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

Transcription

1 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

2 Copyright 2003 by Jin Ho Yoon

3 This document is dedicated to my grandfather.

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

5 TABLE OF CONTENTS Page ACKNOWLEDGMENTS... iv LIST OF TABLES... vii LIST OF FIGURES... viii ABSTRACT... ix CHAPTER INTRODUCTION... 2 EXPERIMENT...7 Methods...7 Subjects...7 Apparatus...7 Hopper and Keypecking Training...8 FR Shaping...9 Baseline...0 Drugs and Drug Administration Procedure... Acute Dosing (Acute)... Chronic Variable-Dosing with Same Unit Price (SUP)...2 Results...3 Dose-Response Functions...3 Unit Price...5 Discussion EXPERIMENT 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

6 4 EXPERIMENT Method...32 Subjects nd Apparatus...32 Chronic Fixed-Dosing with Same Unit-Price (FIX)...32 Chronic Fixed-Dosing with Same Unit-Price and Lower Chronic Dose (FIX2) 32 Results...33 Dose-Response Functions...33 Unit Price...34 Discussion GENERAL DISCUSSION...38 LIST OF REFERENCES...4 BIOGRAPHICAL SKETCH...43 vi

7 LIST OF TABLES Table page. Acute administrations Chronic variable dosing ED50 values...22 vii

8 LIST OF FIGURES Figure page. Dose-response functions Experiment Dose-response functions as a proportion of saline Experiment Unit price Experiment Dose-response functions as a proportion of saline Experiment Dose-response functions as a proportion of saline Experiment Unit price Experiment Dose-response functions as a proportin of saline Experiment Unit price Experiment viii

9 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 Chair: Marc N. Branch Major Department: Psychology By Jin Ho Yoon May 2003 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 0, 30, or pecks were required for each delivery of food. In Experiment, 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 were reinstated, i.e., unit price was equated. Making unit price different and then the same again had little ix

10 influence on effects of cocaine. In Experiment 3, a fixed dose of cocaine was administered before each session. Under these conditions, tolerance became peckrequirement 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

11 CHAPTER 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, 978; Wolgin, 989; Hardman, Gilman, & Limbird, 995). 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, 983; Wolgin, 989). This line of interpretation has emanated largely from research that follows upon a method introduced by Chen (968). 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 twoturn 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

12 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, 97). 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 (966). 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

13 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 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, 978 and Wolgin, 989 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 reinforcementloss hypothesis (Corfield-Sumner & Stolerman, 978). Some qualifications for the development of differential tolerance according to the reinforcement-loss hypothesis were suggested in a study conducted by Smith (986a). 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

14 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 (987). 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 25 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, 99; Nickel, Alling, Kleiner, & Poling, 993). 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 (989). Pigeons were exposed to a multiple fixedinterval (FI) schedule of food reinforcement. The FI values (i.e., 5s, 30s, and 20s) approximated the average inter-reinforcement times observed in the Hoffman et al.

15 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 presession 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 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, 995; DeGrandpre, Bickel, Hughes, Laying, & Badger, 993 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

16 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.

17 CHAPTER 2 EXPERIMENT 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 naïve prior to the start of the experiment. Between experimental sessions, the pigeons were individually housed in a temperature-controlled colony room with a 6:8 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.-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.-w, 28-VDC lamps. A static force of 0. N 7

18 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 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.-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, 2 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, 984). 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, 968) 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) -min schedule. Each 3-s hopper presentation was preceded by an 8

19 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 -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) 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, 953) was implemented. Pecking was subsequently observed for both of these subjects after 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 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, 2, 5, 20, 25, 30, 35, 40, 50, 60, 70, 80, 90, and. 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 s. For ratio values greater than or equal to 50, the last 30 responses had to satisfy a -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

20 0 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 schedule, designated the largeratio 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 0 after one session. The medium-ratio component, signaled by a red key, was introduced as an FR 5 and subsequently increased to FR 5 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 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 0 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 s for all subjects.

21 Completion of the FR 0 resulted in s access to grain, completion of the FR 30 resulted in 4.5 s access to grain, and completion of the FR resulted in 5 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 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 (, 3.0, 5.6, and mg/kg). Subjects 46 and 435 later received a lower range of doses (0.3,, 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 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.

22 2 Chronic Variable-Dosing with Same Unit Price (SUP) 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,, 5.6, 3.0, and mg/kg of cocaine in that order, and then the order was repeated. Subjects 46 and 435 received, 5.6, 3.0,, 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, 960). 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 5 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.

23 3 Results Dose-Response Functions Figure 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 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 8 of 8 cases). Tolerance was not observed at the largest individual

24 4 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 doseresponse 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 5 out 8 cases (Table 3). The overall picture, therefore, is that the chronic dosing regimen resulted in modest tolerance that was unrelated to FR parameter.

25 5 Unit Price Figure 3 shows median obtained unit-price values from the sessions that generated the data points in Figures 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.

26 6 Discussion The major outcome of Experiment 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 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., 987; Hughes & Branch, 99; Nickel et al., 993). 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 smallratio 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 unitprice, 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

27 7 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 0 and FR 30 components of the current study. The average of the within-session average pause values from the large-ratio component, however, were s and s for the two pigeons that experienced FR 25 and 7.76 s in the subject whose large-ratio was an FR 50. These values are substantially larger than values shown for the FR 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

28 8 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 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 unitprice.

29 9 Table. Acute administrations. Number of administrations of each dose during the Acute Phase for each subject. Dose Subject Saline Table 2. Chronic variable dosing. Number of cycles completed for each subject during the chronic dosing phases of Experiment and 2. Phase Subject Exp Equal Unit Price Exp 2 Different Unit Price Exp 2 Equal Unit Price

30 Small Medium Large ACUTE SUP 0 C S C S C S C S C S C S RESPONSES/MIN C S C S C S C S C S C S C S C S C S C S C S C S MG/KG COCAINE Figure. 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.

31 46 2 Small Medium Large C C C PROPORTION OF SALINE VALUE C C C C C C C ACUTE SUP C C C C C C C C MG/KG COCAINE Figure 2. Dose-response functions as a proportion of values observed during saline administrations for sessions represented in Fig. 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.

32 Table 3. ED50 values. Obtained ED50 values from Experiments, 2, and 3. Phase Exp Acute Exp 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 Mean

33 Small Medium Large C S C S C S UNIT PRICE (PECKS/S OF FOOD ACCESS) C S C S C S C S C S C S C S ACUTE SUP C S C S C S C S C S C S C S C S 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.. 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..

34 CHAPTER 3 EXPERIMENT 2 Method Subjects and Apparatus Subjects and apparatus used in Experiment remained the same in Experiment 2. Chronic Variable-Dosing with Different Unit Price (DUP) Experiment 2 began immediately on completion of Experiment. Its first condition was similar to the variable-dosing condition in Experiment 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 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 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 variabledosing condition of Experiment and continued until at least 5 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

35 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 (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 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 3 out 8 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 3 of 8 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. Figure 5 shows dose-response functions from the variable-dosing condition of Experiment and the identical condition in Experiment 2. Dose-response functions observed during Experiment were generally recaptured during Experiment 2,

36 26 except for Subjects 46 and 693. Subject 46 showed increased tolerance in the mediumratio 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 0 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. (987) experiment. That is, pronounced FRvalue 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. Another potential explanation for this failure to replicate may be that tolerance, once obtained is difficult to eliminate. That is, repeated

37 27 exposure to cocaine in Experiment, 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 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, 989), one would not necessarily expect the recovered responding in the large-ratio component that had developed in Experiment 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, 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 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 foodaccess 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

38 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.

39 46 29 Small Medium Large 435 C C C C C C PROPORTION OF SALINE VALUE C C C C ACUTE SUP2 DUP C C C C C C C C 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.

40 46 30 Small Medium Large C C C PROPORTION OF SALINE VALUE C C C C C C C SUP SUP2 C C C C C C C C MG/KG COCAINE Figure 5. Dose-response functions from chronic variable dosing administrations with equal unit price during Experiment (grey filled circles) and Experiment 2 (white filled circles). All other details are as in Fig. 2.

41 Small Medium Large C S C S C S C S C S C S UNIT PRICE (PECKS/S ACCESS OF FOOD) C S C S C S ACUTE SUP SUP2 DUP C S C S C S F FIX C S C S C S C S C S C S 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..

42 CHAPTER 4 EXPERIMENT 3 Method Subjects and Apparatus Subjects and apparatus used in Experiment and 2 remained the same in Experiment 3. Chronic Fixed-Dosing with Same Unit-Price (FIX) 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, 993; 32

43 33 Stafford & Branch, 996; 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 46, 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 (46 & 654) or changed little (435). Subject 46 also revealed a similar FR-parameter dependent effect. Throughout all the chronic-dosing regimens of Experiments, 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),