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Interactions Among Unit Price, Fixed-Ratio Value, and Dosing Regimen in Determining Effects of Repeated Cocaine Administ...


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INTERACTIONS AMONG UNIT PRICE, FIXED-RATIO VALUE, AND DOSING REGIMEN IN DETERMINING EFFE CTS OF REPEATED COCAINE ADMINISTRATION By JIN HO YOON A THESIS PRESENTED TO THE GRADUATE SCHOOL OF THE UNIVERSITY OF FLOR IDA IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF MASTER OF SCIENCE UNIVERSITY OF FLORIDA 2003

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Copyright 2003 by Jin Ho Yoon

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This document is dedicated to my grandfather.

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ACKNOWLEDGMENTS I thank my family and friends who have supported me all this time. iv

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TABLE OF CONTENTS Page ACKNOWLEDGMENTS.................................................................................................iv LIST OF TABLES............................................................................................................vii LIST OF FIGURES.........................................................................................................viii ABSTRACT.......................................................................................................................ix CHAPTER 1 INTRODUCTION............................................................................................................1 2 EXPERIMENT 1..............................................................................................................7 Methods........................................................................................................................7 Subjects..................................................................................................................7 Apparatus...............................................................................................................7 Hopper and Keypecking Training.........................................................................8 FR Shaping............................................................................................................9 Baseline...............................................................................................................10 Drugs and Drug Administration Procedure.........................................................11 Acute Dosing (Acute)..........................................................................................11 Chronic Variable-Dosing with Same Unit Price (SUP1)....................................12 Results.........................................................................................................................13 Dose-Response Functions...................................................................................13 Unit Price.............................................................................................................15 Discussion...................................................................................................................16 3 EXPERIMENT 2............................................................................................................24 Method........................................................................................................................24 Subjects and Apparatus.......................................................................................24 Chronic Variable-Dosing with Different Unit Price (DUP)................................24 Chronic Variable-Dosing with Same Unit Price (SUP2)....................................24 Results.........................................................................................................................25 Dose-Response Functions...................................................................................25 Unit Price.............................................................................................................26 Discussion...................................................................................................................26 v

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4 EXPERIMENT 3............................................................................................................32 Method........................................................................................................................32 Subjects nd Apparatus.........................................................................................32 Chronic Fixed-Dosing with Same Unit-Price (FIX1).........................................32 Chronic Fixed-Dosing with Same Unit-Price and Lower Chronic Dose (FIX2)32 Results.........................................................................................................................33 Dose-Response Functions...................................................................................33 Unit Price.............................................................................................................34 Discussion...................................................................................................................34 5 GENERAL DISCUSSION.............................................................................................38 LIST OF REFERENCES...................................................................................................41 BIOGRAPHICAL SKETCH.............................................................................................43 vi

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LIST OF TABLES Table page 1. Acute administrations......................................................................................19 2. Chronic variable dosing...................................................................................19 3. ED50 values.....................................................................................................22 vii

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LIST OF FIGURES Figure page 1. Dose-response functions Experiment 1...........................................................20 2. Dose-response functions as a proportion of saline Experiment 1....................21 3. Unit price Experiment 1...................................................................................23 4. Dose-response functions as a proportion of saline Experiment 2....................29 5. Dose-response functions as a proportion of saline Experiment 2....................30 6. Unit price Experiment 1...................................................................................31 7. Dose-response functions as a proportin of saline Experiment 3......................36 8. Unit price Experiment 3...................................................................................37 viii

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Abstract of Thesis Presented to the Graduate School of the University of Florida in Partial Fulfillment of the Requirements for the Degree of Master of Science INTERACTIONS AMONG UNIT PRICE, FIXED-RATIO VALUE, AND DOSING REGIMEN IN DETERMINING EFFECTS OF REPEATED COCAINE ADMINISTRATION By Jin Ho Yoon May 2003 Chair: Marc N. Branch Major Department: Psychology Three experiments examined effects of repeated administration of cocaine to pigeons. The pigeons were trained to key peck under a three-component multiple schedule of food presentation according to which either 10, 30, or 100 pecks were required for each delivery of food. In Experiment 1, time of access to food was correlated with the number of pecks required so that unit price (pecks per second of access to food) was equated. After assessing effects of a range of doses of cocaine administered once per week, drug administration occurred daily before each session, with the dose varying from day to day. Tolerance, the magnitude of which was unrelated to the peck requirement, developed under the repeated-dosing regimen. In Experiment 2, daily drug administration continued using the variable-dose regimen, but the amount of food presented each time was fixed, yielding different unit prices under the three pecking requirements. Subsequently, the conditions of Experiment 1 were reinstated, i.e., unit price was equated. Making unit price different and then the same again had little ix

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influence on effects of cocaine. In Experiment 3, a fixed dose of cocaine was administered before each session. Under these conditions, tolerance became peck-requirement related. Tolerance was most prevalent under the smaller requirements and less robust or absent when the largest requirement was in effect. Differences in unit price, therefore, were not related to degree of tolerance, but work requirement was. Differences in effects of cocaine across responses requirements, however, were observed only when each session was preceded by the same dose, not when dose varied from session to session. x

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CHAPTER 1 INTRODUCTION Descriptively, tolerance refers to an attenuation of the initial effects of a drug, following repeated or prolonged exposure, such that increased dose is required to recapture the initial effect (Corfield-Sumner & Stolerman, 1978; Wolgin, 1989; Hardman, Gilman, & Limbird, 1995). The term tolerance may also be used mechanistically, and several mechanisms have been suggested. For example, one suggestion has been that tolerance is mediated through some form of behavioral compensation (Demellweek & Goudie, 1983; Wolgin, 1989). This line of interpretation has emanated largely from research that follows upon a method introduced by Chen (1968). His study described a useful procedure for assessing the potential role of instrumental learning in the development of tolerance, and the procedure suggested a behavioral mechanism of tolerance. Two groups of rats received daily administrations of alcohol. Subjects received reinforcement (i.e., bits of spaghetti) for completing a two-turn circular-maze task. The Before Group received drug prior to each session while the After Group received drug following the session. Disruption in maze running was observed in the Before Group when the rats first received the drug. No effect of receiving repeated administrations of post-session drug was observed in the After Group. Tolerance, as demonstrated by a return to baseline levels of reinforcement following several exposures to alcohol and the testing situation, was observed to the initial disruptive effects of pre-session drug in the Before Group. Once tolerance in the Before Group was observed, the After Group began receiving drug prior to sessions for the first 1

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2 time while the Before Group continued to receive drug immediately prior to sessions. Subjects in the After Group showed no tolerance when this regimen began. If the development of tolerance was solely dependent on drug exposure alone, performance in the After Group should have been indistinguishable from that of the Before Group since both groups had received an equal number of administrations of the drug. Instead, performance in the After Group resembled that of the Before Group receiving pre-session drug for the first time. The development of tolerance therefore depended upon the time of drug administration in relation to the behavioral task and not simply drug exposure alone. This type of tolerance has been described as contingent tolerance (Carlton & Wolgin, 1971). Differences in performance between the two groups were attributed to differences in behavioral experience. One plausible interpretation of contingent tolerance is that the initial loss of reinforcement due to drug administration promoted the Before Group to engage in some form of behavioral compensation, whereas animals in the After Group experienced no loss of reinforcement during the period of post-session administration and had no opportunity to develop behavior that would compensate for the loss occasioned by pre-session administration. The role of reinforcement loss in the development of tolerance was first suggested in an experiment conducted by Schuster, Dockens, and Woods (1966). Three rats were used as subjects. Subjects received administrations of amphetamine immediately prior to exposure to a two-component multiple schedule. One component provided differential reinforcement for low rates of responding (DRL) while the other delivered reinforcement on a fixed-interval (FI) schedule. Effective doses of amphetamine resulted in rate increases in both components for two rats, which resulted in decreased rates of

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3 reinforcement in the DRL component. Decreases in rate across both components were observed for the third subject, which resulted in loss of reinforcement in the FI component. After repeated administrations of 1.0 mg/kg of drug, tolerance to the initial effects of amphetamine was observed for all subjects only in the components in which an initial loss of reinforcement had been observed. Similar effects have been observed in a wide variety of experiments (see Corfield-Sumner & Stolerman, 1978 and Wolgin, 1989 for reviews). The view that tolerance to the behavioral effects of drug depends on the initial effect of drug on reinforcement received has been coined as the reinforcement-loss hypothesis (Corfield-Sumner & Stolerman, 1978). Some qualifications for the development of differential tolerance according to the reinforcement-loss hypothesis were suggested in a study conducted by Smith (1986a). Smith investigated the effects of amphetamine on responding in rats on a multiple random-ratio (RR) DRL schedule of reinforcement. Initially, amphetamine caused decreased rates of responding in the RR component and increased rates of responding in the DRL component, resulting in loss of reinforcement in both components. Tolerance during repeated exposure to amphetamine was observed only in the RR component. Tolerance, however, did develop in the DRL component when it was presented alone, and that tolerance subsequently disappeared when the RR component was reintroduced. The results suggest that tolerance in a situation can depend on the context in which that situation appears. Specifically, the author noted that tolerance could be influenced by global reinforcement rates. The loss of reinforcement in the DRL schedule might have been relatively insignificant when compared to the overall rate of reinforcement when the

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4 RR schedule was present, as opposed to when the DRL schedule was the only one available. An example of differential tolerance that depended on reinforcement-schedule type was demonstrated in research conducted by Hoffman, Branch, and Sizemore (1987). Pigeons were placed on a three-component multiple fixed-ratio (FR) schedule of reinforcement. Pigeons were exposed to a multiple FR 5 FR 25 and either FR 125 or 50. Initial exposure to various doses of pre-session cocaine resulted in dose-dependent decreases in rates of responding across all three components. After chronic administration of pre-session cocaine, dose-response functions were reassessed. Generally, more tolerance to the initial rate-decreasing effects of cocaine was observed in the small and medium sized FR components, and little if any tolerance was observed in the large FR component. Other research has also identified parameter-specific tolerance in the context of multiple FR schedules (e.g., Hughes & Branch, 1991; Nickel, Alling, Kleiner, & Poling, 1993). In these studies, as well as that of Hoffman et al., less tolerance was observed in the largest FR component, which had a lower rate of reinforcement when compared to that of the small and medium FR components. Thus, one possible interpretation is that the development of tolerance is influenced by rate of reinforcement. A view of tolerance based on relative baseline rates of reinforcement, however, cannot explain the results of a follow-up experiment to the Hoffman et al. study conducted by Schama and Branch (1989). Pigeons were exposed to a multiple fixed-interval (FI) schedule of food reinforcement. The FI values (i.e., 5s, 30s, and 120s) approximated the average inter-reinforcement times observed in the Hoffman et al.

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5 experiment. Dose-dependent decreases in rates of responding to the initial administrations of pre-session cocaine were observed for all subjects across the three FI components, a result similar to that seen by Hoffman et al. Unlike the Hoffman et al. study, however, similar levels of tolerance to the initial rate-reducing effects of pre-session cocaine for a given subject were observed across the different components after chronic administration of pre-session cocaine. That is, tolerance did not depend on the schedule parameter, and therefore not on reinforcement rate. Schama and Branch suggested an alternative possibility. One difference between the Schama and Branch study and the Hoffman et al. experiment was the number of required responses for reinforcement to be delivered. In an FR schedule, the number of responses required for reinforcement delivered is simply the ratio value. In an FI schedule, however, only 1 response is required for reinforcement to be delivered. Schama and Branchs suggestion that response requirement might be important in producing schedule dependent tolerance points to a more thorough analysis of response requirement. One method that has been utilized to quantify the relationship between response requirement and reinforcement is the concept of unit price, a term borrowed from micro-economics (see Bickel, Green, & Vuchinich, 1995; DeGrandpre, Bickel, Hughes, Laying, & Badger, 1993 for reviews). Unit price refers to the cost-benefit ratio, which can be interpreted as the response effort divided by the reinforcement magnitude. From a unit-price perspective, the various FI components in the Schama and Branch study all had the same unit price. Unit price in the Hoffman et al. experiment, however, was different for each component; since the same amount of reinforcement was delivered regardless of the size of the ratio completed, unit price increased with FR size. A

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6 possible account of the differences in outcomes of the two studies therefore is that they reflect the effects of differences in unit price. The purpose of the current experiment was to investigate explicitly the relation between unit price and parameter-specific tolerance under FR schedules.

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CHAPTER 2 EXPERIMENT 1 Methods Subjects Six adult, male White Carneau pigeons maintained at 80% of their free-feeding weights served as subjects. All subjects were both experimentally and drug nave prior to the start of the experiment. Between experimental sessions, the pigeons were individually housed in a temperature-controlled colony room with a 16:8 hr light/dark cycle. While in the home cages, pigeons had continuous access to vitamin-enriched water and health grit. Apparatus Sessions were conducted in an operant-conditioning chamber for pigeons. The inside of the chamber was 30 cm wide, 36 cm tall, and 35.5 cm deep. The ceiling and walls were painted white except for the work panel, which was brushed aluminum. Chamber illumination was provided by a 1.1-W, 28-VDC lamp (houselight) that was horizontally centered on the work panel and located 2 cm below the chamber ceiling. An aluminum shield below the bulb deflected light towards the ceiling. In addition to the houselight, the work panel was equipped with 3 circular, horizontally aligned response keys and an aperture through which food could be made available. Each response key was 2.5 cm in diameter and located 8.5 cm from the chamber ceiling. Each response key could be transilluminated. Only the center response key was used, and it could be transilluminated yellow, green, or red by 1.1-W, 28-VDC lamps. A static force of 0.11 N 7

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8 registered as a response. Responses on the illuminated center response key resulted in a 30-ms tone. Responses were recorded with a Gerbrands Model C-3 cumulative-response recorder, which provided continuous recording of responses. The cumulative recorder was paused during grain deliveries. Mixed grain was made available via a food aperture that was located below the center key and 11 cm from the chamber floor. The food aperture was 6 cm wide and 5 cm tall. When grain was available, the houselight and keylight were off, and the food aperture was illuminated by a 1.1-W, 28-VDC lamp. Head-in-hopper time was measured with a MED Associates Single Channel I/R Source, Detector, and Control. The device generated an infrared beam across the opening of the food aperature. Entries and exits into and out of the food aperture were detected by breaks in the photobeam. A steel mesh covered the chamber floor, and a ventilation fan, located on the back wall, operated during the entire session. White noise of approximately 95 dB was also continuously present in the room that housed the experimental chamber. A half-silvered glass, 21 cm by 24 cm, in the door of the chamber allowed observation of the pigeon. Events were controlled and data collected by a dedicated computer system (Walter & Palya, 1984). Hopper and Keypecking Training Pigeons were initially trained to eat from the food hopper. Hopper training was completed in a single session for each subject. A modified autoshaping procedure (Brown & Jenkins, 1968) was then implemented in order to establish pecking on the white response key. Sessions were preceded by a 5-min blackout during which all lights in the chamber were turned off and no programmed contingencies were in effect. Sessions began with all lights in the chamber turned off. Access to grain was presented on a fixed-time (FT) 1-min schedule. Each 3-s hopper presentation was preceded by an 8

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9 s illumination of the response key by yellow and the houselight. If a peck did not occur on the illuminated keylight, the session was concluded after 30 hopper presentations on the FT 1-min schedule. All hopper presentations were accompanied by illumination of the hopper aperture and all other chamber lights were extinguished. If a peck occurred on the illuminated response key, 3 s of access to grain was presented immediately. Subsequently, the houselight and keylight were turned on, and food was presented on a fixed-ratio (FR) 1 schedule for 50 food presentations. Pecking on the illuminated response key was not observed for two subjects (i.e., 46 and 435) after 8 sessions of the autoshaping procedure. Therefore, shaping via reinforcement of successive approximations (cf. Ferster, 1953) was implemented. Pecking was subsequently observed for both of these subjects after 1 session of shaping. FR Shaping All subsequent sessions continued to be preceded by a 5-min blackout and began with illumination of the houselight and response key. Once responding on the yellow response key reliably occurred on an FR 1 schedule of reinforcement for two consecutive sessions, the response requirement was gradually increased both within and across sessions utilizing the following FR values: 2, 3, 4, 5, 7, 9, 12, 15, 20, 25, 30, 35, 40, 50, 60, 70, 80, 90, and 100. The FR value was increased after 4 consecutive ratios were completed that all satisfied an inter-response time (IRT) criterion. For ratio values less than 50, all IRTs had to be equal to or less than 1 s. For ratio values greater than or equal to 50, the last 30 responses had to satisfy a 1-s IRT criterion, and all other responses had to terminate an IRT of 30 s or less. Sessions began with the last FR value that had satisfied the IRT criterion in the previous session. Occasionally, smaller FR values were also included for the first several FR values if erratic responding was observed in the

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10 previous session. Completion of the FR requirement resulted in 3 s access to grain. Sessions were concluded once either 50 reinforcers were delivered or 40 min had elapsed, whichever came first. Baseline Once responding reliably occurred on the FR 100 schedule, designated the large-ratio component, two additional components were introduced at the same time. The small-ratio component, signaled by a green key, was increased from FR 4 to FR 10 after one session. The medium-ratio component, signaled by a red key, was introduced as an FR 5 and subsequently increased to FR 15 then FR 30 across daily sessions. Sessions were conducted 7 days a week at approximately the same time each day. Each session was arranged into 4 blocks where a block consisted of one presentation each of the small-FR, medium-FR, and large-FR components. Components were presented randomly without repetition within a block. Components were separated by a 20-s blackout and were concluded once either the FR requirement had been completed or a time limit had elapsed. The time limits for the small, medium, and large components were 1 min, 2 min, and 6 min, respectively. The timer that controlled access to grain started once a pigeon inserted its head into the hopper, as detected by the photobeam. Head-in-hopper time was recorded to measure obtained unit prices. If a pigeon did not approach the hopper when presented, a limited hold was in force. If the pigeon did not insert its head into the hopper within 10 s of a hopper presentation, the hopper was lowered and the inter-component blackout was initiated, after which the next component ensued. Typical latencies to hopper entry were approximately 1 s for all subjects.

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11 Completion of the FR 10 resulted in 1.5 s access to grain, completion of the FR 30 resulted in 4.5 s access to grain, and completion of the FR 100 resulted in 15 s access to grain. Therefore, the unit price was held constant across components at a value of 6.67 pecks/s of access to grain. Baseline continued until at least 30 sessions had been conducted and rates across components appeared stable as judged by visual inspection of daily response rates and cumulative records (36 to 42 days). Drugs and Drug Administration Procedure Cocaine hydrochloride was dissolved in 0.9% sodium chloride (saline) solution. Drug doses were computed as the salt. Injection volumes were 1 ml/kg. Injections were administered immediately prior to sessions via intramuscular injections into the pectoral muscle. When injections occurred daily, the injection site was alternated between the left and right pectoral muscles in order to minimize any potential bruising. The range of doses that a given subject received during Phase 2 was the same as that administered during acute dose administrations. Acute Dosing (Acute) All subjects initially received the same range of cocaine doses (1.0, 3.0, 5.6, and 10.0 mg/kg). Subjects 46 and 435 later received a lower range of doses (0.3, 1.0, 3.0, and 5.6 mg/kg) based on dose-response curves generated with the original doses. Each dose was administered at least twice under this regimen. Further administrations with some doses were conducted as necessary for individual doses whenever it was deemed necessary to obtain a better estimate of the mean effect. Table 1 shows the number of acute-dose administrations for each dose that each subject received during the Acute Phase. All injections were separated by at least 5 days, and sessions conducted the day before drug-test or vehicle-test sessions provided control values.

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12 Chronic Variable-Dosing with Same Unit Price (SUP1) Pre-session injections were administered immediately prior to every session according to a variable-dosing regimen. Branch, Wilhelm, and Pinkston (2000) and Miller and Branch (2002) demonstrated that a chronic variable-dosing regimen produced similar levels of tolerance to the initial disruptive effects of pre-session cocaine on FR performance when compared to a chronic fixed-dosing regimen, so such a regimen was chosen here. Specifically, beginning with saline, various doses of cocaine were administered in descending order of dose magnitude. That is, on successive days, subjects received pre-session injections of 0.0, 10.0, 5.6, 3.0, and 1.0 mg/kg of cocaine in that order, and then the order was repeated. Subjects 46 and 435 received 0.0, 5.6, 3.0, 1.0, and 0.3 mg/kg of cocaine. Doses were administered in a fixed as opposed to random order so that order effects, should they exist, could better be observed (cf. Sidman, 1960). Additionally, Miller and Branch (2002) showed similar degrees of tolerance across three groups of pigeons that were exposed to variable-dosing regimens with different dose orders. Once through the dose-response sequence was defined as a cycle. Thus, a cycle consisted of five sessions. If deviations from the procedure were observed for a particular session (e.g., apparatus failure, incorrect dose administration, etc.), the data from that cycle were neither plotted nor utilized in judging stability. Table 2 shows the number of cycles completed for each subject during Chronic Variable-Dosing. The phase was carried out until at least 15 cycles were conducted, and stable rates across components were observed as judged by visual inspection of plots of response rates for successive dose administrations. The rates for the last 5 successive exposures for each component under each dose were used to judge stability.

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13 Results Dose-Response Functions Figure 1 shows dose-response functions generated from the Acute Phase and Chronic Variable-Dosing. Unit price was equal across components of the multiple schedule in both phases. Figure 2 shows dose-response curves generated from both phases with rate expressed as a proportion of those observed following saline administrations. For both Figure 1 and Figure 2, means for Acute points represent the average of all acute administrations while means for chronic administration were generated from averaging the results of the last five administrations of each dose. Dose-related decreases in response rate were observed for all subjects during the Acute Phase (black filled circles). Overall, visual inspection of the acute dose-response functions showed no consistent differences in the effects of cocaine across components. Response rates for Subjects 435 and 693 showed greater decreases at some doses in the large-ratio component as compared to the decreases in the small-ratio and medium-ratio, but such differences were not seen in other subjects. In contrast, Subject 46 showed some responding at 3.0 mg/kg in the medium-ratio and large-ratio component while no responding was observed in the small-ratio component after this dose. For the remaining pigeons, dose-response functions were similar across components, with the similarity most clearly evident in the normalized data of Figure 2. A comparison of dose-response curves generated from Acute administrations and repeated variable-dosing shows that tolerance developed to the initial rate-decreasing effects of cocaine for all subjects at the smallest dose that lowered rates beyond the control range acutely. This was true in all 3 components of the multiple schedule for all six pigeons (i.e., in 18 of 18 cases). Tolerance was not observed at the largest individual

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14 dose administered for any subject except for 693. Overall, even though different degrees of tolerance were observed across subjects, similar levels of tolerance were observed across components for each individual subject. That is, tolerance generally was not related systematically to FR value. For example, effects at the largest dose, one that produced similar decreases in all three components, are comparable across all three ratio values. For Subjects 435 and 693 tolerance was somewhat greater in the larger-ratio component, due mainly to the between-component differences in acute effects. For both these subjects, rates returned toward baseline levels at all doses that produced decreases acutely. A quantitative measure based on the dose-response function is the effective dose (ED50) at which responding is suppressed to 50% of Baseline. The ED50 values were calculated by finding the slope of the descending limb of the normalized dose-response function (Figure 2). The descending portion of the dose-response function began at the last point at which rates were at least 90% of those observed during saline sessions and extended through all higher-dose points until rate was zero or to the highest dose presented if no dose eliminated pecking. If none of the points on the normalized dose-response function were above 90%, all the points were utilized. The second and third sets of columns of Table 3 show the ED50s from acute administrations and chronic variable-dosing. These data confirm the visual impression that drug effects were not related systematically to FR value. For example, after chronic dosing, ED50 values were higher than the Acute ED50 values across subjects and components in 15 out 18 cases (Table 3). The overall picture, therefore, is that the chronic dosing regimen resulted in modest tolerance that was unrelated to FR parameter.

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15 Unit Price Figure 3 shows median obtained unit-price values from the sessions that generated the data points in Figures 1 and 2. The unit-price for each component was calculated by dividing the ratio requirement by the median head-in-hopper time for all data points during assessment of acute effects. Medians from the last five sessions at each dose were used to summarize data from the repeated-dosing condition. The median instead of average head-in-hopper time values was utilized to minimize the influence of outliers from a few sessions in which the head-in-hopper time was particularly low. Generally, little or no difference was observed between unit-prices calculated from the median vs. average head-in-hopper time values. Absent data points are due either to reinforcers never being obtained in those conditions or to head-in-hopper time values of 0 seconds when the hopper was presented. Note that the y-axis for Subject 46 is expanded for the medium-ratio and large-ratio components to accommodate very high unit prices at the 5.6 mg/kg dose. Overall, under control conditions and following administration of saline, obtained unit-price was very similar for a given subject across components. A modest tendency for price to be slightly higher in the large-ratio component price was observed but obtained values were still close to the programmed value. Cocaine administration produced small increases in unit price across all three components and did so under both acute and chronic-administration conditions. Occasionally, large doses resulted in very high unit prices as a result of reduced head-in-hopper times, but overall we were successful in equating unit price across components.

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16 Discussion The major outcome of Experiment 1 was that a modest degree of tolerance to cocaines effects developed, and tolerance was not related systematically to FR parameter value. Thus, the results of Experiment 1 did not systematically replicate the results of previous experiments investigating tolerance to the effects of cocaine under a multiple FR schedule of food reinforcement (Hoffman et al., 1987; Hughes & Branch, 1991; Nickel et al., 1993). In the current experiment, with unit price equated across components, similar degrees of tolerance were produced across different sized FR values. Previous research on the other hand, with unit price uncontrolled, has shown greater degrees of tolerance in the smaller-ratio components when compared to larger-ratio ones. When differences in tolerance development were observed in the present study, the magnitude of tolerance tended to be greater in the large-ratio component, rather than in the small-ratio component, exactly the reverse of the pattern evident in the previous literature. The findings, therefore, are consistent with the view that ratio-parameter-dependent tolerance reported in other studies may have been related to the fact that different unit-prices were arranged by the different schedules of reinforcement. Such a conclusion remains tentative, however, because besides differences in unit-price, the current experimental procedure differed in several other ways from the previous studies. The current procedure was most similar to the Hoffman et al. study so relevant comparisons will focus on these two experiments. The current experiments FR shaping procedure, combined with the equating of unit-prices, produced shorter pauses in the large-ratio component than reported by Hoffman et al. Table 4 shows the average, minimum, maximum, and standard deviation of the pre-ratio pauses obtained from control sessions during the following acute administrations. For all subjects, the pause

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17 was short under the smaller two ratios and somewhat longer in the largest ratio. Although Hoffman et al. did not report overall average session pause values, they did provide average pause values obtained from within-session blocks. Pause values they obtained in the FR 5 and FR 25 components were comparable to those observed in the FR 10 and FR 30 components of the current study. The average of the within-session average pause values from the large-ratio component, however, were 62.82 s and 75.98 s for the two pigeons that experienced FR 125 and 17.76 s in the subject whose large-ratio was an FR 50. These values are substantially larger than values shown for the FR 100 in Table 5. It may be, therefore, that the differential tolerance reported by Hoffman et al. was due, at least in part, to the fact that the large-ratio component controlled behavior was characterized by relatively long pauses. Whether these differences in pause length in the large-ratio component were due to use of equal unit prices in the present study or to the FR training procedure used here remains to be investigated. Longer pauses result in lower reinforcement rate under ratio schedules, so it is possible that an important difference between the current study and that of Hoffman et al. is the difference in reinforcement rates. From a reinforcement-rate perspective, the shorter large-ratio pauses in the current experiment made the rate of access to food between components more similar, which may have contributed to the comparable levels of tolerance. Table 5 shows average rates of food hopper presentations during control sessions for the current study and those from Hoffman et al. Rates of food presentation for the Hoffman et al. study were calculated by first determining the average of the average rates of responding across blocks then these rates of responding and the FR value for a particular component were used to calculate the average rate of food delivery. The

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18 left 3 columns show the rates of reinforcer deliveries. Differences across components were larger in the Hoffman et al. study. The differences in baseline responding across components may also have contributed to the modest differences observed in the acute effects of cocaine between the current experiment and the Hoffman et al. study. The dose-response functions generated from acute administrations of cocaine in the Hoffman et al. experiment showed greater dose-related decreases in the larger-ratio components than the smaller-ratio components. Acute dose-response curves generated from the current study were generally similar across components. An additional difference between the procedure of Experiment 1 and that in the Hoffman et al. study was the chronic dosing regimen. Hoffman et al. used a regimen in which the same dose of cocaine was administered prior to every session. In the current study, a variable-dosing regimen was used in which different doses of drug were delivered prior to each session. The potential role of chronic variable-dosing in producing the current results was explored in greater detail in Experiment 3. The results of the current experiment showed similar degrees of tolerance across different sized ratio-values. In an attempt to elucidate potential factors that might have been responsible for the current results, Experiment 2 began with a shift to different unit-price.

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19 Table 1. Acute administrations. Number of administrations of each dose during the Acute Phase for each subject. Dose Subject Saline .3 1.0 3.0 5.6 10 46 8 5 3 4 4 435 4 3 2 4 3 405 4 3 2 2 2 416 3 2 4 3 2 654 4 2 4 3 3 603 4 2 2 2 2 Table 2. Chronic variable dosing. Number of cycles completed for each subject during the chronic dosing phases of Experiment 1 and 2. Phase Subject Exp 1 Equal Unit Price Exp 2 Different Unit Price Exp 2 Equal Unit Price 46 26 27 26 405 22 38 15 416 15 27 17 435 18 23 40 654 16 27 16 693 15 39 21

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20 CS0.3135.6 0100200300 CS0.3135.6 0100200300 CS0.3135.6 0100200300 ACUTE SUP1 CS0.3135.6 0100200300 CS0.3135.6 0100200300 CS0.3135.6 0100200300 CS135.610 0100200300 CS135.610 0100200300 CS135.610 0100200300 CS135.610 0100200300 CS135.610 0100200300 CS135.610 0100200300 CS135.610 0100200300 CS135.610 0100200300 CS135.610 0100200300 CS135.610 0100200300 CS135.610 0100200300 CS135.610 0100200300 Small Medium Large 46 435 RESPONSES/MIN 416 405 654 693 MG/KG COCAINE Figure 1. Pecks/minute as a function of dose of cocaine. Data for each subject are presented horizontally while components are presented vertically. Black filled circles represent mean values under conditions of acute administration. Grey filled circles represent mean values for the last five administrations under conditions of chronic variable dosing where access to food was correlated with ratio size (same unit price) and a the chronic dose changed for every session. Points above C show means from control sessions immediately preceding injection sessions. Points above S are means from sessions preceded by saline injections. Vertical bars through control values represent 99% confidence intervals.

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21 C0.3135.6 0.00.51.01.5 C0.3135.6 0.00.51.01.5 C0.3135.6 0.00.51.01.5 C0.3135.6 0.00.51.01.5 C0.3135.6 0.00.51.01.5 C0.3135.6 0.00.51.01.5 C135.610 0.00.51.01.5 C135.610 0.00.51.01.5 C135.610 0.00.51.01.5 ACUTE SUP1 C135.610 0.00.51.01.5 C135.610 0.00.51.01.5 C135.610 0.00.51.01.5 C135.610 0.00.51.01.5 C135.610 0.00.51.01.5 C135.610 0.00.51.01.5 C135.610 0.00.51.01.5 C135.610 0.00.51.01.5 C135.610 0.00.51.01.5 Small Medium Large 46 435 PROPORTION OF SALINE VALUE 654 416 405 693 MG/KG COCAINE Figure 2. Dose-response functions as a proportion of values observed during saline administrations for sessions represented in Fig. 1 during acute administrations (black filled circles) and chronic variable dosing administrations with equal unit price (grey filled circles). The vertical bar above C represents 99% confidence intervals as a proportion of saline values. All other details are as in Fig.

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Table 3. ED50 values. Obtained ED50 values from Experiments 1, 2, and 3. Phase Exp 1 Acute Exp 1 Chronic Exp 2 Unequal Unit Price Exp 2 Equal Unit Price Exp 3 Subject S M L S M L S M L S M L S M L 46 1.92 2.16 2.37 2.93 2.9 4.15 3.4 4.14 6.46 3.06 6.08 12.96 2.47 4.96 6.35 435 2.53 1.74 0.18 4 2.73 1.3 4.07 2.76 1.69 3.55 3.22 1.26 15.95 3.5 1.65 405 1.7 2.53 1.12 1.63 2.31 2.07 1.94 1.24 0.94 2.26 2.04 1.7 2.21 1.82 1.43 416 4.34 3.29 2.73 5.44 3.73 2.2 12.54 7.48 4.37 4.96 5.8 2.67 6.78 7.93 1.07 654 2.53 3.19 3.04 6.38 6.05 4.81 8.45 8.09 6.19 7.9 7.64 5.17 26.89 14.08 3.25 693 7.5 7.49 3.07 9.03 8.34 7.24 6.69 5.4 1.94 3.42 2.7 1.89 2.81 2.38 1.89 Mean 3.42 3.40 2.09 4.90 4.34 3.63 6.18 4.85 3.60 4.19 4.58 4.28 9.52 5.78 2.61 22

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23 CS0.3135.6 110100 CS0.3135.6 1101001000 CS0.3135.6 1101001000 CS0.3135.6 110100 CS0.3135.6 110100 CS0.3135.6 110100 CS135.610 110100 CS135.610 110100 CS135.610 110100 ACUTE SUP1 CS135.610 110100 CS135.610 110100 CS135.610 110100 CS135.610 110100 CS135.610 110100 CS135.610 110100 CS135.610 110100 CS135.610 110100 CS135.610 110100 Sm all Medium Large 46 435 UNIT PRICE ( PECKS/S OF FOOD ACCESS ) 654 416 405 693 MG/KG COCAINE Figure 3. Unit price (average component ratio value divided by the average component head-in-hopper time) as a function of dose of cocaine for sessions represented in Fig. 1. Values in which head-in-hopper time was zero or the ratio requirement was not completed were not used. All other details are as in Fig. 1.

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CHAPTER 3 EXPERIMENT 2 Method Subjects and Apparatus Subjects and apparatus used in Experiment 1 remained the same in Experiment 2. Chronic Variable-Dosing with Different Unit Price (DUP) Experiment 2 began immediately on completion of Experiment 1. Its first condition was similar to the variable-dosing condition in Experiment 1 except that completion of each FR requirement resulted in 4.5 s access to grain, regardless of ratio size. Thus, a different unit price was arranged for each component. The same daily variable-dosing regimen utilized in Experiment 1 was continued during Experiment 2. The phase was carried out until at least the same number of cycles completed in the variable-dosing condition of Experiment 1 had been conducted and stable rates were observed as judged by visual inspection of the last 5 exposures for each component under each dose. Chronic Variable-Dosing with Same Unit Price (SUP2) The second condition of Experiment 2 was a direct replication of the variable-dosing condition of Experiment 1 and continued until at least 15 cycles were conducted and stable rates were observed as judged by visual inspection. Table 2 shows the number of cycles completed for each subject in the two conditions of Experiment 2. 24

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25 Results Dose-Response Functions Figure 4 shows dose-response functions generated from the condition with unequal unit prices (white squares) and the subsequent return to equal unit prices (open circles) with rate presented as a proportion of those following saline administrations. Also plotted for comparison are dose-response functions from the acute administrations from Experiment 1(black circles). When, in the context of daily variable dosing, unit price was made unequal across components, no large changes were observed. The modest tolerance, however that had been evident in Experiment 1 was no longer present in Subjects 405 and 693. During the unequal unit-price condition ED50 values were ordered such that they were the smallest in the large-ratio component and greatest in the small-ratio component for 5 out of 6 subjects as seen in Table 3. Overall, across all components ED50 values obtained with unequal unit price were greater in than those seen with equal unit prices 13 out 18 components across subjects, but in several cases just barely so. When unit-price was equated across components again in the second condition of Experiment 2, few substantial changes were observed, but in 13 of 18 components, the ED50 decreased. Thus, Experiment 2 revealed a modest trend in which tolerance was slightly greater under conditions of unequal unit price. No consistent systematic relations between tolerance and ratio values, however, were observed. Recall that the second phase of Experiment 2 was a direct replication of the second part of Experiment 1. Figure 5 shows dose-response functions from the variable-dosing condition of Experiment 1 and the identical condition in Experiment 2. Dose-response functions observed during Experiment 1 were generally recaptured during Experiment 2,

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26 except for Subjects 46 and 693. Subject 46 showed increased tolerance in the medium-ratio and large-ratio components in the second exposure to the condition, whereas Subject 693 showed increased sensitization across components. The general tendency for the effects to be similar is validated by examination of the fourth column of Table 3, which shows that in 10 cases, the ED50 increased and in 8 it decreased. Unit Price Figure 6 shows median obtained unit-price values from acute assessments and the two conditions where unit price was equated. Programmed unit-prices were the same for all data points represented by circles and for points in the medium-ratio component when unit prices were different. Programmed unit-price values were different only in the small-ratio and large-ratio in the first condition of Experiment 2 (open squares). Subjects showed similar obtained unit-price values wherever programmed unit-price values were the same. That is, obtained unit prices were different only when they were programmed to be different. Overall, smaller doses of cocaine left obtained unit price unchanged. Larger doses often increased it. Again, unit price was generally controlled as predicted. Discussion The purpose of Experiment 2 was to investigate the effects of altering unit-price during a regimen of daily variable dosing. Overall, when the same amount of food was made available regardless of ratio size, the current results generally failed to replicate the findings observed in the Hoffman et al. (1987) experiment. That is, pronounced FR-value specific tolerance did not develop. In addition to the differences between the Hoffman et al. study and the present one noted in the discussion of Experiment 1. Another potential explanation for this failure to replicate may be that tolerance, once obtained is difficult to eliminate. That is, repeated

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27 exposure to cocaine in Experiment 1, where unit prices were equated, resulted in tolerance in all three components of the multiple schedule, and when unit prices were made different the tolerance that had developed in the FR 100 component carried over to Experiment 2, making FR-value-specific tolerance harder to detect. To the degree that tolerance represents some form of learned compensatory response (Wolgin, 1989), one would not necessarily expect the recovered responding in the large-ratio component that had developed in Experiment 1 to disappear with a decrease in reinforcer duration. Although tolerance in the large-ratio component may have been initially driven by the larger reinforcer magnitude in Experiment 1, responding may well have been maintained with reduced food-duration time as long as that food-duration time still functioned as a reinforcer, which it obviously did. A moderate increase in overall levels of tolerance was observed when unit price was not equal across components when compared to the second conditions of Experiment 1 and Experiment 2, where unit price was equated. One potential contributing factor may have been differences in absolute amount of available reinforcement between conditions. When unit price was equated across components food was available for 84 s in each session. When unit price varied across components in Experiment 2, the total food-access time was 54 s. The globally smaller amount of reinforcement may have increased the reinforcing efficacy of food presentations when unit prices varied in Experiment 2 and resulted in moderately greater levels of tolerance. A potential reason for the failure to see schedule-parameter-dependent tolerance when unit priced varied in Experiment 2 was the use of the variable-dosing regimen to assess effects of repeated cocaine exposure. The Hoffman et al. study involved a

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28 chronic-fixed dosing regimen (i.e., the same dose was given daily). The decision to use a variable-dosing regimen in the present study was based on reports by Branch et al. (2000) and Miller and Branch (2002), who demonstrated that comparable degrees of tolerance were produced by chronic variable-dosing and fixed-dosing regimens. Both of those studies, however, examined an FR 20 schedule of reinforcement. Differences in tolerance with different dosing regimens for larger ratio values, or larger ratio values in the context of smaller ratio values, have yet to be examined. In the variable-dosing regimen we used, administrations of small doses of drug and saline were intermixed with larger ones, and it may have made recovery of responding in the large-ratio component more likely. In an attempt to assess this possibility, Experiment 3 examined effects of changing the dosing routine to a chronic fixed-dosing regimen.

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29 C0.3135.6 0.00.51.01.5 C0.3135.6 0.00.51.01.5 C0.3135.6 0.00.51.01.5 C0.3135.6 0.00.51.01.5 C0.3135.6 0.00.51.01.5 C0.3135.6 0.00.51.01.5 C135.610 0.00.51.01.5 C135.610 0.00.51.01.5 C135.610 0.00.51.01.5 ACUTE SUP2 DUP C135.610 0.00.51.01.5 C135.610 0.00.51.01.5 C135.610 0.00.51.01.5 C135.610 0.00.51.01.5 C135.610 0.00.51.01.5 C135.610 0.00.51.01.5 C135.610 0.00.51.01.5 C135.610 0.00.51.01.5 C135.610 0.00.51.01.5 Small Medium Large 46 435 PROPORTION OF SALINE VALUE 654 416 405 693 MG/KG COCAINE Figure 4. Pecks/min as a proportion of values observed during saline administrations for acute administrations (black filled circles), chronic variable dosing with unequal unit price (white open squares), and chronic variable dosing with equal unit price (white open circles). During chronic variable dosing with unequal unit price, access to food was the same regardless of ratio size. All other details are as in Fig. 2.

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30 C0.3135.6 0.00.51.01.5 C0.3135.6 0.00.51.01.5 C0.3135.6 0.00.51.01.5 C0.3135.6 0.00.51.01.5 C0.3135.6 0.00.51.01.5 C0.3135.6 0.00.51.01.5 C135.610 0.00.51.01.5 C135.610 0.00.51.01.5 C135.610 0.00.51.01.5 SUP1 SUP2 C135.610 0.00.51.01.5 C135.610 0.00.51.01.5 C135.610 0.00.51.01.5 C135.610 0.00.51.01.5 C135.610 0.00.51.01.5 C135.610 0.00.51.01.5 C135.610 0.00.51.01.5 C135.610 0.00.51.01.5 C135.610 0.00.51.01.5 Small Medium Large 46 435 PROPORTION OF SALINE VALUE 654 416 405 693 MG/KG COCAINE Figure 5. Dose-response functions from chronic variable dosing administrations with equal unit price during Experiment 1 (grey filled circles) and Experiment 2 (white filled circles). All other details are as in Fig. 2.

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31 CS0.3135.6 110100 CS0.3135.6 1101001000 CS0.3135.6 1101001000 CS0.3135.6 110100 CS0.3135.6 110100 CS0.3135.6 110100 CS135.610 110100 CS135.610 110100 CS135.610 110100 FI X FI X 2F FI X ACUTE SUP1 SUP2 DUP CS135.610 110100 CS135.610 110100 CS135.610 110100 CS135.610 110100 CS135.610 110100 CS135.610 110100 CS135.610 110100 CS135.610 110100 CS135.610 110100 Sm all Medium Large 46 435 UNIT PRICE ( PECKS/S ACCESS OF FOOD ) 654 416 405 693 MG/KG COCAINE Figure 6. Unit price as a function of dose of cocaine for sessions represented in Fig. 4 and 5 are shown. All other details are as in Fig. 1.

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CHAPTER 4 EXPERIMENT 3 Method Subjects and Apparatus Subjects and apparatus used in Experiment 1 and 2 remained the same in Experiment 3. Chronic Fixed-Dosing with Same Unit-Price (FIX1) Experiment 3 began immediately on completion of Experiment 2. The only change was that subjects were administered 5.6 mg/kg of cocaine immediately prior to every session. Unit price remained equal across components. After at least 50 sessions were conducted and stability in daily response rates were observed, occasional sessions were preceded by different doses of cocaine or saline, with these probe administrations spaced by at least 5 sessions. Each dose was administered at least twice. Data from sessions preceding substitute doses served as representative sessions for 5.6 mg/kg of cocaine. Chronic Fixed-Dosing with Same Unit-Price and Lower Chronic Dose (FIX2) Only Subjects 405 and 693 participated in this condition. This second condition of Experiment 3 was conducted in a manner similar to the first condition, except that subjects received daily administrations of 3.0 mg/kg, rather than 5.6 mg/kg, of cocaine immediately prior to every session. The shift to the smaller dose was made because previous studies have shown that daily administrations of a relatively large dose of chronic cocaine may reduce or eliminate tolerance (Bowen, Faller, & Kallman, 1993; 32

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33 Stafford & Branch, 1996; Branch et al. 2000). Pigeons 405 and 693 showed little or no tolerance when 5.6 mg/kg was given daily. The shift to a smaller dose was therefore made to see if 5.6 mg/kg was too large a dose to produce tolerance. After at least 50 sessions had occurred and stability in rates was observed, dose-response functions were assessed. Data from sessions preceding probe doses were used to characterize the effects of 3.0 mg/kg of cocaine. Results Dose-Response Functions Figure 7 shows dose-response functions generated during daily administrations of 5.6 mg/kg (white triangles) and 3.0 mg/kg (white diamonds), where subjects received daily administrations of the same dose of cocaine. The original acute dose-response functions are also represented by black-filled circles for comparison. Subjects 405 and 693, as they had in Experiment 2, exhibited little or no tolerance in any component, either during repeated exposure to 5.6 mg/kg or to 3.0 mg/kg. The remaining four pigeons, however, did show tolerance, and its magnitude was related to the FR value. The differences are obvious for Subjects 416, 435, and 654, where tolerance was much more pronounced at the lower ratios and less so at the largest ratio. These changes are confirmed in the ED50s shown in Table 3. Following the transition from variable dosing at the end of Experiment 2 to fixed dosing in Experiment 3, the ED50s for the small ratio increased substantially, whereas the ED50s for the large ratio either decreased (416 & 654) or changed little (435). Subject 46 also revealed a similar FR-parameter dependent effect. Throughout all the chronic-dosing regimens of Experiments 1, 2, and 3, this subject had higher ED50s in the larger ratios, but when the shift was made from variable dosing to fixed dosing, the ED50 in the large ratio was decreased by half (see Table 3),

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34 whereas the ED50s in the other two components were decreased by a bit less than 20%. Even the two subjects that showed no tolerance had their ED50s ordered such that the largest was in the small ratio and smallest in the large ratio. The overall picture across subjects, therefore, was that if tolerance was evident, its magnitude was influenced by the FR parameter value. Unit Price Figure 8 shows median obtained unit-price values from Experiment 3. Overall, obtained unit-price was similar across components for a given subject and similar to obtained unit-prices obtained in previous conditions when programmed unit-price remained the same. Discussion Two general trends were observed once the chronic dosing-regimen was shifted from variable-dosing to a fixed-dosing regimen. Four of the subjects showed tolerance that was influenced by the FR parameter value. These four subjects exhibited a pattern of tolerance similar to that observed by Hoffman et al. (1987). Fixed dosing led to diminished relative tolerance in the large-ratio component. The remaining two, although not showing tolerance, had their ED50s ordered from largest to smallest across increasing ratios. (It is important to recall, however, that for Subject 693 this ordering was present at the outset of Experiment 1). This outcome suggests three important conclusions. One, schedule-parameter-dependent tolerance does not depend on difference in unit price across the different schedules. Unit price was essentially equal across components of the multiple schedule, yet parameter-dependent tolerance was observed. Two, parameter-dependent tolerance does not depend on differences in the acute effects of cocaine. In the present study, acute effects were relatively similar across components, a state of affairs

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35 that stands in contrast to those observed by Hoffman et al. Three, the observation of schedule-parameter dependence may depend on repeated exposure to a fixed dose. The failure of tolerance to develop to any significant degree in two of the subjects remains a puzzle. There were no features of their performances that suggested that their behavior was controlled in a manner different from that of the other subjects. Previous research with pigeons responding under FR schedules of food presentation has revealed little or no tolerance in a minority of subjects (Branch et al., 200; Miller & Branch, 2002), but the origins of these individual differences remain obscure. The parameter dependence of tolerance evident when the daily pre-session dose was fixed suggests that the training method, which produced higher-rate large FR performance, was not the key factor. Even though baseline response and reinforcement rates were more similar in the present study than in previously reported work, parameter-dependent tolerance was still observed. These results therefore increase the generality of the ratio-parameter dependence of tolerance.

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36 C0.3135.6 0.00.51.01.5 C0.3135.6 0.00.51.01.5 C0.3135.6 0.00.51.01.5 C0.3135.6 0.00.51.01.5 C0.3135.6 0.00.51.01.5 C0.3135.6 0.00.51.01.5 C135.610 0.00.51.01.5 C135.610 0.00.51.01.5 C135.610 0.00.51.01.5 ACUTE FIX FIX2 C135.610 0.00.51.01.5 C135.610 0.00.51.01.5 C135.610 0.00.51.01.5 C135.610 0.00.51.01.5 C135.610 0.00.51.01.5 C135.610 0.00.51.01.5 C135.610 0.00.51.01.5 C135.610 0.00.51.01.5 C135.610 0.00.51.01.5 Small Medium Large 46 435 PROPORTION OF SALINE VALUES 654 416 405 693 MG/KG COCAINE Figure 7. Dose-response functions from acute administrations (black filled circles) and chronic fixed-dosing administrations with 5.6 mg/kg of cocaine (open triangles) are shown. Subjects 46, 405, and 693 also received chronic fixed-dosing administrations with 3.0 mg/kg of cocaine (white diamonds). For all data points, values represent the mean of all administrations at a particular dose. All other details are as in Fig. 2.

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37 CS0.3135.6 110100 CS0.3135.6 110100 CS0.3135.6 110100 CS0.3135.6 110100 CS0.3135.6 110100 CS0.3135.6 110100 CS135.610 110100 CS135.610 110100 CS135.610 110100 ACUTE FIX FIX2 CS135.610 110100 CS135.610 110100 CS135.610 110100 CS135.610 110100 CS135.610 110100 CS135.610 110100 CS135.610 110100 CS135.610 110100 CS135.610 110100 Sm all Medium Large 46 435 UNIT PRICE ( PECKS/S OF FOOD ACCESS ) 654 416 405 693 MG/KG COCAINE Figure 8. Unit price as a function of dose of cocaine for sessions represented in Fig. 9 are shown. All other details are as in Fig. 1.

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CHAPTER 5 GENERAL DISCUSSION The main purpose of the current experiment was to see if equating unit price would result in similar levels of tolerance across different size fixed ratios, and that was observed in Experiment 1. The results of Experiment 1 showed that similar levels of tolerance were evident across FR values when unit price was equated across different FR values and when a chronic variable-dosing regimen was used. The magnitude of tolerance increased slightly when unit price differed across components in Experiment 2, but schedule-parameter-dependent tolerance did not develop. When unit price was equated once again, however, and fixed-dosing was implemented, parameter-specific tolerance emerged in the four subjects that consistently exhibited tolerance. It appears, therefore, that repeated exposure to a fixed dose was critical in producing FR parameter-dependent effects. It is not clear why repeated exposure to a fixed dose should have promoted the influence of schedule parameter whereas repeated exposure to varied doses did not. Previous research comparing fixed and variable dosing (Branch et al., 2000; Miller & Branch, 2002) has illustrated the similarity in effects of the two approaches to chronic drugging. Those studies, like the present work, involved the use of FR schedules, but only a single schedule parameter was employed, in contrast to the three values used here. Theories to account for the development of tolerance to a drugs behavioral effects on operant performance have emphasized the role played by learning, learning to cope with the drugs disruption of the ability to obtain reinforcement (Corfield-Sumner & 38

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39 Stolerman, 1978; Schuster et al., 1966; Wolgin, 1989). Because the relative decrease in rate of reinforcement was greater in the small-ratio component as compared to that in the large-ratio component, one might predict better learning in the small-ratio component, but still puzzling is why that difference in learning should be amplified by experience with a fixed dose, rather than repeated variable dosing. One possibility that may have played a role in the present set of experiments is the amount of exposure to each dose. In the variable dosing procedures, each dose was experienced 15 to 40 times over the course of each experiment, with the total number of exposures to each dose ranging from 59 to 81 (see Table 2) across all 3 experiments. In the fixed dosing experiment, the same dose was experienced at least 50 times before probed doses were tested, and at least 40 additional exposures occurred while does-effects were being assessed. The notable difference, therefore, is not in the total number of exposures, but instead the fact that under the fixed-dosing regimen the same dose, and presumably therefore the same drug state, was present in each session. That feature of the regimen may have made learning to cope easier. A useful follow-up experiment that might confirm the difference between variableand fixed-repeated dosing would be one in which the conditions were arranged in an order the reverse of that in the present study. That is, after establishment of a baseline of responding with small and large ratios, a fixed-dosing regimen could be imposed that would result in parameter-specific tolerance. The regimen could then be changed to variable dosing to determine if the parameter dependence remained or not. The present results also suggest that, at least in the context of receiving a fixed dose of cocaine each session, unit price differences are not crucial for observing FR-schedule dependent tolerance. In Experiment 3, unit prices were equal across components, yet FR

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40 parameter dependent effects were evident when cocaine was given repeatedly. The apparent lack of importance of unit price raises the question of what it is about ratio schedules that promotes parameter dependence of tolerance. Previous research suggests that reinforcement-rate differences are not the key (Schama & Branch, 1989), so what remains is simply the work requirement. Other methods of producing differential amounts of required effort should be a productive avenue for research on this issue.

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LIST OF REFERENCES Bickel, W.K., Green, L., & Vuchinich, R.E. (1995). Behavioral economics. Journal of the Experimental Analysis of Behavior, 64(3), 257-262. 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. Pschopharmacology, 113(1), 67-75. Branch, M.N., Wilhelm, M.J., & Pinkston, J.W. (2000). A comparison of fixed and variable doses of cocaine in producing and augmenting tolerance to its effects on schedule-controlled behavior. Behavioural Pharmacology, 11(7-8), 555-569. Brown, P.L., & Jenkins, H.M. (1968). Auto-shaping of the pigeons key-peck. Journal of the Experimental Analysis of Behavior, 11(1), 1-8. Carlton, P.L., & Wolgin, D.L. (1971). Contingent tolerance to the anorexigenic effects of amphetamine. Physiology & Behavior, 7(2), 221-223. Chen, C.S. (1968). A study of the alcohol-tolerance effect and an introduction of a new behavioral technique. Psychopharmacologia, 27, 265-274. Corfield-Sumner, P.K., & Stolerman, I.P. (1978). Behavioral tolerance. In D.E. Blackman & D.J. Sanger (Eds.), Contemporary research in behavioral Pharmacology (pp. 391-448). New York : Plenum. DeGrandpre, R.J., Bickel, W.K., Hughes, J.R., & Layng, M.P. (1993). Unit price as a useful metric in analyzing effects of reinforcer magnitude. Journal of the Experimental Analysis of Behavior, 60(3), 641-666. Demellweek, C., & Goudie, A.J. (1983). Behavioral tolerance to amphetamine and other psychostimulants: The case for considering behavioral mechanisms. Pscyhopharmacology, 73, 165-167. Ferster, C.B. (1953). The use of the free operant in the analysis of behavior. Psychological Bulletin, 50, 263-274. Hardman, J.G., Gilman, A.G., & Limbird, L.E., eds. (1995). The Pharmacological Basis of Therapeutics (9th ed.). New York: McGraw-Hill. 41

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42 Hoffman, S.H., Branch, M.N., & Sizemore, G.M. (1987). Cocaine tolerance: Acute versus chronic effects as dependent upon fixed-ratio size. Journal of the Experimental Analysis of Behavior, 47, 363-376. Hughes, C.E., & Branch, M.N. (1991). Tolerance to and residual effects of cocaine in squirrel monkeys depend on reinforcement-schedule parameter. Journal of the Experimental Analysis of Behavior, 56(2), 345-360. Miller, M.L., & Branch, M.N. (2002). Role of dose order in the development of tolerance to effects of cocaine on schedule-controlled behavior in pigeons. Psychopharmacology, 163(3-4), 302-309. Nickel, M., Alling, K., Kleiner, M., & Poling, A. (1993). Fixed-ratio size as a determinant of tolerance to cocaine: Is relative or absolute size important? Behavioural Pharmacology, 4(5), 471-478. Schama, K.F., & Branch, M.N. (1989). Tolerance to effects of cocaine on schedule-controlled behavior: Effects of fixed-interval schedule parameter. Pharmacology, Biochemistry & Behavior, 32(1), 267-274. Schuster, C.R., Dockens, W.S., & Woods, J.H. (1966). Behavioral variables affecting the development of amphetamine tolerance. Psychopharmacologia, 9, 170-182. Sidman, M. (1960). Tactics of scientific research: Evaluating experimental data in psychology. New York: Basic Books, Inc. Smith, J.B. (1986). Effects of chronically administered d-amphetamine on spaced responding maintained under multiple and singlecomponent schedules. Psychopharmacology, 88(3), 296-300. Stafford, D., & Branch, M.N. (1996). Relations between dose magnitude, subject sensitivity, and the development of tolerance to cocaine-induced behavioral disruptions in pigeons. Behavioral Pharmacology, 7, 324-333. Walter, D.E., & Palya, W.L. (1984). An inexpensive controller for stand-alone applications or distributed processing networks. Behavior Research Methods, Instruments, & Computers, 16, 125-134. Wolgin, D.L. (1989). The role of Instrumental learning in behavioral tolerance to drugs. In A.J. Goudie & M.W. Emmett-Oglesby (Eds.), Psychoactive Drugs: Tolerance and Sensitization (pp. 17-114). Clifton, NJ: Humana Press.

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BIOGRAPHICAL SKETCH Jin Ho Yoon graduated from the University of Pennsylvania in 1996. He then worked at Childrens Seashore House first as an intern and then as a clinical specialist with developmentally delayed individuals with severe problem behavior. It was at Childrens Seashore House that Jin decided to forgo a medical career in favor of conducting behavior analysis research. Jin was accepted to the University of Florida graduate program in psychology with a specialization in experimental analysis of behavior and continues in pursuit of a PhD. 43


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Title: Interactions Among Unit Price, Fixed-Ratio Value, and Dosing Regimen in Determining Effects of Repeated Cocaine Administration
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Material Information

Title: Interactions Among Unit Price, Fixed-Ratio Value, and Dosing Regimen in Determining Effects of Repeated Cocaine Administration
Physical Description: Mixed Material
Copyright Date: 2008

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Source Institution: University of Florida
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INTERACTIONS AMONG UNIT PRICE, FIXED-RATIO VALUE, AND DOSING
REGIMEN IN DETERMINING EFFECTS OF REPEATED COCAINE
ADMINISTRATION















By

JIN HO YOON


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


2003

































Copyright 2003

by

Jin Ho Yoon

































This document is dedicated to my grandfather.















ACKNOWLEDGMENTS

I thank my family and friends who have supported me all this time.
















TABLE OF CONTENTS
Page

A C K N O W L E D G M E N T S ................................................................................................. iv

LIST OF TABLES ........ ............ .......... ..................... ...... ........vii

LIST OF FIGURES ................ .............. .. ................. ... .... ............. viii

A B STR A C T ............................ .............. ..... ix

CHAPTER

1 INTRODUCTION .............. ... .............................. ......... ..1

2 EXPERIM EN T 1 ...................................... ........... ................ 7

M eth od s ........................................................................... . 7
Subjects ........................................................................ ............... 7
A apparatus ........................ ....... ............ ....... .................... 7
H opper and K eypecking Training ........................................ ................ 8
F R S h ap in g ....................................................... 9
Baseline ........................................................10
Drugs and Drug Administration Procedure .................................................. 11
A cute D osing (A cute) .................................................................................... 11
Chronic Variable-Dosing with Same Unit Price (SUP1) ............... ................12
R e su lts ........................... .... .. ...............................................................1 3
Dose-Response Functions ................. .................................13
Unit Price ......... .... ..... ............. ...............15
D iscu ssio n ......... ...... ............ ................................... ...........................16

3 E X P E R IM E N T 2 .................................................................24

M ethod ............... ... ............. ............................................ 24
Subjects and A pparatus .......................................................... ............... 24
Chronic Variable-Dosing with Different Unit Price (DUP) .............................24
Chronic Variable-Dosing with Same Unit Price (SUP2) ..................................24
R e su lts ...............................................................................................2 5
Dose-Response Functions ................. .................................25
U nit P rice ................................................................................................... ........ 26
D isc u ssio n .......................................................................................2 6



v









4 EXPERIM ENT 3 .................................... .. ... ............ ......... .... 32

M e th o d ......................................................................................................3 2
Subjects nd A pparatus ............... ................ ........... ...................32
Chronic Fixed-Dosing with Same Unit-Price (FIX1) ......................................32
Chronic Fixed-Dosing with Same Unit-Price and Lower Chronic Dose (FIX2) 32
R e su lts ............... ......... ..............................................................3 3
D ose-R response Functions ............................................................................33
Unit Price ............. ..... ......... .......... ...............34
Discussion .................... ...... ..................... 34

5 G EN E R A L D ISC U SSIO N ...................................................................... ..................38

LIST OF REFEREN CES ............................................. ........................ ............... 41

BIOGRAPH ICAL SKETCH .............. ........ ............ ..................... ...............43
















LIST OF TABLES

Table page

1. A cute adm inistrations. ........................................ ...................................... 19

2. Chronic variable dosing....................................................................19

3 E D 50 v alu es.. ...................................................................... 22
















LIST OF FIGURES


Figure p

1. Dose-response functions Experiment 1. .................................. .................20

2. Dose-response functions as a proportion of saline Experiment 1 ..................21

3. Unit price Experim ent 1 ................................. ......................................23

4. Dose-response functions as a proportion of saline Experiment 2 ..................29

5. Dose-response functions as a proportion of saline Experiment 2....................30

6. U nit price Experim ent 1 .............................................................................31

7. Dose-response functions as a proportion of saline Experiment 3....................36

8. U nit price Experim ent 3 ..................................................... ...................37















Abstract of Thesis Presented to the Graduate School
of the University of Florida in Partial Fulfillment of the
Requirements for the Degree of Master of Science

INTERACTIONS AMONG UNIT PRICE, FIXED-RATIO VALUE, AND DOSING
REGIMEN IN DETERMINING EFFECTS OF REPEATED COCAINE
ADMINISTRATION

By

Jin Ho Yoon

May 2003

Chair: Marc N. Branch
Major Department: Psychology

Three experiments examined effects of repeated administration of cocaine to

pigeons. The pigeons were trained to key peck under a three-component multiple

schedule of food presentation according to which either 10, 30, or 100 pecks were

required for each delivery of food. In Experiment 1, time of access to food was

correlated with the number of pecks required so that unit price (pecks per second of

access to food) was equated. After assessing effects of a range of doses of cocaine

administered once per week, drug administration occurred daily before each session, with

the dose varying from day to day. Tolerance, the magnitude of which was unrelated to

the peck requirement, developed under the repeated-dosing regimen. In Experiment 2,

daily drug administration continued using the variable-dose regimen, but the amount of

food presented each time was fixed, yielding different unit prices under the three pecking

requirements. Subsequently, the conditions of Experiment 1 were reinstated, i.e., unit

price was equated. Making unit price different and then the same again had little









influence on effects of cocaine. In Experiment 3, a fixed dose of cocaine was

administered before each session. Under these conditions, tolerance became peck-

requirement related. Tolerance was most prevalent under the smaller requirements and

less robust or absent when the largest requirement was in effect. Differences in unit

price, therefore, were not related to degree of tolerance, but work requirement was.

Differences in effects of cocaine across responses requirements, however, were observed

only when each session was preceded by the same dose, not when dose varied from

session to session.














CHAPTER 1
INTRODUCTION

Descriptively, tolerance refers to an attenuation of the initial effects of a drug,

following repeated or prolonged exposure, such that increased dose is required to

recapture the initial effect (Corfield-Sumner & Stolerman, 1978; Wolgin, 1989;

Hardman, Gilman, & Limbird, 1995). The term tolerance may also be used

mechanistically, and several mechanisms have been suggested. For example, one

suggestion has been that tolerance is mediated through some form of behavioral

compensation (Demellweek & Goudie, 1983; Wolgin, 1989). This line of interpretation

has emanated largely from research that follows upon a method introduced by Chen

(1968). His study described a useful procedure for assessing the potential role of

instrumental learning in the development of tolerance, and the procedure suggested a

behavioral mechanism of tolerance. Two groups of rats received daily administrations of

alcohol. Subjects received reinforcement (i.e., bits of spaghetti) for completing a two-

turn circular-maze task. The Before Group received drug prior to each session while the

After Group received drug following the session. Disruption in maze running was

observed in the Before Group when the rats first received the drug. No effect of

receiving repeated administrations of post-session drug was observed in the After Group.

Tolerance, as demonstrated by a return to baseline levels of reinforcement following

several exposures to alcohol and the testing situation, was observed to the initial

disruptive effects of pre-session drug in the Before Group. Once tolerance in the Before

Group was observed, the After Group began receiving drug prior to sessions for the first









time while the Before Group continued to receive drug immediately prior to sessions.

Subjects in the After Group showed no tolerance when this regimen began. If the

development of tolerance was solely dependent on drug exposure alone, performance in

the After Group should have been indistinguishable from that of the Before Group since

both groups had received an equal number of administrations of the drug. Instead,

performance in the After Group resembled that of the Before Group receiving pre-session

drug for the first time. The development of tolerance therefore depended upon the time

of drug administration in relation to the behavioral task and not simply drug exposure

alone. This type of tolerance has been described as "contingent tolerance" (Carlton &

Wolgin, 1971). Differences in performance between the two groups were attributed to

differences in behavioral experience. One plausible interpretation of contingent tolerance

is that the initial loss of reinforcement due to drug administration promoted the Before

Group to engage in some form of behavioral compensation, whereas animals in the After

Group experienced no loss of reinforcement during the period of post-session

administration and had no opportunity to develop behavior that would compensate for the

loss occasioned by pre-session administration.

The role of reinforcement loss in the development of tolerance was first suggested

in an experiment conducted by Schuster, Dockens, and Woods (1966). Three rats were

used as subjects. Subjects received administrations of amphetamine immediately prior to

exposure to a two-component multiple schedule. One component provided differential

reinforcement for low rates of responding (DRL) while the other delivered reinforcement

on a fixed-interval (FI) schedule. Effective doses of amphetamine resulted in rate

increases in both components for two rats, which resulted in decreased rates of









reinforcement in the DRL component. Decreases in rate across both components were

observed for the third subject, which resulted in loss of reinforcement in the FI

component. After repeated administrations of 1.0 mg/kg of drug, tolerance to the initial

effects of amphetamine was observed for all subjects only in the components in which an

initial loss of reinforcement had been observed. Similar effects have been observed in a

wide variety of experiments (see Corfield-Sumner & Stolerman, 1978 and Wolgin, 1989

for reviews). The view that tolerance to the behavioral effects of drug depends on the

initial effect of drug on reinforcement received has been coined as the "reinforcement-

loss hypothesis" (Corfield-Sumner & Stolerman, 1978).

Some qualifications for the development of differential tolerance according to the

reinforcement-loss hypothesis were suggested in a study conducted by Smith (1986a).

Smith investigated the effects of amphetamine on responding in rats on a multiple

random-ratio (RR) DRL schedule of reinforcement. Initially, amphetamine caused

decreased rates of responding in the RR component and increased rates of responding in

the DRL component, resulting in loss of reinforcement in both components. Tolerance

during repeated exposure to amphetamine was observed only in the RR component.

Tolerance, however, did develop in the DRL component when it was presented alone,

and that tolerance subsequently disappeared when the RR component was reintroduced.

The results suggest that tolerance in a situation can depend on the context in which that

situation appears. Specifically, the author noted that tolerance could be influenced by

global reinforcement rates. The loss of reinforcement in the DRL schedule might have

been relatively insignificant when compared to the overall rate of reinforcement when the









RR schedule was present, as opposed to when the DRL schedule was the only one

available.

An example of differential tolerance that depended on reinforcement-schedule

type was demonstrated in research conducted by Hoffman, Branch, and Sizemore (1987).

Pigeons were placed on a three-component multiple fixed-ratio (FR) schedule of

reinforcement. Pigeons were exposed to a multiple FR 5 FR 25 and either FR 125 or 50.

Initial exposure to various doses of pre-session cocaine resulted in dose-dependent

decreases in rates of responding across all three components. After chronic

administration of pre-session cocaine, dose-response functions were reassessed.

Generally, more tolerance to the initial rate-decreasing effects of cocaine was observed in

the small and medium sized FR components, and little if any tolerance was observed in

the large FR component. Other research has also identified parameter-specific tolerance

in the context of multiple FR schedules (e.g., Hughes & Branch, 1991; Nickel, Alling,

Kleiner, & Poling, 1993). In these studies, as well as that of Hoffman et al., less

tolerance was observed in the largest FR component, which had a lower rate of

reinforcement when compared to that of the small and medium FR components. Thus,

one possible interpretation is that the development of tolerance is influenced by rate of

reinforcement.

A view of tolerance based on relative baseline rates of reinforcement, however,

cannot explain the results of a follow-up experiment to the Hoffman et al. study

conducted by Schama and Branch (1989). Pigeons were exposed to a multiple fixed-

interval (FI) schedule of food reinforcement. The FI values (i.e., 5s, 30s, and 120s)

approximated the average inter-reinforcement times observed in the Hoffman et al.









experiment. Dose-dependent decreases in rates of responding to the initial

administrations of pre-session cocaine were observed for all subjects across the three FI

components, a result similar to that seen by Hoffman et al. Unlike the Hoffman et al.

study, however, similar levels of tolerance to the initial rate-reducing effects of pre-

session cocaine for a given subject were observed across the different components after

chronic administration of pre-session cocaine. That is, tolerance did not depend on the

schedule parameter, and therefore not on reinforcement rate.

Schama and Branch suggested an alternative possibility. One difference between

the Schama and Branch study and the Hoffman et al. experiment was the number of

required responses for reinforcement to be delivered. In an FR schedule, the number of

responses required for reinforcement delivered is simply the ratio value. In an FI

schedule, however, only 1 response is required for reinforcement to be delivered.

Schama and Branch's suggestion that response requirement might be important in

producing schedule dependent tolerance points to a more thorough analysis of response

requirement. One method that has been utilized to quantify the relationship between

response requirement and reinforcement is the concept of unit price, a term borrowed

from micro-economics (see Bickel, Green, & Vuchinich, 1995; DeGrandpre, Bickel,

Hughes, Laying, & Badger, 1993 for reviews). Unit price refers to the cost-benefit ratio,

which can be interpreted as the response effort divided by the reinforcement magnitude.

From a unit-price perspective, the various FI components in the Schama and Branch

study all had the same unit price. Unit price in the Hoffman et al. experiment, however,

was different for each component; since the same amount of reinforcement was delivered

regardless of the size of the ratio completed, unit price increased with FR size. A






6


possible account of the differences in outcomes of the two studies therefore is that they

reflect the effects of differences in unit price. The purpose of the current experiment was

to investigate explicitly the relation between unit price and parameter-specific tolerance

under FR schedules.














CHAPTER 2
EXPERIMENT 1

Methods

Subjects

Six adult, male White Carneau pigeons maintained at 80% of their free-feeding

weights served as subjects. All subjects were both experimentally and drug naive prior to

the start of the experiment. Between experimental sessions, the pigeons were

individually housed in a temperature-controlled colony room with a 16:8 hr light/dark

cycle. While in the home cages, pigeons had continuous access to vitamin-enriched

water and health grit.

Apparatus

Sessions were conducted in an operant-conditioning chamber for pigeons. The

inside of the chamber was 30 cm wide, 36 cm tall, and 35.5 cm deep. The ceiling and

walls were painted white except for the work panel, which was brushed aluminum.

Chamber illumination was provided by a 1.1-W, 28-VDC lamp (houselight) that was

horizontally centered on the work panel and located 2 cm below the chamber ceiling. An

aluminum shield below the bulb deflected light towards the ceiling. In addition to the

houselight, the work panel was equipped with 3 circular, horizontally aligned response

keys and an aperture through which food could be made available. Each response key

was 2.5 cm in diameter and located 8.5 cm from the chamber ceiling. Each response key

could be transilluminated. Only the center response key was used, and it could be

transilluminated yellow, green, or red by 1.1-W, 28-VDC lamps. A static force of 0.11 N









registered as a response. Responses on the illuminated center response key resulted in a

30-ms tone. Responses were recorded with a Gerbrands Model C-3 cumulative-response

recorder, which provided continuous recording of responses. The cumulative recorder

was paused during grain deliveries. Mixed grain was made available via a food aperture

that was located below the center key and 11 cm from the chamber floor. The food

aperture was 6 cm wide and 5 cm tall. When grain was available, the houselight and

keylight were off, and the food aperture was illuminated by a 1.1-W, 28-VDC lamp.

Head-in-hopper time was measured with a MED Associates Single Channel I/R Source,

Detector, and Control. The device generated an infrared beam across the opening of the

food aperature. Entries and exits into and out of the food aperture were detected by

breaks in the photobeam. A steel mesh covered the chamber floor, and a ventilation fan,

located on the back wall, operated during the entire session. White noise of

approximately 95 dB was also continuously present in the room that housed the

experimental chamber. A half-silvered glass, 21 cm by 24 cm, in the door of the chamber

allowed observation of the pigeon. Events were controlled and data collected by a

dedicated computer system (Walter & Palya, 1984).

Hopper and Keypecking Training

Pigeons were initially trained to eat from the food hopper. Hopper training was

completed in a single session for each subject. A modified autoshaping procedure

(Brown & Jenkins, 1968) was then implemented in order to establish pecking on the

white response key. Sessions were preceded by a 5-min blackout during which all lights

in the chamber were turned off and no programmed contingencies were in effect.

Sessions began with all lights in the chamber turned off. Access to grain was presented

on a fixed-time (FT) 1-min schedule. Each 3-s hopper presentation was preceded by an 8









s illumination of the response key by yellow and the houselight. If a peck did not occur

on the illuminated keylight, the session was concluded after 30 hopper presentations on

the FT 1-min schedule. All hopper presentations were accompanied by illumination of

the hopper aperture and all other chamber lights were extinguished. If a peck occurred on

the illuminated response key, 3 s of access to grain was presented immediately.

Subsequently, the houselight and keylight were turned on, and food was presented on a

fixed-ratio (FR) 1 schedule for 50 food presentations. Pecking on the illuminated

response key was not observed for two subjects (i.e., 46 and 435) after 8 sessions of the

autoshaping procedure. Therefore, shaping via reinforcement of successive

approximations (cf. Ferster, 1953) was implemented. Pecking was subsequently

observed for both of these subjects after 1 session of shaping.

FR Shaping

All subsequent sessions continued to be preceded by a 5-min blackout and began

with illumination of the houselight and response key. Once responding on the yellow

response key reliably occurred on an FR 1 schedule of reinforcement for two consecutive

sessions, the response requirement was gradually increased both within and across

sessions utilizing the following FR values: 2, 3, 4, 5, 7, 9, 12, 15, 20, 25, 30, 35, 40, 50,

60, 70, 80, 90, and 100. The FR value was increased after 4 consecutive ratios were

completed that all satisfied an inter-response time (IRT) criterion. For ratio values less

than 50, all IRTs had to be equal to or less than 1 s. For ratio values greater than or equal

to 50, the last 30 responses had to satisfy a 1-s IRT criterion, and all other responses had

to terminate an IRT of 30 s or less. Sessions began with the last FR value that had

satisfied the IRT criterion in the previous session. Occasionally, smaller FR values were

also included for the first several FR values if erratic responding was observed in the









previous session. Completion of the FR requirement resulted in 3 s access to grain.

Sessions were concluded once either 50 reinforcers were delivered or 40 min had elapsed,

whichever came first.

Baseline

Once responding reliably occurred on the FR 100 schedule, designated the large-

ratio component, two additional components were introduced at the same time. The

small-ratio component, signaled by a green key, was increased from FR 4 to FR 10 after

one session. The medium-ratio component, signaled by a red key, was introduced as an

FR 5 and subsequently increased to FR 15 then FR 30 across daily sessions. Sessions

were conducted 7 days a week at approximately the same time each day. Each session

was arranged into 4 blocks where a block consisted of one presentation each of the small-

FR, medium-FR, and large-FR components. Components were presented randomly

without repetition within a block. Components were separated by a 20-s blackout and

were concluded once either the FR requirement had been completed or a time limit had

elapsed. The time limits for the small, medium, and large components were 1 min, 2

min, and 6 min, respectively.

The timer that controlled access to grain started once a pigeon inserted its head

into the hopper, as detected by the photobeam. Head-in-hopper time was recorded to

measure obtained unit prices. If a pigeon did not approach the hopper when presented, a

limited hold was in force. If the pigeon did not insert its head into the hopper within 10 s

of a hopper presentation, the hopper was lowered and the inter-component blackout was

initiated, after which the next component ensued. Typical latencies to hopper entry were

approximately 1 s for all subjects.









Completion of the FR 10 resulted in 1.5 s access to grain, completion of the FR 30

resulted in 4.5 s access to grain, and completion of the FR 100 resulted in 15 s access to

grain. Therefore, the unit price was held constant across components at a value of 6.67

pecks/s of access to grain. Baseline continued until at least 30 sessions had been

conducted and rates across components appeared stable as judged by visual inspection of

daily response rates and cumulative records (36 to 42 days).

Drugs and Drug Administration Procedure

Cocaine hydrochloride was dissolved in 0.9% sodium chloride (saline) solution.

Drug doses were computed as the salt. Injection volumes were 1 ml/kg. Injections were

administered immediately prior to sessions via intramuscular injections into the pectoral

muscle. When injections occurred daily, the injection site was alternated between the left

and right pectoral muscles in order to minimize any potential bruising. The range of

doses that a given subject received during Phase 2 was the same as that administered

during acute dose administrations.

Acute Dosing (Acute)

All subjects initially received the same range of cocaine doses (1.0, 3.0, 5.6, and

10.0 mg/kg). Subjects 46 and 435 later received a lower range of doses (0.3, 1.0, 3.0, and

5.6 mg/kg) based on dose-response curves generated with the original doses. Each dose

was administered at least twice under this regimen. Further administrations with some

doses were conducted as necessary for individual doses whenever it was deemed

necessary to obtain a better estimate of the mean effect. Table 1 shows the number of

acute-dose administrations for each dose that each subject received during the Acute

Phase. All injections were separated by at least 5 days, and sessions conducted the day

before drug-test or vehicle-test sessions provided control values.









Chronic Variable-Dosing with Same Unit Price (SUP1)

Pre-session injections were administered immediately prior to every session

according to a variable-dosing regimen. Branch, Wilhelm, and Pinkston (2000) and

Miller and Branch (2002) demonstrated that a chronic variable-dosing regimen produced

similar levels of tolerance to the initial disruptive effects of pre-session cocaine on FR

performance when compared to a chronic fixed-dosing regimen, so such a regimen was

chosen here. Specifically, beginning with saline, various doses of cocaine were

administered in descending order of dose magnitude. That is, on successive days,

subjects received pre-session injections of 0.0, 10.0, 5.6, 3.0, and 1.0 mg/kg of cocaine in

that order, and then the order was repeated. Subjects 46 and 435 received 0.0, 5.6, 3.0,

1.0, and 0.3 mg/kg of cocaine. Doses were administered in a fixed as opposed to random

order so that order effects, should they exist, could better be observed (cf. Sidman, 1960).

Additionally, Miller and Branch (2002) showed similar degrees of tolerance across three

groups of pigeons that were exposed to variable-dosing regimens with different dose

orders.

Once through the dose-response sequence was defined as a cycle. Thus, a cycle

consisted of five sessions. If deviations from the procedure were observed for a

particular session (e.g., apparatus failure, incorrect dose administration, etc.), the data

from that cycle were neither plotted nor utilized in judging stability. Table 2 shows the

number of cycles completed for each subject during Chronic Variable-Dosing. The phase

was carried out until at least 15 cycles were conducted, and stable rates across

components were observed as judged by visual inspection of plots of response rates for

successive dose administrations. The rates for the last 5 successive exposures for each

component under each dose were used to judge stability.









Results

Dose-Response Functions

Figure 1 shows dose-response functions generated from the Acute Phase and

Chronic Variable-Dosing. Unit price was equal across components of the multiple

schedule in both phases. Figure 2 shows dose-response curves generated from both

phases with rate expressed as a proportion of those observed following saline

administrations. For both Figure 1 and Figure 2, means for Acute points represent the

average of all acute administrations while means for chronic administration were

generated from averaging the results of the last five administrations of each dose.

Dose-related decreases in response rate were observed for all subjects during the

Acute Phase (black filled circles). Overall, visual inspection of the acute dose-response

functions showed no consistent differences in the effects of cocaine across components.

Response rates for Subjects 435 and 693 showed greater decreases at some doses in the

large-ratio component as compared to the decreases in the small-ratio and medium-ratio,

but such differences were not seen in other subjects. In contrast, Subject 46 showed

some responding at 3.0 mg/kg in the medium-ratio and large-ratio component while no

responding was observed in the small-ratio component after this dose. For the remaining

pigeons, dose-response functions were similar across components, with the similarity

most clearly evident in the normalized data of Figure 2.

A comparison of dose-response curves generated from Acute administrations and

repeated variable-dosing shows that tolerance developed to the initial rate-decreasing

effects of cocaine for all subjects at the smallest dose that lowered rates beyond the

control range acutely. This was true in all 3 components of the multiple schedule for all

six pigeons (i.e., in 18 of 18 cases). Tolerance was not observed at the largest individual









dose administered for any subject except for 693. Overall, even though different degrees

of tolerance were observed across subjects, similar levels of tolerance were observed

across components for each individual subject. That is, tolerance generally was not

related systematically to FR value. For example, effects at the largest dose, one that

produced similar decreases in all three components, are comparable across all three ratio

values. For Subjects 435 and 693 tolerance was somewhat greater in the larger-ratio

component, due mainly to the between-component differences in acute effects. For both

these subjects, rates returned toward baseline levels at all doses that produced decreases

acutely.

A quantitative measure based on the dose-response function is the effective dose

(ED50) at which responding is suppressed to 50% of Baseline. The ED50 values were

calculated by finding the slope of the descending limb of the normalized dose-response

function (Figure 2). The descending portion of the dose-response function began at the

last point at which rates were at least 90% of those observed during saline sessions and

extended through all higher-dose points until rate was zero or to the highest dose

presented if no dose eliminated pecking. If none of the points on the normalized dose-

response function were above 90%, all the points were utilized. The second and third

sets of columns of Table 3 show the ED50s from acute administrations and chronic

variable-dosing. These data confirm the visual impression that drug effects were

not related systematically to FR value. For example, after chronic dosing, ED50 values

were higher than the Acute ED50 values across subjects and components in 15 out 18

cases (Table 3). The overall picture, therefore, is that the chronic dosing regimen

resulted in modest tolerance that was unrelated to FR parameter.











Unit Price

Figure 3 shows median obtained unit-price values from the sessions that generated

the data points in Figures 1 and 2. The unit-price for each component was calculated by

dividing the ratio requirement by the median head-in-hopper time for all data points

during assessment of acute effects. Medians from the last five sessions at each dose were

used to summarize data from the repeated-dosing condition. The median instead of

average head-in-hopper time values was utilized to minimize the influence of outliers

from a few sessions in which the head-in-hopper time was particularly low. Generally,

little or no difference was observed between unit-prices calculated from the median vs.

average head-in-hopper time values. Absent data points are due either to reinforcers

never being obtained in those conditions or to head-in-hopper time values of 0 seconds

when the hopper was presented. Note that the y-axis for Subject 46 is expanded for the

medium-ratio and large-ratio components to accommodate very high unit prices at the 5.6

mg/kg dose. Overall, under control conditions and following administration of saline,

obtained unit-price was very similar for a given subject across components. A modest

tendency for price to be slightly higher in the large-ratio component price was observed

but obtained values were still close to the programmed value. Cocaine administration

produced small increases in unit price across all three components and did so under both

acute and chronic-administration conditions. Occasionally, large doses resulted in very

high unit prices as a result of reduced head-in-hopper times, but overall we were

successful in equating unit price across components.









Discussion

The major outcome of Experiment 1 was that a modest degree of tolerance to

cocaine's effects developed, and tolerance was not related systematically to FR parameter

value. Thus, the results of Experiment 1 did not systematically replicate the results of

previous experiments investigating tolerance to the effects of cocaine under a multiple FR

schedule of food reinforcement (Hoffman et al., 1987; Hughes & Branch, 1991; Nickel

et al., 1993). In the current experiment, with unit price equated across components,

similar degrees of tolerance were produced across different sized FR values. Previous

research on the other hand, with unit price uncontrolled, has shown greater degrees of

tolerance in the smaller-ratio components when compared to larger-ratio ones. When

differences in tolerance development were observed in the present study, the magnitude

of tolerance tended to be greater in the large-ratio component, rather than in the small-

ratio component, exactly the reverse of the pattern evident in the previous literature. The

findings, therefore, are consistent with the view that ratio-parameter-dependent tolerance

reported in other studies may have been related to the fact that different unit-prices were

arranged by the different schedules of reinforcement.

Such a conclusion remains tentative, however, because besides differences in unit-

price, the current experimental procedure differed in several other ways from the

previous studies. The current procedure was most similar to the Hoffman et al. study so

relevant comparisons will focus on these two experiments. The current experiment's FR

shaping procedure, combined with the equating of unit-prices, produced shorter pauses in

the large-ratio component than reported by Hoffman et al. Table 4 shows the average,

minimum, maximum, and standard deviation of the pre-ratio pauses obtained from

control sessions during the following acute administrations. For all subjects, the pause









was short under the smaller two ratios and somewhat longer in the largest ratio.

Although Hoffman et al. did not report overall average session pause values, they did

provide average pause values obtained from within-session blocks. Pause values they

obtained in the FR 5 and FR 25 components were comparable to those observed in the FR

10 and FR 30 components of the current study. The average of the within-session

average pause values from the large-ratio component, however, were 62.82 s and 75.98 s

for the two pigeons that experienced FR 125 and 17.76 s in the subject whose large-ratio

was an FR 50. These values are substantially larger than values shown for the FR 100 in

Table 5. It may be, therefore, that the differential tolerance reported by Hoffman et al.

was due, at least in part, to the fact that the large-ratio component controlled behavior

was characterized by relatively long pauses. Whether these differences in pause length in

the large-ratio component were due to use of equal unit prices in the present study or to

the FR training procedure used here remains to be investigated.

Longer pauses result in lower reinforcement rate under ratio schedules, so it is

possible that an important difference between the current study and that of Hoffman et al.

is the difference in reinforcement rates. From a reinforcement-rate perspective, the

shorter large-ratio pauses in the current experiment made the rate of access to food

between components more similar, which may have contributed to the comparable levels

of tolerance. Table 5 shows average rates of food hopper presentations during control

sessions for the current study and those from Hoffman et al. Rates of food presentation

for the Hoffman et al. study were calculated by first determining the average of the

average rates of responding across blocks then these rates of responding and the FR value

for a particular component were used to calculate the average rate of food delivery. The









left 3 columns show the rates of reinforcer deliveries. Differences across components

were larger in the Hoffman et al. study.

The differences in baseline responding across components may also have

contributed to the modest differences observed in the acute effects of cocaine between the

current experiment and the Hoffman et al. study. The dose-response functions generated

from acute administrations of cocaine in the Hoffman et al. experiment showed greater

dose-related decreases in the larger-ratio components than the smaller-ratio components.

Acute dose-response curves generated from the current study were generally similar

across components.

An additional difference between the procedure of Experiment 1 and that in the

Hoffman et al. study was the chronic dosing regimen. Hoffman et al. used a regimen in

which the same dose of cocaine was administered prior to every session. In the current

study, a variable-dosing regimen was used in which different doses of drug were

delivered prior to each session. The potential role of chronic variable-dosing in

producing the current results was explored in greater detail in Experiment 3.

The results of the current experiment showed similar degrees of tolerance across

different sized ratio-values. In an attempt to elucidate potential factors that might have

been responsible for the current results, Experiment 2 began with a shift to different unit-

price.









Table 1. Acute administrations. Number of administrations of each dose during the
Acute Phase for each subject.

Dose

Subject Saline .3 1.0 3.0 5.6 10

46 8 5 3 4 4

435 4 3 2 4 3

405 4 3 2 2 2

416 3 2 4 3 2

654 4 2 4 3 3

603 4 2 2 2 2


Table 2. Chronic variable dosing. Number of cycles completed for each subject during
the chronic dosing phases of Experiment 1 and 2.


Phase

Exp 1 Exp 2 Exp 2
Subject Equal Unit Price Different Unit Price Equal Unit Price

46 26 27 26

405 22 38 15

416 15 27 17

435 18 23 40

654 16 27 16

693 15 39 21












Small


100


CS 03 1 3 56


Medium


100 100

0 0
Cs 03 1 3 56


Large


-0 ACUTE
-0- SUPI

00


03 1 3 56--


300 i

200


C S


200

100


CS 1 3 56 10

300

200

100


1 3 56 10
C S 1 3 56 10


654


200


C S


200

100


CS 1 3 56 10


200

100

0
CS

300

200


U


100 100


0 1 3 5610
CS 3 56 10


300

200

100


C 03 1 3 56

300

200

100

0
CS 1 3 56 10

300

200

100


CS 1 3 56 10

300

200

100


CS 1 3 56 10


200 .

100


200

100


c-s-1 0- o- 0-
CS 1 3 56 10 C S 1


300

200

100


3 56 10 CS 1 3 56 10


MG/KG COCAINE


Figure 1. Pecks/minute as a function of dose of cocaine. Data for each subject are

presented horizontally while components are presented vertically. Black filled

circles represent mean values under conditions of acute administration. Grey

filled circles represent mean values for the last five administrations under

conditions of chronic variable dosing where access to food was correlated

with ratio size (same unit price) and a the chronic dose changed for every

session. Points above C show means from control sessions immediately

preceding injection sessions. Points above S are means from sessions

preceded by saline injections. Vertical bars through control values represent

99% confidence intervals.


435


693












Small


10 10

05 05

o0 oo00
C 03 1 3 56

15 15

10 1 10

05 05

00 00
C 03 1 3 56

15 15

10 1 0

05 156 0 E


ooC 1 3 oo
C 1 3 56 10


416


654


C 1 3 56 10 C


Medium


10

05

00
03 1 3 56

15

10

05


03 1 3 56


Large


C 03 1 3 56


--- ACUTE
1 0--SUP1

05

oo II
C 1 3 56 10

15

10

05


C 1 3 56 10

15

10

05

0 0
C 1 3 56 10


10

05


00 1 3 56 10
C 1 3 56 10


10

05


00
C 1


10

05

00
3 56 10 C 1 3 56 10


MG/KG COCAINE


Figure 2. Dose-response functions as a proportion of values observed during saline

administrations for sessions represented in Fig. 1 during acute administrations

(black filled circles) and chronic variable dosing administrations with equal

unit price (grey filled circles). The vertical bar above C represents 99%

confidence intervals as a proportion of saline values. All other details are as

in Fig.











ED50 values. Obtained ED50 values from Experiments 1, 2, and 3.


Phase Exp 1 Exp 1 Exp 2 Exp 2 Exp 3
Acute Chronic Unequal Unit Price Equal Unit Price
SubjectS M L S M L S M L S M L S M L


46 1.92 2.16 2.37 2.93 2.9 4.15 3.4 4.14 6.46 3.06 6.08 12.96 2.47 4.96 6.35


435 2.53 1.74 0.18 4 2.73 1.3 4.07 2.76 1.69 3.55 3.22 1.26 15.95 3.5 1.65


405 1.7 2.53 1.12 1.63 2.31 2.07 1.94 1.24 0.94 2.26 2.04 1.7 2.21 1.82 1.43


416 4.34 3.29 2.73 5.44 3.73 2.2 12.54 7.48 4.37 4.96 5.8 2.67 6.78 7.93 1.07


654 2.53 3.19 3.04 6.38 6.05 4.81 8.45 8.09 6.19 7.9 7.64 5.17 26.89 14.08 3.25


693 7.5 7.49 3.07 9.03 8.34 7.24 6.69 5.4 1.94 3.42 2.7 1.89 2.81 2.38 1.89


Mean 3.42 3.40 2.09 4.90 4.34 3.63 6.18 4.85 3.60 4.19 4.58 4.28 9.52 5.78 2.61


Table 3.















Large
00

00

10


3 56 CS 03

100 i


3 56 CS 03


3 56


10l 1 o lo 10 *O0 --


3 56 C S 03 1 3

100


S 10 O0


CS 1 3 56 10 CS 1

100


10 o lO O10 *O O


1 1--t
CS 1 3 56 10 CS 1


56 C S 03


3 56


100


10 0
ACUTE
-0- SUP1


3 56 10 CS 1 3 56 10


00


3 56 10 CS 1 3 56 10


100


O- 10 O0


654


CS 1 3 56 10 CS 1


693


3 56 10 CS 1 3 56 10

100


10 o0 10 *0 10 0O


C S 1 3 56 10 CS 1


3 56 10 CS 1 3 56 10


MG/KG COCAINE


Figure 3. Unit price (average component ratio value divided by the average component

head-in-hopper time) as a function of dose of cocaine for sessions represented
in Fig. 1. Values in which head-in-hopper time was zero or the ratio

requirement was not completed were not used. All other details are as in Fig.


Small


Medium


10 O


100

10


C S 03


C S 03


10 10


100


10 o Q- 10














CHAPTER 3
EXPERIMENT 2

Method

Subjects and Apparatus

Subjects and apparatus used in Experiment 1 remained the same in Experiment 2.

Chronic Variable-Dosing with Different Unit Price (DUP)

Experiment 2 began immediately on completion of Experiment 1. Its first

condition was similar to the variable-dosing condition in Experiment 1 except that

completion of each FR requirement resulted in 4.5 s access to grain, regardless of ratio

size. Thus, a different unit price was arranged for each component. The same daily

variable-dosing regimen utilized in Experiment 1 was continued during Experiment 2.

The phase was carried out until at least the same number of cycles completed in the

variable-dosing condition of Experiment 1 had been conducted and stable rates were

observed as judged by visual inspection of the last 5 exposures for each component under

each dose.

Chronic Variable-Dosing with Same Unit Price (SUP2)

The second condition of Experiment 2 was a direct replication of the variable-

dosing condition of Experiment 1 and continued until at least 15 cycles were conducted

and stable rates were observed as judged by visual inspection. Table 2 shows the number

of cycles completed for each subject in the two conditions of Experiment 2.









Results

Dose-Response Functions

Figure 4 shows dose-response functions generated from the condition with

unequal unit prices (white squares) and the subsequent return to equal unit prices (open

circles) with rate presented as a proportion of those following saline administrations.

Also plotted for comparison are dose-response functions from the acute administrations

from Experiment 1(black circles). When, in the context of daily variable dosing, unit

price was made unequal across components, no large changes were observed. The

modest tolerance, however that had been evident in Experiment 1 was no longer present

in Subjects 405 and 693. During the unequal unit-price condition ED50 values were

ordered such that they were the smallest in the large-ratio component and greatest in the

small-ratio component for 5 out of 6 subjects as seen in Table 3. Overall, across all

components ED50 values obtained with unequal unit price were greater in than those

seen with equal unit prices 13 out 18 components across subjects, but in several cases just

barely so.

When unit-price was equated across components again in the second condition of

Experiment 2, few substantial changes were observed, but in 13 of 18 components, the

ED50 decreased. Thus, Experiment 2 revealed a modest trend in which tolerance was

slightly greater under conditions of unequal unit price. No consistent systematic relations

between tolerance and ratio values, however, were observed.

Recall that the second phase of Experiment 2 was a direct replication of the second

part of Experiment 1. Figure 5 shows dose-response functions from the variable-dosing

condition of Experiment 1 and the identical condition in Experiment 2. Dose-response

functions observed during Experiment 1 were generally recaptured during Experiment 2,









except for Subjects 46 and 693. Subject 46 showed increased tolerance in the medium-

ratio and large-ratio components in the second exposure to the condition, whereas Subject

693 showed increased sensitization across components. The general tendency for the

effects to be similar is validated by examination of the fourth column of Table 3, which

shows that in 10 cases, the ED50 increased and in 8 it decreased.

Unit Price

Figure 6 shows median obtained unit-price values from acute assessments and the

two conditions where unit price was equated. Programmed unit-prices were the same for

all data points represented by circles and for points in the medium-ratio component when

unit prices were different. Programmed unit-price values were different only in the

small-ratio and large-ratio in the first condition of Experiment 2 (open squares). Subjects

showed similar obtained unit-price values wherever programmed unit-price values were

the same. That is, obtained unit prices were different only when they were programmed

to be different. Overall, smaller doses of cocaine left obtained unit price unchanged.

Larger doses often increased it. Again, unit price was generally controlled as predicted.

Discussion

The purpose of Experiment 2 was to investigate the effects of altering unit-price

during a regimen of daily variable dosing. Overall, when the same amount of food was

made available regardless of ratio size, the current results generally failed to replicate the

findings observed in the Hoffman et al. (1987) experiment. That is, pronounced FR-

value specific tolerance did not develop.

In addition to the differences between the Hoffman et al. study and the present one

noted in the discussion of Experiment 1. Another potential explanation for this failure to

replicate may be that tolerance, once obtained is difficult to eliminate. That is, repeated









exposure to cocaine in Experiment 1, where unit prices were equated, resulted in

tolerance in all three components of the multiple schedule, and when unit prices were

made different the tolerance that had developed in the FR 100 component carried over to

Experiment 2, making FR-value-specific tolerance harder to detect. To the degree that

tolerance represents some form of learned compensatory response (Wolgin, 1989), one

would not necessarily expect the recovered responding in the large-ratio component that

had developed in Experiment 1 to disappear with a decrease in reinforcer duration.

Although tolerance in the large-ratio component may have been initially driven by the

larger reinforcer magnitude in Experiment 1, responding may well have been maintained

with reduced food-duration time as long as that food-duration time still functioned as a

reinforcer, which it obviously did.

A moderate increase in overall levels of tolerance was observed when unit price

was not equal across components when compared to the second conditions of Experiment

1 and Experiment 2, where unit price was equated. One potential contributing factor may

have been differences in absolute amount of available reinforcement between conditions.

When unit price was equated across components food was available for 84 s in each

session. When unit price varied across components in Experiment 2, the total food-

access time was 54 s. The globally smaller amount of reinforcement may have increased

the reinforcing efficacy of food presentations when unit prices varied in Experiment 2

and resulted in moderately greater levels of tolerance.

A potential reason for the failure to see schedule-parameter-dependent tolerance

when unit priced varied in Experiment 2 was the use of the variable-dosing regimen to

assess effects of repeated cocaine exposure. The Hoffman et al. study involved a









chronic-fixed dosing regimen (i.e., the same dose was given daily). The decision to use a

variable-dosing regimen in the present study was based on reports by Branch et al. (2000)

and Miller and Branch (2002), who demonstrated that comparable degrees of tolerance

were produced by chronic variable-dosing and fixed-dosing regimens. Both of those

studies, however, examined an FR 20 schedule of reinforcement. Differences in

tolerance with different dosing regimens for larger ratio values, or larger ratio values in

the context of smaller ratio values, have yet to be examined. In the variable-dosing

regimen we used, administrations of small doses of drug and saline were intermixed with

larger ones, and it may have made recovery of responding in the large-ratio component

more likely. In an attempt to assess this possibility, Experiment 3 examined effects of

changing the dosing routine to a chronic fixed-dosing regimen.












Small


10 I& 10

05 05

00 00
C 03 1 3 56 C


15


15


10 I =_ 10

05 05


00 00
C 03 1 3 56 C

5 15


Medium


10

05


03 1 3 56

15

10

05

J _____1__ 5600
03 1 3 56


10

05


C 1 3 56 10


Large


C 03 1 3 56


ACUTE
1 0 -0- SUP2
S 1 DUP
05

00
C 1 3 56 10


on


654


10


3 56 10 C


10 10

05 05

00 00
C 1 3 56 10 C


15

10

05

00
C 1 3 56 10


MG/KG COCAINE





Figure 4. Pecks/min as a proportion of values observed during saline administrations for

acute administrations (black filled circles), chronic variable dosing with

unequal unit price (white open squares), and chronic variable dosing with

equal unit price (white open circles). During chronic variable dosing with

unequal unit price, access to food was the same regardless of ratio size. All

other details are as in Fig. 2.


405


693












Small


05 05


C 03 1 3 56 C

15 15

10 10

05 05

00 00
C 03 1 3 56 C


Medium
15

100

05

1 l100
03 1 3 56

15

10

05

00
03 1 3 56


10 1

05 0


3 56 10 C 1 3 56 10


10 10

05 05


C 1 3 56 10 C

15 15

10 I 010

05 05


C 1 3 56 10 C

15 15

10 10

05 05


C 1 3 56 10 C


1 3 56 10


Large







0-'


C 03


3 56


C 03 1 3 56

-0- SUP1
-0- SUP2





C 1 3 56 10

5







C 1 3 56 10

5
C 1 3 56 10









C 1 3 56 10


15

10

05

00
oo 1 3 56 10
C 1 3 56 10


MG/KG COCAINE





Figure 5. Dose-response functions from chronic variable dosing administrations with

equal unit price during Experiment 1 (grey filled circles) and Experiment 2

(white filled circles). All other details are as in Fig. 2.


435


654


693










Small Medium Large
46 100 1000 1000
46
10 100 100

0--E 10 6 10 e0
10

1 1---------- 1
CS 03 1 3 56 C S 03 1 3 56 CS 03 1 3 56
100 100 100
435

10 10 10


i ~--------- i ~--------- i.----
CS 03 1 3 56 CS 03 1 3 56 CS 03 1 3 56
100 100 100
S lOO ACUTE -- SUP2
S405 -SUP1 -0- DUP
F0 10 *0 10 1o0 0n 10 *ft h

S[D-------]
S1 --- 1 --- 1
C S 1 3 56 10 CS 1 3 56 10 CS 1 3 56 10
S100 100 100


S 10 o 010 0- 10 *O

- 1 1
C S 1 3 56 10 CS 1 3 56 10 CS 1 3 56 10

100 100 100
S654 4

lo 0 10o lo 00 O -



CS 1 3 56 10 CS 1 3 56 10 CS 1 3 56 10
100 100 100
693

10o 10 lo0 100
0 0
1 --1 1 --
CS 1 3 56 10 CS 1 3 56 10 CS 1 3 56 10


MG/KG COCAINE




Figure 6. Unit price as a function of dose of cocaine for sessions represented in Fig. 4
and 5 are shown. All other details are as in Fig. 1.















CHAPTER 4
EXPERIMENT 3

Method

Subjects and Apparatus

Subjects and apparatus used in Experiment 1 and 2 remained the same in

Experiment 3.

Chronic Fixed-Dosing with Same Unit-Price (FIX1)

Experiment 3 began immediately on completion of Experiment 2. The only

change was that subjects were administered 5.6 mg/kg of cocaine immediately prior to

every session. Unit price remained equal across components. After at least 50 sessions

were conducted and stability in daily response rates were observed, occasional sessions

were preceded by different doses of cocaine or saline, with these "probe" administrations

spaced by at least 5 sessions. Each dose was administered at least twice. Data from

sessions preceding substitute doses served as representative sessions for 5.6 mg/kg of

cocaine.

Chronic Fixed-Dosing with Same Unit-Price and Lower Chronic Dose (FIX2)

Only Subjects 405 and 693 participated in this condition. This second condition

of Experiment 3 was conducted in a manner similar to the first condition, except that

subjects received daily administrations of 3.0 mg/kg, rather than 5.6 mg/kg, of cocaine

immediately prior to every session. The shift to the smaller dose was made because

previous studies have shown that daily administrations of a relatively large dose of

chronic cocaine may reduce or eliminate tolerance (Bowen, Faller, & Kallman, 1993;









Stafford & Branch, 1996; Branch et al. 2000). Pigeons 405 and 693 showed little or no

tolerance when 5.6 mg/kg was given daily. The shift to a smaller dose was therefore

made to see if 5.6 mg/kg was too large a dose to produce tolerance. After at least 50

sessions had occurred and stability in rates was observed, dose-response functions were

assessed. Data from sessions preceding probe doses were used to characterize the effects

of 3.0 mg/kg of cocaine.

Results

Dose-Response Functions

Figure 7 shows dose-response functions generated during daily administrations of

5.6 mg/kg (white triangles) and 3.0 mg/kg (white diamonds), where subjects received

daily administrations of the same dose of cocaine. The original acute dose-response

functions are also represented by black-filled circles for comparison. Subjects 405 and

693, as they had in Experiment 2, exhibited little or no tolerance in any component, either

during repeated exposure to 5.6 mg/kg or to 3.0 mg/kg. The remaining four pigeons,

however, did show tolerance, and its magnitude was related to the FR value. The

differences are obvious for Subjects 416, 435, and 654, where tolerance was much more

pronounced at the lower ratios and less so at the largest ratio. These changes are

confirmed in the ED50s shown in Table 3. Following the transition from variable dosing

at the end of Experiment 2 to fixed dosing in Experiment 3, the ED50s for the small ratio

increased substantially, whereas the ED50s for the large ratio either decreased (416 &

654) or changed little (435). Subject 46 also revealed a similar FR-parameter dependent

effect. Throughout all the chronic-dosing regimens of Experiments 1, 2, and 3, this

subject had higher ED50s in the larger ratios, but when the shift was made from variable

dosing to fixed dosing, the ED50 in the large ratio was decreased by half (see Table 3),









whereas the ED50s in the other two components were decreased by a bit less than 20%.

Even the two subjects that showed no tolerance had their ED50s ordered such that the

largest was in the small ratio and smallest in the large ratio. The overall picture across

subjects, therefore, was that if tolerance was evident, its magnitude was influenced by the

FR parameter value.

Unit Price

Figure 8 shows median obtained unit-price values from Experiment 3. Overall,

obtained unit-price was similar across components for a given subject and similar to

obtained unit-prices obtained in previous conditions when programmed unit-price

remained the same.

Discussion

Two general trends were observed once the chronic dosing-regimen was shifted

from variable-dosing to a fixed-dosing regimen. Four of the subjects showed tolerance

that was influenced by the FR parameter value. These four subjects exhibited a pattern of

tolerance similar to that observed by Hoffman et al. (1987). Fixed dosing led to

diminished relative tolerance in the large-ratio component. The remaining two, although

not showing tolerance, had their ED50s ordered from largest to smallest across increasing

ratios. (It is important to recall, however, that for Subject 693 this "ordering" was present

at the outset of Experiment 1). This outcome suggests three important conclusions. One,

schedule-parameter-dependent tolerance does not depend on difference in unit price

across the different schedules. Unit price was essentially equal across components of the

multiple schedule, yet parameter-dependent tolerance was observed. Two, parameter-

dependent tolerance does not depend on differences in the acute effects of cocaine. In the

present study, acute effects were relatively similar across components, a state of affairs









that stands in contrast to those observed by Hoffman et al. Three, the observation of

schedule-parameter dependence may depend on repeated exposure to a fixed dose.

The failure of tolerance to develop to any significant degree in two of the subjects

remains a puzzle. There were no features of their performances that suggested that their

behavior was controlled in a manner different from that of the other subjects. Previous

research with pigeons responding under FR schedules of food presentation has revealed

little or no tolerance in a minority of subjects (Branch et al., 200; Miller & Branch,

2002), but the origins of these individual differences remain obscure.

The parameter dependence of tolerance evident when the daily pre-session dose

was fixed suggests that the training method, which produced higher-rate large FR

performance, was not the key factor. Even though baseline response and reinforcement

rates were more similar in the present study than in previously reported work, parameter-

dependent tolerance was still observed. These results therefore increase the generality of

the ratio-parameter dependence of tolerance.











Small


10 A 10

05 05

00 o 00 C
C 03 1 3 56 C


Medium


10

05

00
03 1 3 56


10 0 0

C 03 1 3 05


3 56 C 03 1 3 56


C 03 1 3 56


1 10

05 05

00 3 56 00
C 1 3 56 10


C 1 3 56 10


654


10 1 10

05 05

00 00
C 1 3 56 10


693


-- ACUTE
10 -- FIX
FIX2
05

oo
C 1 3 56 10

15

10

05

oo00
C 1 3 56 10

15

10

05

00
C 1 3 56 10

15

10

05

00


MG/KG COCAINE




Figure 7. Dose-response functions from acute administrations (black filled circles) and
chronic fixed-dosing administrations with 5.6 mg/kg of cocaine (open
triangles) are shown. Subjects 46, 405, and 693 also received chronic fixed-
dosing administrations with 3.0 mg/kg of cocaine (white diamonds). For all
data points, values represent the mean of all administrations at a particular
dose. All other details are as in Fig. 2.


Large


435


00 _
C 03 1


405








416


0











Small
6 100
46 .

10 j



1 s 03 1 3 56


37

Medium Large
100 100


10 s 3 1 3 5 10



CS 03 1 3 56 CS 03 1 3 56


100 100 100
435




10 10 10
C 03 1 3 56 CS 03 1 3 56 CS 03 1 3 56

100 100 100
405

10 10 o 10Q -
S ACUTE
-c- FIX2
S1 3 56 10 1 13 56 10
CS 1 3 56 10 CS 1 3 56 10 CS 1 3 56 10


416 100

10



CS 1 3 56 10


100



10



CS 1 3 56


100



10



CS 1 3 56 10


S100 100 100
654

o10 o10 lo 10


1 1 1
CS 1 3 56 10 CS 1 3 56 10 CS 1 3 56 10

100 100 100
693

10 10 10


1 1 1
CS 1 3 56 10 CS 1 3 56 10 CS 1 3 56 10


MG/KG COCAINE




Figure 8. Unit price as a function of dose of cocaine for sessions represented in Fig. 9
are shown. All other details are as in Fig. 1.














CHAPTER 5
GENERAL DISCUSSION

The main purpose of the current experiment was to see if equating unit price would

result in similar levels of tolerance across different size fixed ratios, and that was

observed in Experiment 1. The results of Experiment 1 showed that similar levels of

tolerance were evident across FR values when unit price was equated across different FR

values and when a chronic variable-dosing regimen was used. The magnitude of

tolerance increased slightly when unit price differed across components in Experiment 2,

but schedule-parameter-dependent tolerance did not develop. When unit price was

equated once again, however, and fixed-dosing was implemented, parameter-specific

tolerance emerged in the four subjects that consistently exhibited tolerance. It appears,

therefore, that repeated exposure to a fixed dose was critical in producing FR parameter-

dependent effects.

It is not clear why repeated exposure to a fixed dose should have promoted the

influence of schedule parameter whereas repeated exposure to varied doses did not.

Previous research comparing fixed and variable dosing (Branch et al., 2000; Miller &

Branch, 2002) has illustrated the similarity in effects of the two approaches to chronic

drugging. Those studies, like the present work, involved the use of FR schedules, but

only a single schedule parameter was employed, in contrast to the three values used here.

Theories to account for the development of tolerance to a drug's behavioral effects on

operant performance have emphasized the role played by learning, learning to cope with

the drug's disruption of the ability to obtain reinforcement (Corfield-Sumner &









Stolerman, 1978; Schuster et al., 1966; Wolgin, 1989). Because the relative decrease in

rate of reinforcement was greater in the small-ratio component as compared to that in the

large-ratio component, one might predict better learning in the small-ratio component,

but still puzzling is why that difference in learning should be amplified by experience

with a fixed dose, rather than repeated variable dosing. One possibility that may have

played a role in the present set of experiments is the amount of exposure to each dose. In

the variable dosing procedures, each dose was experienced 15 to 40 times over the course

of each experiment, with the total number of exposures to each dose ranging from 59 to

81 (see Table 2) across all 3 experiments. In the fixed dosing experiment, the same dose

was experienced at least 50 times before probed doses were tested, and at least 40

additional exposures occurred while does-effects were being assessed. The notable

difference, therefore, is not in the total number of exposures, but instead the fact that

under the fixed-dosing regimen the same dose, and presumably therefore the same drug

state, was present in each session. That feature of the regimen may have made learning

to cope easier. A useful follow-up experiment that might confirm the difference between

variable- and fixed-repeated dosing would be one in which the conditions were arranged

in an order the reverse of that in the present study. That is, after establishment of a

baseline of responding with small and large ratios, a fixed-dosing regimen could be

imposed that would result in parameter-specific tolerance. The regimen could then be

changed to variable dosing to determine if the parameter dependence remained or not.

The present results also suggest that, at least in the context of receiving a fixed dose

of cocaine each session, unit price differences are not crucial for observing FR-schedule

dependent tolerance. In Experiment 3, unit prices were equal across components, yet FR






40


parameter dependent effects were evident when cocaine was given repeatedly. The

apparent lack of importance of unit price raises the question of what it is about ratio

schedules that promotes parameter dependence of tolerance. Previous research suggests

that reinforcement-rate differences are not the key (Schama & Branch, 1989), so what

remains is simply the work requirement. Other methods of producing differential

amounts of required effort should be a productive avenue for research on this issue.















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BIOGRAPHICAL SKETCH

Jin Ho Yoon graduated from the University of Pennsylvania in 1996. He then

worked at Children's Seashore House first as an intern and then as a clinical specialist

with developmentally delayed individuals with severe problem behavior. It was at

Children's Seashore House that Jin decided to forgo a medical career in favor of

conducting behavior analysis research. Jin was accepted to the University of Florida

graduate program in psychology with a specialization in experimental analysis of

behavior and continues in pursuit of a PhD.