 mg/kg probes for Pigeon 1859. FR parameters for each component are displayed by row. P hase change lines separate the acute (circle data points), chronic (square data points), and withdrawal (triangle data points) conditions. Gaps in the data path represent sessions intervening between 5.6 mg/kg probe administrations.

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51 CHAPTER 4 DISCUSSION The purpose of the present experiment was to determine whether tolerance decreasing and pause increasing effects and, if it did, whether the degree of tolerance developed differentially across FR parameters. To do so, we arrang ed a three component multiple FR schedule of food reinforcement, and the effects of a series of doses of cocaine (i.e., response rate and pause) were assessed before, during, and after chronic pre session administration of a low dose that produced no chang Following chronic administration, 4 of 5 pigeons demonstrated decreased sensitivity to doses of cocaine that acutely produced diminution, and even elimination, of responding, and following a withdrawal period, tolerance was reversed entirely or attenuated. For 1 pigeon the extent to which tolerance developed was markedly less pronounced relative to the other pigeons. Nonetheless, an overall pattern revealed the degree of tolerance was invers ely related to the FR requirement, with tolerance generally being greater as the FR requirement decreased for all pigeons. Acute cocaine administration produced dose dependent decreases in responding across all three components of the multiple schedule, a finding that is consistent with those obtained in other studies employing FR arrangements either as a multiple schedule or a single schedule (e.g., Hoffman et al., 1987; Hughes & Branch, 1991; Pinkston & Branch, 2004; Schaal, Miller, & Odum, 1995; Staffor d & Branch, 1996). Follow acute cocaine administration, within and across session responding remained stable throughout chronic cocaine administration of the behaviorally inactive dose, which further supported the declaration made during acute probing (co nsisting of just

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52 1859, 3.0 for Pigeons 1163, 1166, and 1186, and 5.6 mg/kg for Pigeon 1082). Had we assessed the effects of doses between 1.0 and 3.0 mg/kg for Pige on 1859 during acute probing, we may have been able to identify a behaviorally inactive dose greater than 1.0 mg/kg. Chronic administration of said hypothetical dose may have occasioned more apparent and convincing tolerance comparable to that observed wit h the other 4 pigeons. Thus, parametric assessment of the behaviorally inactive dose (and, relatedly, duration of the chronic administration phase) certainly is worthy of future investigation. To our knowledge, this is the first demonstration of tolerance to behavioral effects of larger doses of cocaine following chronic pre session administration of a behaviorally inactive dose. Bowen et al. (1993) assessed tolerance to the suppressive effec t of cocaine on a milk drinking task in rats using a low, moderate, or high dose. They found that dose specific tolerance developed to effects of the low dose, but it failed to generalize during administration of higher probe doses. Note that because to lerance developed with the low dose, it could not have been behaviorally inactive. Furthermore, the tolerance observed in our experiment compellingly was not dose specific. Rather, when we probed for tolerance by occasionally substituting higher doses for the chronic dose, tolerance was evident at a range of higher doses, inconsistent with findings reported by Bowen et al. Our findings confirm and extend the results reported by both Stafford and Branch (1996) and Pinkston and Branch (2004). Whereas Stafford and Branch demonstrated that chronic pre disrup tive effects on responding maintained by an FR 30 schedule of reinforcement,

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53 Pinkston and Branch arranged a multiple FR 5 FR 100 schedule and demonstrated that tolerance developed following chronic pre session administration of a low dose. The effect repo rted by Pinkston and Branch occurred only for 3 of 6 pigeons, all of which previous had been exposed to a chronic post session administration condition. Their pigeons not only had a history of drug administration, but also the low dose was selected for pr e session administration because it had no effect on within session response when post session administrations were administered acutely. By the end of chronic post session administration of the low dose, within and across session response rates no long er were identical to control response rates. Response rates had decreased in either the small or large ratio component for 4 of 7 pigeons. Thus, the changes observed as a result of chronic post session administration indicate that the dose may have had some behavioral action that became apparent only during repeated administration. In our experiment we were able to demonstrate that pre session administration of a behaviorally inactive dose did not affect response rates across chronic administration ses sions. When administration of the chronic dose was withdrawn, and saline was administered chronically, response rates persisted at relatively stable levels (i.e., did not change). Additionally, we found that the degree of tolerance often depended on the FR parameter, consistent with previous studies showing that the response requirement is a key determinant of the development of tolerance. That is, tolerance generally is limited to responding under small ratio components, and not under large ratio compo nents, of a multiple schedule (Branch, 1990; Hoffman et al., 1987; Hughes & Branch, 1991; Nickel & Poling, 1990; Nickel et al., 1993; Pinkston & Branch, 2004; Van Haaren & Anderson,

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54 1994; Yoon & Branch, 2004). A noteworthy feature of the present data was that for 4 of 5 pigeons, some degree of tolerance developed in the large ratio component. For example, for Pigeons 1082, 1163, 1186 moderate tolerance developed in that component to the effects 10.0 mg/kg evidenced by response rate means, upper ranges, or both that are comparable to control and saline levels of responding. Tolerance failed to develop to the effects of 13.0 mg/kg (1082 and 1186) or 17.0 mg/kg (1163) in the large ratio component; the same was not true in the small ratio component, however. Similarly, for Pigeon 1163 some tolerance to the effects of 5.6 mg/kg but not 10.0 mg/kg was evident in the large ratio component, even though tolerance occurred to the effects of 10.0 mg/kg in the small ratio component. It would be premature to conclud e that lesser tolerance observed in the large ratio components implicates FR 125 (for Pigeons 1082, 1166, and 1186), FR 80 (for Pigeon 1163), and FR 45 (for Pigeon 1859) as upper limits of response requirements beyond which tolerance becomes increasingly u nlikely to occur. Rather, it is more probable that tolerance was least evident in the large ratio components due the context of the multiple schedule. For instance, it is unknown whether and the degree to which tolerance would dec reasing effects on responding under a single FR 125, FR 80, or FR 45 schedule following chronic administration of a behaviorally inactive dose. Smith (1986) clearly demonstrated the effect of context on tolerance. In his study, rats pressed a lever unde r a multiple differential reinforcement of low rates (DRL) random ratio (RR) schedule. Administration of amphetamine increased rates under the DRL component and decreased rates under the RR component, resulting in a decreased rate of reinforcement in both components. During chronic administration

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55 tolerance occurred in the RR component but not in the DRL component. Chronic amphetamine administration under a DRL schedule alone, after the RR component was removed from the procedure, however, did engender to lerance to the rate increasing effects of amphetamine. Smith noted that in the multiple schedule context, when both schedules alternated, the drug induced loss of reinforcement was proportionally much greater in the RR component relative to that in the DR L component, and he concluded that is why tolerance developed only in the RR component. That is, little to no tolerance occurred in the DRL component because the rats were adjusting and allocating their behavior to compensate for the proportionally greate r reinforcement loss in the RR component. When the DRL component was presented independently from the RR context, tolerance did develop in the DRL schedule. Presumably the dissociation between DRL responding tolerance in a single but not multiple schedul e materialized because the loss of reinforcement no longer was relative to an additional context. Under the DRL alone condition, the rats behaved efficiently by adjusting response rates and recouping the drug induced reinforcement loss. Perhaps the most st riking feature of the present findings is that tolerance developed despite no apparent loss, or even reduction, of reinforcement rate in any of the FR components during chronic administration of the small dose. Such a finding cannot be accounted for by th e long standing, widely supported explanation for behavioral tolerance known as the reinforcement loss hypothesis (Schuster et al., 1966), which asserts that tolerance is an adaptive mechanism allowing an organism to adjust its behavior to compensate for t he decreased rate of reinforcement in the presence of drug effects. The reinforcement loss hypothesis is silent with respect to

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56 the development of tolerance when there is no evidence of disruption during chronic administration. One could argue the pige ons in the present experiment rapidly adjusted to the loss of reinforcement during acute administration of larger doses. Such a position would suggest that upon repeated tests with a particular dose during acute administration, second and subsequent admin istrations should reveal effects consistent with the development of tolerance. No such effects were observed. Although the chronic dose never disrupted behavior such that rate of reinforcement was altered (i.e., responding under the chronic dose was indi stinguishable from control responding), we cannot dismiss entirely the role of reinforcement rate. At least in some senses, reinforcement rate still may be relevant in an interpretation of the present data. Because FR schedules were employed, reinforceme nt rate in a given component depended on response rates: increased responses rates proportionally increase the reinforcement rate. Across components, even if response rates were equivalent, reinforcement rates differed because of the differences in respon se requirement (e.g., completing an FR 125 requires more time than does completing an FR 5). Under baseline conditions, response rate was highest in the medium ratio component and lowest in the large ratio component. Responding under ratio schedules is known to increase and then decrease with increases in response requirement (e.g., Baum, 1993). If baseline response rates are conceptualized as strength of the response, and acute cocaine administration disrupts responding, then we should have observed th e greatest and least relative reduction in rates to occur in the large and medium ratio components, respectively. Behavioral

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57 momentum theory (Nevin, 1974), however, asserts that behavior in the context of higher reinforcement rates, by virtue of stimulu s reinforcer pairings, will be more resistant to change upon subsequent presentation of disruptor variables, independent of baseline response rates (i.e., response reinforcer pairings). This perspective seems to provide a better account for the present d ata in that the obtained reinforcement rate was greatest in the small ratio component and responding under this component also was case that the greatest degree of to lerance will occur in contexts that engender the least initial disruption of responding. That is, behavioral momentum may be predictive of subsequent tolerance. Nevertheless, two caveats are noteworthy here. First, both Branch ( 1990 ) and Schama and Bran ch ( 1989 ) did not find a systematic relationship between differential reinforcement rates and the degree to which tolerance developed across components of multiple schedules. Second, response strength indexed using pharmacological disruptors often produce s different effects than when traditional disruptors, such as extinction and prefeeding, are employed (Cohen, 1986). Overall, tolerance generally was greatest in the components with smaller ratios, and f ollowing a withdrawal phase, tolerance was usually diminished. These results could occur by chronic low dose administration. Moreover, our results demonstrate that under these conditions, repeated exposure to the delet erious effects of cocaine on food maintained responding is not a necessary factor in the development of tolerance. At first glance, it is tempting to explain the tolerance obtained in the present study by pointing to physiological and pharmacological mech anisms given that we were unable

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58 to track the emergence of tolerance across sessions during chronic administration. The use of a behaviorally inactive dose obstructed observable changes in behavior during chronic administration, and we only were able to d etermine that tolerance had occurred via occasional probing with higher doses. The use of the multiple schedule allowed us to demonstrate that tolerance was not equal across components, therefore, metabolic or physiological changes alone cannot explain ou r results. Identification and parametric assessment of other conditions under which the reinforcement loss hypothesis fails to account for behavioral tolerance should be the focus of future research. A question that was not addressed by the present data was whether an injection of the behaviorally inactive dose was discriminable from an injection of saline. Empirically addressing questions of this nature could prove fruitful in contributing to and enhancing the understanding of potential interactions bet ween physiological and behavioral mechanisms of drug tolerance.

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59 LIST OF REFERENCES Barrett, J. E. (1976). Effects of alcohol, chlordiazepoxide, cocaine and pentobarbital on responding maintained under fixed interval schedules of food or shock pr esentation. Journal of Pharmacology and Experimental Therapeutics, 196 605 615. Bowen, S. E., Fowler, S. C., & Kallman, M. J. (1993). Effects of variation in chronic dose of cocaine on contingent tolerance as assessed in a milk drinking task. Psychopharm acology, 113 67 75. Branch, M.N. (1990). Cocaine tolerance: Interactions among random ratio and random interval reinforcement schedule parameters and repeated exposure to cocaine. Drug Development Research, 20 19 30. Branch, M.N., & Dearing, M.E. (1982). Effects of acute and daily cocaine administration on performance under a delayed matching to sample procedure. Pharmacology, Biochemistry and Behavior, 16 713 718. Branch, M.N., Walker, D. J., & Brodkorb, G.W. (1999). Attenuation of cocaine induced res ponse rate increases during repeated administration despite increases in rate of reinforcement. Psychopharmacologia, 141 413 420. Branch, M.N, Wilhelm, M.J., & Pinkston, J.W. (2000). A comparison of fixed and variable doses of cocaine in producing and aug menting tolerance to its effects on schedule controlled behavior. Behavioral Pharmacology, 11 555 569. Baum, W. M. (1993). Performances on ratio and interval schedules of reinforcement: Data and theory. Journal of the Experimental Analysis of Behavior, 59 245 264. Carlton, P.L., & Wolgin, D.L. (1971). Contingent tolerance to the anorexigenic effects of amphetamine. Physiology and Behavior, 7 221 223. Cohen, S. L. (1986). A pharmacological examination of the resistance to change hypothesis of respons e strength. Journal of the Experimental Analysis of Behavior, 46 363 379. Demellweek, C., & Goudie, A. J. (1982). The role of reinforcement loss in the development of tolerance to amphetamine anorexia. IRCS Medical Science, 10 903 904. Dews, P. B. (195 5). Studies on behavior. I. Differential sensitivity to pentobarbital of pecking performance in pigeons depending on the schedule of reward. Journal of Pharmacology and Experimental Therapeutics, 113 393 401. Dews, P. B. (1958). Analysis of effects of ps ychopharmacological agents in behavioral terms. Federation Proceedings, 17 1024 1030.

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61 Johanson, C.E. (1978). Effec ts of intravenous cocaine, diethylpropion, d amphetamine and perphenazine on responding maintained by food delivery and shock avoidance in rhesus monkeys. Journal of Pharmacology and Experimental Therapeutics, 204 118 129. Kelleher, R. T., & Morse, W. H. (1964). Escape behavior and punished behavior. Federation Proceedings, 23, 808 817. Kelleher, R. T., & Morse, W. H. (1968). Determinants of the specificity of behavioral effects of drugs. Ergebnisse der Physiologie, Biologischen Chemie, und Experimentelle n Pharmakologie, 60, 1 56. Laties, V. (1972). The modification of drug effects on behavior by external discriminative stimuli. Journal of Pharmacology and Experimental Therapeutics, 183 1 13. Nevin, J. A. (1974). Response strength in multiple schedules. Journal of the Experimental Analysis of Behavior, 54 163 172. MacPhail, R. C., & Seiden, L. R. (1975). Time courses for the effects of cocaine on fixed ratio water reinforced responding in rats. Psychopharmacologia, 44 1 4. Makhay, M., Alling, K., & Po ling, A. (1994). Effects of cocaine on fixed ratio responding of rats: Modulation by required response force. Pharmacology, Biochemistry, and Behavior, 48, 511 514. Marusich, J. A., & Branch, M. N. (2009). Environmental and pharmacological factors in the development of noncontingent tolerance to cocaine in pigeons. Experimental and Clinical Psychopharmacology, 17, 266 282. McMillan, D. E. (1969). Effects of d amphetamine on performan ce under several parameters of multiple fixed ratio, fixed interval schedules. The Journal of Pharmacology and Experimental Therapeutics, 167, 26 33. National Institute on Drug Abuse. (Revised 2010, September). NIDA research report: Cocaine abuse and add iction (NIH Publication No. 10 4166). Rockville, MD: National Clearinghouse on Alcohol and Drug Information. Nickel, M., Alling, K., Kleiner, M., & Poling, A. (1993). Fixed ratio size as a determinant of tolerance to cocaine: Is relative or absolute size i mportant? Behavioural Pharmacology, 4, 471 478. Palya, W. L., & Walter, D. E. (1993). A powerful, inexpensive experiment controller or IBM PC interface and experiment control language. Behavior Research Methods, Instruments & Computers, 25 127 136. Pinks ton, J, W., & Branch, M. N. (2004). Repeated post or presession cocaine administration: Roles of dose and fixed ratio schedule. Journal of the Experimental Analysis of Behavior, 81 169 188.

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62 Pinkston, J.W., & Branch, M.N. (2010). Acute and chronic effec ts of cocaine on the spontaneous behavior of pigeons. Journal of the Experimental Analysis of Behavior. 94 25 36. Pinkston, J. W., Ginsburg, B. C., & Lamb, R. J. (2009). Examination of reinforcement magnitude on the pharmacological disruption of fixed ratio performance. Experimental and Clinical Psychopharmacology, 17, 237 246. Poling, A., & Nickel, M. (1993). Fixed ratio size as a determinant of the development of tolerance to morphine. Behavioral Pharmacology, 1 436 467. Ross, L., & Schaal, D. W. (2002). Time of supplemental feeding alters the effects of cocaine on lever pressing of rats. Journal of the Experimental Analysis of Behavior, 77, 199 208 Salisbury, J. J., & Wolgin, D. L. (1985). Role of anorexia and behavioral activation in amphetamine induced suppression of feeding: Implications for understanding tolerance. Behavioral Neuroscience, 99 1153 1161. Schaal, D. W., & Branch, M. N. (1992). Changes due to food deprivation in the effects of cocaine on the responding of pigeons. Behavioural Pharmacology, 3, 5 9. Schaal, D. W., Miller, M. A., reinforced pecking in pigeons depend on food deprivati on level. Journal of the Experimental Analysis of Behavior, 64 61 73. Schama, K. F., & Branch, M. N. (1989). Tolerance to effects of cocaine on schedule controlled behavior: Effects of fixed interval schedule parameter. Pharmacology, Biochemistry, and Beh avior, 32, 267 274. upon repeated administration. Journal of the Experimental Analysis of Behavior, 62 45 56. Schuster, C. R. (1978). Theoretical basis of behavioral to lerance: Implications of the phenomenon for problems of drug abuse. In Krasnegor, N. A. (Ed.), Behavioral Tolerance: Research and Treatment Implications, National Institute Drug Abuse Research Monograph (pp. 4 17), Washington, DC: U.S. Government Printing Office. Schuster, C. R., Dockens, W. S., & Woods, J. H. (1966). Behavioral variables affecting the development of amphetamine tolerance. Psychopharmacologia, 9, 170 182. Schuster, C. R., & Zimmerman, J. (1961). Timing behavior during prolonged treatment with dl amphetamine. Journal of the Experimental Analysis of Behavior, 4 327 330.

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64 Yoon, J.H., & Branch, M.N. (2004). Interactions among unit price, fixed ratio value, and dosing regimen in determining effects of repeated cocaine administrat ion. Behavioural Processes, 67, 363 381.

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65 BIOGRAPHICAL SKETCH Vanessa Minervini grew up in Pawleys Island SC where s he attended Waccamaw High School and graduated in the top 5 of her class Upon graduation, s he was admitted to the College of Charleston Honors College where she completed her undergraduate studies supported by the Palmetto Fellows and South Carolina Life scholarships Sh e graduated in 2010 with a Bachelor of Science in psychology and a minor in h ealth. The focus of her w as food demand elasticity as a function of session duration in rats Vanessa pursued her interested in the experimental analysis of behavior by enter ing a doctoral program in p sychology at the University of Florida Vanessa ay 2013 from the University of Florida and plans to continue her career in academia by finishing her doctorate completing post doctoral training, and obtaining a faculty position at a research institution.