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Choosing to take cocaine in the human laboratory: effects of cocaine dose, inter-choice interval, and magnitude of alternative reinforcement
Drug and Alcohol Dependence 69 (2003) 289 /301 www.elsevier.com/locate/drugalcdep
Choosing to take cocaine in the human laboratory: effects of cocaine dose, inter-choice interval, and magnitude of alternative reinforcement Eric C. Donny *, George E. Bigelow, Sharon L. Walsh Behavioral Pharmacology Research Unit, Department of Psychiatry and Behavioral Sciences, Johns Hopkins School of Medicine, 5510 Nathan Shock Drive, Baltimore, MD 21224, USA Received 5 March 2002; received in revised form 16 September 2002; accepted 16 October 2002
Abstract Cocaine abuse involves a variety of behaviors including the initiation of cocaine-seeking, the self-selected patterning of cocaine administrations, and the cessation of cocaine-taking. To date, most human laboratory models of cocaine self-administration have only assessed the amount of cocaine consumed under a fixed set of conditions. This double-blind, randomized, within-subject, inpatient study evaluated a novel model of human cocaine self-administration that aimed to quantify the reinforcing value of cocaine after cocaine-taking was initiated. Cocaine-dependent volunteers (n /8) sampled cocaine (12.5, 25 or 50 mg per 70 kg i.v.) or placebo and were subsequently allowed to choose between another injection of the same dose or money over six trials during 12 experimental sessions. The value of the monetary alternative increased with each trial from $1 to 16. Each cocaine dose was assessed under three inter-choice intervals: 15 min, 30 min, and an interval selected by the volunteer. Injection choices increased dose dependently; however, there was little relationship between the value of the alternative reinforcer and the choice to take cocaine. Most volunteers exclusively chose injections when active cocaine was available and money when placebo was available. Inter-choice interval did not affect cocaine choices. These results illustrate the persistence of cocaine self-administration once cocaine-taking has been initiated. # 2002 Elsevier Science Ireland Ltd. All rights reserved. Keywords: Self-administration; Stimulant; Cocaine; Priming; Reinforcement
1. Introduction Cocaine abuse is characterized by a complex set of behaviors. An individual must initiate cocaine-seeking, persist in the attempt to acquire cocaine despite obstacles, prepare the cocaine for consumption, and self-administer cocaine within the context of a set of environmental factors. The individual may self-administer a single dose of cocaine, a few doses with either short or long intervals between doses, or may consume large amounts of cocaine in a relatively short period of time (i.e., a binge). Once a bout of cocaine selfadministration has ended, the individual may remain
* Corresponding author. Tel.: /1-410-550-5953; fax: /1-410-5500030 E-mail address: [email protected] (E.C. Donny).
abstinent for as little as a few hours or as long as several weeks or months before initiating cocaine-seeking behavior again. Animal models of drug self-administration have been designed to assess different aspects of drug-seeking and drug-taking behavior (Arnold and Roberts, 1997); these models differ in their sensitivity to a variety of factors including dose (Roberts et al., 1989b), sex (Donny et al., 2000), estrus cycle (Roberts et al., 1989a), neurophysiological manipulation (McGregor and Roberts, 1993, 1995), and conditioned stimuli (Ranaldi and Roberts, 1996). In order to understand the factors that affect human cocaine abuse, including medications for cocaine dependence, it is essential that clinical researchers also refine the methodology used to assess the set of behaviors related to cocaine abuse. Most human laboratory models of cocaine selfadministration have focused on evaluating the total number of cocaine injections taken within a self-admin-
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istration session using a choice procedure first developed in laboratory animals (Johanson and Schuster, 1975). Volunteers are typically presented with a series of discrete choices (usually 4/7) between an alternative monetary reinforcer and either an immediate administration of cocaine (e.g., Foltin and Fischman, 1996; Haney et al., 2001) or a token later redeemable for cocaine (e.g., Dudish-Poulsen and Hatsukami, 1997) at a fixed interval. The dose of cocaine, the value of any alternative reinforcer and the response cost for either choice (e.g., FR200) are held constant within a session. A strength of this procedure is the ability to assess changes in the amount of cocaine self-administered under a fixed set of conditions because both the response and the economic cost of taking cocaine are constant. However, the procedure is not designed to evaluate changes in the motivation to start taking cocaine, the elasticity of cocaine-taking behavior, the self-selected pacing of cocaine administration, the role of conditioned stimuli in maintaining cocaine-seeking behavior, or the ability to stop taking cocaine once cocaine has already been consumed. Each of these aspects of cocaine-taking may require different experimental models. We have recently developed two novel models of cocaine self-administration (Walsh et al., 2001). One model assessed the initiation of cocaine-taking during a state of abstinence (see Walsh et al., 2001 for details). The second model, characterized in detail here, was designed to evaluate the cessation of cocaine-taking once cocaine self-administration has been initiated. The cessation model was similar to a progressive ratio schedule of reinforcement in which the response cost of self-administration increases with each reinforcement (Haney et al., 1998). This procedure, however, attempted to capitalize on the documented relationship between the value of the alternative reinforcer and the choice to take cocaine, rather than employing a work response requirement. Previous research has shown that when the value of an alternative reinforcer (e.g., money) is increased either across sessions (Higgins et al., 1994) or in separate groups of volunteers (Hatsukami et al., 1994), the number of choices for cocaine decreases. In our model, the amount of money available as an alternative choice to cocaine increased within a session to provide incentive for individuals to stop taking cocaine. The dollar amounts were initially low ($1) and increased successively with each of six choice trials within a session (up to $16). The range of monetary reinforcers was chosen to span and surpass the estimated street value of the doses of cocaine available for self-administration. The choice for cocaine was expected to decline as the available alternative dollar amounts increased across trials. A single dose (40 mg) and interchoice interval (15 min) was assessed by Walsh et al. (2001). The results indicated that all eight participants
chose cocaine when the alternative was $1 or 4. Increasing the alternative monetary amount to $7, decreased the number of participants choosing cocaine over money to five; however, there were no further decreases in the number of cocaine choices as the dollar amount increased up to $16. Most participants continued to take cocaine despite increasing alternative reinforcement. In the present study, we extended this work by examining the effects of cocaine dose and inter-choice interval on the choice to take cocaine using the same ascending schedule of alternative reinforcement. Since smaller doses of cocaine have previously been shown to produce lower break points (i.e., largest ratio completed) in both preclinical (Roberts et al., 1989b) and clinical studies (Fischman, 1989; Haney et al., 1998), we hypothesized that choice behavior would be more sensitive to alternative reinforcement at lower cocaine doses. Preclinical work has also shown that the interval between self-administration trials influences operant responding; longer inter-trial intervals and limited holds produced higher break points in rhesus monkeys trained to self-administer cocaine on a progressive ratio schedule of reinforcement (Rowlett et al., 1996). Clinical studies have not systematically varied inter-choice interval. The present study evaluated two fixed interval conditions and a variable interval condition in which the volunteer selected the interval between each trial. Based on similar preclinical studies (Rowlett et al., 1996) we hypothesized that a longer inter-choice interval (e.g., 30 min) would result in a greater preference for cocaine over money at higher dollar values compared with a shorter inter-choice interval (i.e., 15 min). Previous work from our laboratory had demonstrated that moderate to high doses of cocaine could be administered safely at intervals as short as 15 min (Walsh et al., 2001); practical limitations in session duration limited the longer inter-choice interval to 30 min. The variable interval condition was included to allow assessment of whether the volunteer’s control over the timing of cocaine administrations would modify the relative reinforcing value of cocaine and to allow for doserelated shifts in the patterning of self-administration.
2. Methods 2.1. Volunteers Volunteers were recruited through local newspaper advertisements and word-of-mouth. Seven AfricanAmerican males and one African-American female [average age: 34.49/3.7 (S.D.)] completed the protocol. Two additional volunteers were discharged prior to study completion because their response to cocaine challenge in the laboratory exceeded our safety criteria
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(see below). Only the data from the eight volunteers completing the study are presented. Volunteers were required to present with a history of cocaine abuse of at least 6 months duration, have used cocaine by a rapid onset (e.g., smoked or intravenous) route of administration at least three times per week for 4 of the preceding 6 weeks, and provide at least one cocainepositive urine during the screening process. There was no specific criterion for the quantity of cocaine reported per episode of use because it is difficult to quantify accurately illicit doses. During the initial screening process, any participant who described a frequency or intensity of use that was judged to be less than the study doses was excluded. All volunteers completed a standard physical examination, including ECG, blood chemistry, hematology, and routine medical urinalysis, and were determined to be in good health. Potential volunteers were excluded from participation if they were seeking treatment for cocaine dependence, had a history of seizures, cardiovascular disease, diabetes, any current conditions requiring medication, abnormal laboratory values judged clinically significant, were pregnant, had any psychiatric history judged clinically significant (Structured Clinical Interview for DSM-IV; First et al., 1995) or were physically dependent on opioids, benzodiazepines or alcohol. These volunteers reported using cocaine an average of 59.0 months [9/47.0 (S.D.)] and spending $47.59/8.8 on cocaine on 23.99/6.2 of the last 30 days. Three volunteers who smoked ‘‘crack’’ cocaine reported not having used cocaine or other drugs intravenously. Drug and alcohol use was determined by self-report, urinalysis, and/or breathalyzer tests. Volunteers reported an average of 9.39/7.9 days of alcohol use, 4.59/3.7 days of heroin use, and 2.09/2.8 days of cannabis use in the last 30 days. 2.2. Study design The study design and experimental procedures were approved by the Johns Hopkins Bayview Medical Center Institutional Review Board and were in accordance with the 1964 Declaration of Helsinki. Volunteers provided written informed consent to research participation. They were paid for their time and inconvenience. Volunteers remained on the residential research facility for approximately 5 weeks. During this time, participants were not allowed to consume caffeine; smoking was allowed except for 1.5 h before and during experimental sessions. This study used a double-blind, within-subject, crossover, inpatient design to assess the effects of cocaine dose, inter-choice interval, and alternative monetary reinforcement on the choice to take cocaine in a laboratory setting. Volunteers participated in a single
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safety session followed by 12 cocaine self-administration sessions. The dose of cocaine was randomized across choice sessions with one constraint: the first active dose of cocaine was never 50 mg per 70 kg. Inter-choice interval was fully randomized. Sessions were at least 48 h apart. 2.3. Experimental sessions Experimental sessions were conducted in a testing room providing a constant environment. The volunteer was seated in a comfortable chair in front of a personal computer (Apple IIGS, Apple Computer, Cupertino, CA) that recorded subjective and physiological responses. A research assistant, seated behind the computer, initiated the data collection, monitored the volunteer, and provided observer ratings. A slow drip i.v. line was in place throughout each session. Sessions began at 12:00 noon; session length varied according to the inter-choice interval (described below). A physician monitored the ECG for a minimum of 15 min after each injection. The criteria for aborting a session included the occurrence of any of the following: an abnormal ECG, systolic pressure/180 mm Hg, diastolic pressure/120 mm Hg, or heart rate /(220 volunteer’s age) /85 beats per minute (bpm). In addition, it was required that heart rate be B/130 bpm, systolic blood pressure B/165 mm Hg and diastolic blood pressure B/100 mm Hg for the next injection to be administered. If these criteria were not met, the injection was held until the physician judged it safe to proceed. 2.3.1. Safety session During the first experimental session, volunteers received four injections of intravenous cocaine (0, 12.5, 25 and 50 mg per 70 kg) in ascending order with each dose separated by 60 min. Cardiovascular data were used to screen individuals for excessive or idiosyncratic reactions to cocaine. The two volunteers discharged prior to study completion showed no abnormal responses to cocaine during the safety session. In both cases, the safety criteria were exceeded in response to repeated administrations of 50 mg per 70 kg cocaine during a choice session. These cardiovascular responses resolved without incident and the volunteers were medically cleared before discharge. 2.3.2. Choice sessions Volunteers participated in 12 choice sessions during which they were allowed to choose between one of the four doses of cocaine and varying amounts of money. The design of the choice sessions is illustrated in Fig. 1. Sessions began with a 30 min baseline assessment followed by a sampling of the assigned dose for that session at 12:30 PM. The dose of cocaine was constant
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Fig. 1. Schematic representation of the choice sessions. Volunteers (n /8) were administered a sample injection (12.5, 25, 50 mg per 70 kg cocaine or placebo) and then allowed to choose between that dose and money on six subsequent trials. The inter-choice interval varied between sessions (15, 30 min, or an interval selected by the volunteer).
within each session (0, 12.5, 25, or 50 mg per 70 kg). One hour after the sample dose, six choice trials were presented. The volunteer was allowed to choose either the assigned dose of cocaine that was sampled previously or money ($1, 4, 7, 10, 13 or 16 for each trial; Fig. 1). By comparison, the estimated street value of 20 and 40 mg i.v. cocaine in a previous study from our laboratory was approximately $2.90 and 5.00, respectively (Haberny et al., 1995). Thus, we anticipated that the value of the largest test dose would fall approximately in the middle of the range of alternative reinforcer values. The dollar value was increased with each trial (i.e., trial 1 /$1, trial 2 /$4). If the volunteer chose cocaine, an injection was given within 2 min of the choice. If money was chosen, cash was placed in front of the volunteer. All cash was collected at the end of session and the volunteer was given a receipt indicating that their session earnings were added to their account. Session earnings were independent of the compensation for study participation ($24 per night). Compensation for study participation and session earnings were paid to the volunteer after they were discharged. All six choice trials occurred each session regardless of the choices made between money and cocaine. The inter-choice interval varied across sessions. Choice trials were presented every 15, 30 min, or the interval was selected by the volunteer with the imposed constraints of a minimum interval of 15 min (for safety reasons) and a maximum interval of 1 h. Session duration in the self-selected interval condition was limited to 6 h. During self-selected inter-choice interval sessions the volunteer was instructed to make his/her choice at any time within the constraints stated above. Volunteers were given a schematic of the three types of sessions (according to inter-choice interval) and instructed on the timing of the sample injection and the six choice trials prior to the first choice session. The constancy of the dose of cocaine within each session and the increasing order of the monetary alternatives were clearly indicated. In addition, at the start of each choice session volunteers were reminded that the dose of
cocaine available to them during choice session was the same dose they would be sampling at the start of the session. Volunteers were informed of the assigned interchoice interval prior to the start of each session.
2.4. Measures Subjective and physiological data were collected throughout the safety and choice sessions. Only the data collected immediately before (baseline) and for the hour after the sample injection in choice sessions are presented. The purpose of administering the questionnaires during the safety session was to monitor the volunteer’s response to cocaine and provide additional training on the volunteer- and observer-rated measures (see below). Data on the pharmacodynamic effects of cocaine collected during the choice phase of choice sessions are not presented because the pattern of cocaine administration varied between individuals and across conditions according to the choice of the volunteers, yielding an irregular and incomplete data set for choice trials.
2.4.1. Physiological measures Physiological measures included heart rate, systolic blood pressure, diastolic blood pressure, skin temperature, respiratory rate and pupil diameter. Respiratory rate was taken by an observer who visually observed and counted the number of breaths taken by the volunteer for a 30 s period. Pupil diameter was determined from photographs taken in constant room lighting with a Polaroid camera (Polaroid Corp., Cambridge, MA) using a twofold magnification. Pupil diameter and respiratory rate were assessed 15 min before (baseline) and 10, 15, 30, and 45 min after the sample injection. Skin temperature, blood pressure, and heart rate were collected automatically every minute (Noninvasive Patient Monitor model 506; Criticare Systems, Waukesha, WI).
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2.4.2. Volunteer- and observer-rated measures Volunteer-rated measurements included visual analog scales, a street value question and an adjective checklist. The visual analog questions included ‘‘Do you feel any drug effect?, Do you feel a rush?, Does the drug have any good effects?, Does the drug have any bad effects?, How much do you like the drug?’’ and ‘‘How much do you desire cocaine right now?’’ The volunteers responded by positioning an arrow along a 100-point line labeled with ‘‘not at all’’ at one end and ‘‘extremely’’ at the other. These questions were presented at baseline, once each minute for 10 min after the start of the sample injection, and at 15, 30 and 45 min after the sample injection. Street value was measured by asking ‘‘What is the street value of the dose you just received?’’ 10 and 45 min after the sample injection. The volunteer-rated adjective checklist consisted of 22 items rated from 0 (indicating ‘‘not at all’’) to 4 (indicating ‘‘extremely’’). The items were: craving for cocaine, dizzy/lightheaded, drug effect, dry mouth, excited, fearful, feel a thrill, feeling of power, fidgety, irritable, jittery, nervous, numbness, seeing/hearing things, sleepy, stimulated, stomach upset/nausea, suspiciousness, sweating, thirsty, tingling, and tremor. Observer adjectives were rated according to the same 5-point scale, and included drug effect, difficulty concentrating, fidgety, talkative, positive vocalizations, tremor/shaky, sweating, edgy/irritable and moody. Volunteer- and observer-rated adjectives were presented at baseline and 10, 30, and 45 min after the sample injection. 2.4.3. Choice measures Data on the actual choices made were examined as raw data (i.e., discrete choices between injection and money) and then summarized into the following four variables for each session: total number of injection choices, total amount of money earned, the dollar value at which the volunteer first chose money over an injection, and the largest dollar value at which the volunteer chose an injection. The first money choice was scored as $16 if the volunteer chose injections throughout the session, and the largest dollar value at which the volunteer chose an injection was scored as $1 if the volunteer chose money throughout the session. 2.5. Drugs Cocaine powder (Mallinckrodt, Inc., St. Louis, MO) was aseptically prepared under a horizontal laminar flow hood by dissolving it in sterile saline to deliver a dose of 12.5, 25, or 50 mg per 70 kg in 1 ml and filtering the solution through a 0.22 mm Millex-GS Millipore filter (Millipore, Bedford, MA) into a sterile, pyrogenfree vial (Lyphomed, division of Fujisawa USA, Inc., Deerfield, IL). The same volume of sterile saline served as the placebo. Cocaine and placebo were administered
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intravenously at a constant rate by a physician into a venous catheter in the arm over 60 s. During injections, the flow rate of the saline drip was increased to prevent backflow and ensure rapid delivery into the circulatory system. All injections were followed by a 1 ml saline flush through the catheter port. 2.6. Statistical analyses Physiological and subjective data obtained in response to the sample injection were analyzed using both time course and peak score analyses. Time course data were analyzed using a 3-factor within-subject ANOVA (cocaine dose, inter-choice interval, and time) and peak data were analyzed using a 2-factor withinsubject ANOVA (cocaine dose and inter-choice interval). Although, the subsequent inter-choice interval was not expected to produce an effect on the response to the sample injection, it was included as a factor in all analyses since volunteers were informed of the assigned inter-choice interval prior to the start of session. Summary choice data (e.g., total number of cocaine injections) were analyzed using 2-factor ANOVA (cocaine dose and inter-choice interval). All repeated measures data were adjusted for sphericity using Huynh-Feldt corrections. Post hoc comparisons were made using Tukey’s Honestly Significant Difference (HSD). Graphs are presented with error bars representing 1/2 the critical difference value; thus, non-overlapping bars indicate a significant difference. Differences with a probability of P B/0.05 were considered statistically significant.
3. Results 3.1. Sample dose of cocaine: physiological and subjective effects The physiological effects of cocaine were dose-dependent. Time course analyses revealed a significant doserelated increase in heart rate (Fig. 2; P B/0.001), systolic pressure (P B/0.001), diastolic pressure (P B/0.001) and pupil diameter (P B/0.001), and a decrease in skin temperature (P B/0.001) that dissipated over the 1 h period (P B/0.01 for main effect of time). Heart rate is illustrated in Fig. 2 as an example of the cardiovascular effects of cocaine. Pairwise comparisons (Tukey HSD) for heart rate indicated that all doses were significantly different from each other (P B/0.05). The physiological effects of cocaine peaked in the first 10 min postinjection; larger doses of cocaine tended to produce longer-lasting effects that remained elevated compared with placebo throughout the 45 min post-injection period. Analyses of the peak physiological data revealed similar dose-dependent results.
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Fig. 2. Mean (n /8) heart rate, visual analog ratings of ‘‘How much do you like the drug?’’ (upper panel) and ‘‘How much do you desire cocaine right now?’’ (lower panel), and subject ratings of the adjective ‘‘drug effect.’’ 15 min prior to (BL) and for up to 60 min after sampling each of four doses of cocaine. Heart rate data are illustrated as means across the following intervals: 15 min before to 9 min before the injection (BL) and 0 /9, 10 /14, 15 /29, 30 /44, and 45 /59 min post-injection. Data were averaged across the three inter-choice interval conditions for illustration.
Cocaine produced dose-related increases in visual analog ratings of drug effect (P B/0.01), rush (P B/ 0.05), good effect (P B/0.05), liking (P B/0.01; upper panel) and desire for cocaine (P B/0.05; lower panel). Fig. 2 shows mean ratings on the visual analog questions ‘‘How much do you like the drug?’’ and ‘‘How much do you desire cocaine right now?’’ as illustrative examples of subjective measures that may be predictive of choice behavior. Pairwise comparisons (Tukey HSD) indicated that 25 and 50 mg per 70 kg significantly increased ratings of ‘‘liking’’ and ‘‘desire’’ compared with placebo and 12.5 mg per 70 kg (Fig. 2). Significant differences between 25 and 50 mg per kg were restricted to ratings of liking (Fig. 2). Significant effects of cocaine dose (P B/0.05) were also found for the volunteer-rated adjectives dizzy/ lightheaded, craving for cocaine, thirsty, excited, dry mouth, stimulated and drug effect (Fig. 2), and the
observer-rated adjectives drug effect, positive vocalizations, and tremor/shaky. The subject-rated adjective ‘‘drug effect’’ is shown as an example in Fig. 2. Significantly greater ratings of ‘‘drug effect’’ were found for all active doses compared with placebo (P B/0.05) and when 50 mg per 70 kg was compared with 12.5 mg per 70 kg. The subjective effects of cocaine tended to peak at 6/10 min after the injection and then decline over the remainder of the 45 min period. The peak score analyses were concordant with the time course results. The overall street value of the sample injection did not change between the 10 and 45 min post-injection assessments; therefore, only the data from 45 min post-injection are presented. Street value was significantly increased as a function of cocaine dose (P B/ 0.01). Estimated street values for placebo, 12.5, 25, and 50 mg per 70 kg were $0.089/0.05, 2.329/0.40, 3.779/0.49 and 8.259/1.81, respectively.
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3.2. Choice behavior The pattern of choice behavior across all conditions is shown in Fig. 3. The mean inter-choice intervals for the self-selected condition were 15.09/0, 16.69/1.3, 17.39/ 1.0 and 16.89/0.6 min for 0, 12.5, 25 and 50 mg per 70 kg, respectively. Few volunteers chose to take placebo when the alternative was $1 or 4, while none chose placebo over the higher monetary alternatives. When 12.5 mg per 70 kg was available, two of eight volunteers chose money on all six trials for each of the inter-choice intervals. When 25 or 50 mg per 70 kg was available, most volunteers chose cocaine regardless of the value of the alternative reinforcer. There was a tendency for the number of volunteers choosing 50 mg per 70 kg cocaine to decrease during the intermediate trials (e.g., $7 and 10). However, inspection of individual data within each session revealed that, overall, volunteers chose all drug 47% of the time (all when active cocaine was available) and all money 25% of the time (all when either placebo or 12.5 mg of cocaine was available). The total number of injections (Fig. 4, upper left panel) increased with the dose of cocaine [F (3,21) / 27.6, P B/0.001]. When 25 or 50 mg per 70 kg cocaine was available, volunteers chose an average of five to six injections (of a possible six). The 12.5 mg per 70 kg dose, produced an intermediate level of cocaine self-administration, with an average of four injection choices per
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session. The total number of injection choices was not altered by the inter-choice interval. Analysis of the total amount of money chosen (Fig. 4, upper right panel) revealed a dose-dependent decrease in the amount earned (F /30.2, P B/0.001); no effect of inter-choice interval was found. Analysis of the dollar value at which the first choice for money was made (Fig. 4, lower left panel) revealed a significant effect of cocaine dose (F /20.1, P B/0.001), whereby larger doses required a larger dollar value before money was chosen. When choices were presented at 15 min intervals, 25 mg per 70 kg required the largest average dollar value before money was first chosen over cocaine, and this required value tended to decrease when 50 mg per 70 kg was available. In contrast, when choices were presented every 30 min or were under the control of the volunteer (with a mean interval of approximately 17 min), 25 and 50 mg per 70 kg produced near identical results. The drop in value at which volunteers first chose to take money over 50 mg per 70 kg cocaine in the 15 min inter-choice interval condition resulted from five volunteers who took $10 or 13 over cocaine (see Fig. 3). This intermediate money choice lengthened the average inter-infusion interval from 15.45[9/0.47 (S.E.M.)] in the 25 mg per 70 kg condition to 17.349/0.69 in the 50 mg per 70 kg condition. However, all of these volunteers resumed choosing cocaine in subsequent trials after this money choice. In fact, in 82% of the sessions that
Fig. 3. The total number of volunteers (n /8) choosing to take an injection over money during each of six successive choice trials in which the value of the monetary alternative progressively increased with each trial from $1 to 16. The choice between each of four doses of cocaine (represented horizontally) and money was presented every 15 min (upper panels), every 30 min (middle panels), or at a self-selected interval (lower panels).
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Fig. 4. Mean number of injection choices (upper left panel), amount of money earned per session (upper right panel), dollar value at which volunteers first chose to take money instead of cocaine (lower left panel) and the largest amount of money turned down in order to receive an injection (lower right panel). During each session volunteers were allowed to choose between an injection (0, 12.5, 25, 50 mg per 70 kg cocaine) and money ($1 /16) every 15, 30 min, or at a self-selected interval. Error bars represent 1/2 the critical difference; non-overlapping bars indicate a significant difference (P B/0.05; Tukey HSD).
volunteers chose some combination of money and drug, volunteers chose to take at least one more cocaine injection after making a money choice. The remaining 18% of the sessions when volunteers chose an injection and then all money were when placebo was available. There were no sessions in which a volunteer choosing active cocaine transferred to choosing money for the remainder of the session. Similar to the other summary measures of choice, the largest amount of money volunteers turned down in
order to receive an injection (Fig. 4, lower right panel) increased with the dose of cocaine (F /33.7, P B/0.001), but was unaffected by the interval between choices. Volunteers chose to take cocaine over the largest alternative money amount ($16) at both 25 and 50 mg per 70 kg in all but one case when a volunteer chose $16 over 25 mg per 70 kg cocaine. The average maximum amount paid for 0 and 12.5 mg per 70 kg was approximately $1 and 12, respectively, regardless of the inter-choice interval.
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4. Discussion The choice to take cocaine was dose-dependent up to an intravenous dose of 25 mg per 70 kg. The mean number of choices to take an injection instead of the alternative monetary reinforcer increased when active doses of cocaine were available compared with placebo and when 25 and 50 mg per 70 kg were available compared with 12.5 mg per 70 kg cocaine. This dosedependent cocaine self-administration produced a decrease in the total amount of money earned within each session as the dose of cocaine was increased. Larger doses of cocaine increased the average dollar value of the first money choice and the maximum amount of money volunteers were willing to forgo for an injection. These results are similar to those reported in a study in which volunteers could respond on a progressive ratio schedule of reinforcement for either intravenous cocaine or $5 by pressing a computer key (Haney et al., 1998). Higher maximum response outputs (i.e., break points) were obtained with active cocaine compared with placebo and with the two highest doses (16 and 32 mg per 70 kg) compared with the lowest dose (8 mg per 70 kg). Injection choices did not decrease as the value of the alternative reinforcer increased within a session. Most volunteers chose to take either all money or all injections within a session, depending on the cocaine dose. When placebo injections were available, all money choices were made in 75% of sessions. In contrast, the lowest dose of cocaine (12.5 mg per 70 kg) produced all money choices in only 25% of sessions and all cocaine choices in 42% of sessions. When the two highest doses of cocaine (25 and 50 mg per 70 kg) were available, volunteers chose to take some cocaine in all sessions and all cocaine in 88 and 58% of sessions, respectively. Overall, this ascending schedule of alternative reinforcement resulted in some combination of money and drug choices in only 28% of choice sessions. These results resemble previous reports of high cocaine intake in cocaine-dependent participants (Ward et al., 1997), despite the availability of an alternative reinforcer. Similar overwhelming preferences for cocaine have been reported in preclinical studies when the alternative reinforcer was food (e.g., Aigner and Balster, 1978). The point at which money was first chosen over cocaine was conceptualized as similar to a break point. However, in contrast to the standard progressive ratio procedure, the choice to take money did not end the session. This approach was taken in order to keep each choice trial independent and avoid compounding the consequences of eliminating subsequent choice trials (e.g., loss of future money choices). It was hypothesized that, after making a money choice, volunteers would continue to choose money over cocaine during subsequent trials in which the value of the monetary alter-
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native continued to increase. However, examination of the data from individual volunteers that chose money over an active dose of cocaine revealed that in 100% of the cases, volunteers chose at least one subsequent cocaine injection in lieu of an even larger monetary alternative. It is unclear what accounts for the observation that participants returned to choosing cocaine after a money choice was made despite larger alternative reinforcers. One possibility is that the reinforcing value of a given dose of cocaine may increase over time since the last injection. However, longer inter-choice intervals produced little change on any of the choice outcome measures, suggesting that time since last injection was not of critical importance under these schedule conditions. A second possible explanation is that the choice for money at an intermediate trial may represent a transient decrease in the reinforcing efficacy of cocaine related to either acute tolerance or an accumulation of aversive effects following repeated dosing. Acute tolerance following repeated cocaine doses is a well-documented phenomenon in humans (Ambre et al., 1988). However, inspection of the subjective responses to cocaine in this study does not support this hypothesis. Cocaine produced similar effects on visual analog ratings of ‘‘good effect’’ and ‘‘bad effects’’ in trials that preceded a money choice, preceded a cocaine choice, or followed a money choice. A third possibility is that participants titrated their intake of cocaine around some optimal level (i.e., maximizing positive effects and/or avoiding aversive effects) and that the value of the alternative reinforcer was not causally related to either the intermediate money choice or the subsequent choice to take cocaine. The choice to take additional active doses of cocaine was largely independent of the magnitude of the monetary alternative reinforcer. In contrast, previous models of human cocaine self-administration have reported a decrease in cocaine self-administration as the value of the alternative reinforcer was increased (Hatsukami et al., 1994; Higgins et al., 1994). Several differences may account for this discrepancy, including larger cocaine doses in the present study, differences in route of administration, and, importantly, differences in the design used to manipulate the magnitude of alternative reinforcement. The present model increased the value of the alternative reinforcer within each session, while in previous models the monetary alternative was constant within session and either increased across sessions (Higgins et al., 1994) or between participants (Hatsukami et al., 1994). Alternative reinforcers may decrease the likelihood of initiating cocaine self-administration during abstinence, but have little effect once cocaine-taking has been initiated. This is consistent with the report by Walsh et al. (2001) in which the present model of cocaine self-administration was compared with
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a model with two critical differences. The alternative model did not require a sample injection immediately prior to the choice trials and the value of the alternative reinforcer was large on the first choice trial ($16) and decreased with each subsequent trial (i.e., by $3 per trial). This alternative model resulted in fewer cocaine choices than the present model. Furthermore, three times as many individuals chose $16 over cocaine when it was the first as compared with the last choice trial. Moreover, studies employing models in which the alternative reinforcer is constant within a session have found that participants chose either all money or all cocaine in the majority of sessions (79% in Higgins et al., 1994; 58% in Hatsukami et al., 1994), supporting the notion that alternative reinforcement may have only modest effects on cocaine-taking once the behavior has been initiated. Preclinical studies have also indicated that cocaine self-administration may be less affected by increasing response costs than responding maintained by other drugs of abuse (Woolverton et al., 1997; Stafford et al., 1998). The range of monetary alternatives was chosen to span and surpass estimates of the street value of cocaine. However, this amount of money was clearly too low to compete with cocaine in this paradigm. Volunteers overwhelmingly chose cocaine over money at dollar values that far exceeded the estimated street value of that dose of cocaine during the sample session. For example, most volunteers presented with the choice to take either 25 or 50 mg of cocaine or up to $16 chose to take cocaine, despite estimating the value for that dose to be $3.77 and 8.25, respectively. On average, the maximum amount of money volunteers were willing to forgo in order to receive cocaine was 2/4 times greater than their estimated street value of cocaine. This discordance between functional value in the behavioral choice procedure and subjectively reported value on the questionnaire highlights an important distinction between these two methods of assessing reinforcing efficacy. The present study cannot distinguish between several possible explanations for this discrepancy. One is that this discordance between self-report and behavior represents the construct of loss of control over drugtaking behavior that is commonly imputed to be a core feature of drug dependence disorders (APA, 1994). A second possibility is that this discordance reflects the influence of delay discounting, in which the value of a delayed reinforcer is discounted compared with an immediately available reinforcer (Hull, 1943; Mazur, 1987), on choice behavior (as discussed in more detail below). These two explanations may be related. Greater discounting of delayed rewards has been reported in drug-dependent compared with non-dependent individuals (Bickel and Marsch, 2001; Petry, 2001) and may provide a mechanistic explanation of the loss of control construct.
Subjective estimates of street value, as well as other self-report measures of the positive effects of cocaine, were more sensitive to changes in dose than choice behavior. Most volunteers chose to self-administer almost all active doses of cocaine, despite a range of self-administration doses that produced mild to moderate subjective effects. Previous research has demonstrated that when cocaine users are given the choice between two cocaine injections, they prefer higher compared with lower doses (Foltin and Fischman, 1994). However, near-maximal cocaine self-administration is observed across a wide range of active doses of cocaine both when volunteers are allowed to perform an operant response for an active dose of cocaine (Haney et al., 1998) and when they are given a choice between an active dose of cocaine and a constant (Foltin and Fischman, 1996; Haney et al., 2001) or escalating (data shown here) alternative, non-drug reinforcer. This suggests that there may be a relatively low threshold of subjective effects that can initiate cocaine selfadministration, above which cocaine self-administration is robust and largely insensitive to variations in the dose of cocaine. Preclinical research is consistent with this idea; low doses of cocaine can initiate cocaine-seeking (Norman et al., 1999), but the threshold for satiation is high (Tsibulsky and Norman, 1999). The choice to take cocaine in the present study may have been influenced by an array of factors, including priming and the economic conditions of the study (i.e., open vs. closed economies, delay to monetary reward). The intent of this study was to assess the ability of an alternative monetary reinforcer to compete with cocaine self-administration after the volunteer had already initiated taking cocaine. Volunteers were given a ‘‘sample’’ injection and then provided little incentive (e.g., $1) not to take cocaine during the early trials. However, the preference for cocaine over money during subsequent trials (i.e., in the presence of larger alternative reinforcers) may have been enhanced because the previous doses ‘‘primed’’ cocaine self-administration. Priming is the ability of a stimulus (e.g., cocaine) to increase the probability of drug-seeking behavior (de Wit and Stewart, 1981). Preclinical studies have shown that injections of cocaine and pharmacologically related drugs, such as amphetamine, induce cocaine-seeking behavior in abstinent animals (de Wit and Stewart, 1981; Spealman et al., 1999; Sutton et al., 2000) and human experimental studies have demonstrated that alcohol administration increases the choice for alcohol in social drinkers (de Wit and Chutuape, 1993). Similarly, cocaine administration in humans increases selfreported desire for cocaine (present results; Haberny et al., 1995; Haney et al., 1998). Exposure to cocaine when there was little or no cost may have increased the value of subsequent cocaine self-administration. Future studies will attempt to isolate the effect of priming in order
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to determine its contribution to cocaine-taking behavior in the human laboratory. It is also important to recognize two potentially important behavioral economic factors. First, the laboratory constituted a closed economy for cocaine and an open economy for money. Limiting access to cocaine or providing additional sources of monetary reward (e.g., payment for participation) in volunteers residing on a residential unit may greatly increase the value of cocaine relative to money (Carroll et al., 2000). Indirect evidence that this may be an important factor can been seen in choice behavior when volunteers were offered their last opportunity of the session to take cocaine or $16. Despite sometimes choosing money at a lower dollar value, volunteers with access to 25 or 50 mg per 70 kg chose cocaine over money on all but one occasion. Second, because the monetary alternative reinforcer was delayed relative to the immediacy of cocaine administration, the present value of the monetary alternative was likely discounted to some degree (Hull, 1943; Mazur, 1987). Although money was physically presented to the volunteer during session in an attempt to make the monetary reinforcer more salient, the money was collected by the experimenter at the conclusion of the session. The volunteer was unable to retain and spend that money until after discharge from the study, while consumption of cocaine occurred immediately. Manipulating the inter-choice interval had little effect on the choice to take cocaine. Dose-effect functions for cocaine self-administration were nearly identical across the three inter-choice interval conditions; however, because of safety considerations and practical constraints on the session length, the effect of inter-choice interval was examined over a limited range. Further shortening of the inter-choice interval may have reduced cocaine choices, especially at high doses. There was a trend for a small decrease in the total number of injection choices and value of the first money choice as the dose was increased from 25 to 50 mg per 70 kg and this was less evident in the self-selected condition. This decrease was a result of three to five volunteers (depending on condition) making a money choice on an intermediate trial when 50 mg per 70 kg was available. The decrease from 25 to 50 mg per 70 kg was not observed in the self-selected condition because one volunteer chose money on five of six trials when 25 mg per 70 kg was available, producing a decrease in the overall mean at 25 mg per 70 kg; this was not representative of the condition as a whole. The tendency for cocaine self-administration to decrease slightly from 25 to 50 mg per 70 kg suggests an upper limit of cocaine consumption may have resulted in some volunteers making a single money choice during the session. Conversely, if the reinforcing efficacy of cocaine is increased 15 /30 min after a cocaine injection, substantially longer intervals (e.g., 90 min), that allow cocaine’s
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effects to dissipate entirely, may reduce the probability of additional cocaine choices. Participants in the present study were required to have a history of either i.v. or smoked cocaine use prior to investigational administration of i.v. cocaine. The National Advisory Council on Drug Abuse (1997) Guidelines for the Administration of Drugs to Human Subjects stated that the rationale for exposure to ‘‘new routes of administration should be clear and compelling.’’ The Council also emphasized that the ethical responsibility falls upon the investigator and the local Institutional Review Board and that the guidelines are intended ‘‘to encourage a sensitive, ethical approach that is also consistent with the best current practices and experience in the field of drug abuse research.’’ It is important, therefore, to discuss our rationale for including intravenous-naı¨ve participants in the present study. Our recruiting decision was rooted in the principle that participants should not be exposed to routes of administration involving greater abuse liability than those with which they are already experienced. Laboratory assessments of the reinforcing effects of cocaine have found that smoked cocaine has equal or greater abuse liability than intravenous cocaine (Foltin and Fischman, 1992). Furthermore, investigational administration of i.v. cocaine to i.v. inexperienced cocaine users does not appear to increase the risk of recreational i.v. use (Kaufman et al., 2000). This may be, in part, because investigational i.v. cocaine differs considerably from recreational i.v. cocaine use; investigational exposure employs a slower rate of infusion, is injected through an indwelling catheter, is administered by a physician, and occurs in an artificial and controlled environment. Based on the available evidence, we concluded, in partnership with our local Institutional Review Board, that the added risk from the inclusion of both i.v. and smoked cocaine users was minimal and acceptable given the benefits of this approach. These benefits include a history of safe, i.v. cocaine administration in our laboratory (e.g., Nann-Vernotica et al., 2001; Walsh et al., 2001), the ability to employ a doubleblind, placebo-controlled design to evaluate active cocaine without confounding the sensory effects of smoking cocaine, and the inclusion of and consequent generalizability to users of both smoked and i.v. cocaine. In summary, cocaine self-administration was dosedependent in this human laboratory model. The total number of injection choices increased and the total amount of money earned per session decreased when larger doses of cocaine were available. However, most volunteers chose to take either all money or all injections within a session. Increasing the value of an alternative, monetary reinforcer within the session had little effect on the choice to take active doses of cocaine under these conditions. These observations highlight the difficulty in reducing or stopping cocaine self-administration once
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cocaine-taking has been initiated and suggest that the initiation of cocaine-taking may be a critical determinant of subsequent cocaine self-administration (Walsh et al., 2001).
Acknowledgements This research was supported by grants from the National Institute on Drug Abuse R01 DA10753, R01 DA05196, T32 DA07209, and K05 DA00050. The authors thank the staff at BPRU especially Melissa Blank, Heather Cronin, Roxanna Kelly, Tim Mudric, Paul Nuzzo and John Yingling.
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Choosing to take cocaine in the human laboratory: effects of cocaine dose, inter-choice interval, and magnitude of alternative reinforcement Eric C. Donny *, George E. Bigelow, Sharon L. Walsh Behavioral Pharmacology Research Unit, Department of Psychiatry and Behavioral Sciences, Johns Hopkins School of Medicine, 5510 Nathan Shock Drive, Baltimore, MD 21224, USA Received 5 March 2002; received in revised form 16 September 2002; accepted 16 October 2002
Abstract Cocaine abuse involves a variety of behaviors including the initiation of cocaine-seeking, the self-selected patterning of cocaine administrations, and the cessation of cocaine-taking. To date, most human laboratory models of cocaine self-administration have only assessed the amount of cocaine consumed under a fixed set of conditions. This double-blind, randomized, within-subject, inpatient study evaluated a novel model of human cocaine self-administration that aimed to quantify the reinforcing value of cocaine after cocaine-taking was initiated. Cocaine-dependent volunteers (n /8) sampled cocaine (12.5, 25 or 50 mg per 70 kg i.v.) or placebo and were subsequently allowed to choose between another injection of the same dose or money over six trials during 12 experimental sessions. The value of the monetary alternative increased with each trial from $1 to 16. Each cocaine dose was assessed under three inter-choice intervals: 15 min, 30 min, and an interval selected by the volunteer. Injection choices increased dose dependently; however, there was little relationship between the value of the alternative reinforcer and the choice to take cocaine. Most volunteers exclusively chose injections when active cocaine was available and money when placebo was available. Inter-choice interval did not affect cocaine choices. These results illustrate the persistence of cocaine self-administration once cocaine-taking has been initiated. # 2002 Elsevier Science Ireland Ltd. All rights reserved. Keywords: Self-administration; Stimulant; Cocaine; Priming; Reinforcement
1. Introduction Cocaine abuse is characterized by a complex set of behaviors. An individual must initiate cocaine-seeking, persist in the attempt to acquire cocaine despite obstacles, prepare the cocaine for consumption, and self-administer cocaine within the context of a set of environmental factors. The individual may self-administer a single dose of cocaine, a few doses with either short or long intervals between doses, or may consume large amounts of cocaine in a relatively short period of time (i.e., a binge). Once a bout of cocaine selfadministration has ended, the individual may remain
* Corresponding author. Tel.: /1-410-550-5953; fax: /1-410-5500030 E-mail address: [email protected] (E.C. Donny).
abstinent for as little as a few hours or as long as several weeks or months before initiating cocaine-seeking behavior again. Animal models of drug self-administration have been designed to assess different aspects of drug-seeking and drug-taking behavior (Arnold and Roberts, 1997); these models differ in their sensitivity to a variety of factors including dose (Roberts et al., 1989b), sex (Donny et al., 2000), estrus cycle (Roberts et al., 1989a), neurophysiological manipulation (McGregor and Roberts, 1993, 1995), and conditioned stimuli (Ranaldi and Roberts, 1996). In order to understand the factors that affect human cocaine abuse, including medications for cocaine dependence, it is essential that clinical researchers also refine the methodology used to assess the set of behaviors related to cocaine abuse. Most human laboratory models of cocaine selfadministration have focused on evaluating the total number of cocaine injections taken within a self-admin-
03765-8716/02/$ - see front matter # 2002 Elsevier Science Ireland Ltd. All rights reserved. PII: S 0 3 7 6 - 8 7 1 6 ( 0 2 ) 0 0 3 2 7 - 7
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istration session using a choice procedure first developed in laboratory animals (Johanson and Schuster, 1975). Volunteers are typically presented with a series of discrete choices (usually 4/7) between an alternative monetary reinforcer and either an immediate administration of cocaine (e.g., Foltin and Fischman, 1996; Haney et al., 2001) or a token later redeemable for cocaine (e.g., Dudish-Poulsen and Hatsukami, 1997) at a fixed interval. The dose of cocaine, the value of any alternative reinforcer and the response cost for either choice (e.g., FR200) are held constant within a session. A strength of this procedure is the ability to assess changes in the amount of cocaine self-administered under a fixed set of conditions because both the response and the economic cost of taking cocaine are constant. However, the procedure is not designed to evaluate changes in the motivation to start taking cocaine, the elasticity of cocaine-taking behavior, the self-selected pacing of cocaine administration, the role of conditioned stimuli in maintaining cocaine-seeking behavior, or the ability to stop taking cocaine once cocaine has already been consumed. Each of these aspects of cocaine-taking may require different experimental models. We have recently developed two novel models of cocaine self-administration (Walsh et al., 2001). One model assessed the initiation of cocaine-taking during a state of abstinence (see Walsh et al., 2001 for details). The second model, characterized in detail here, was designed to evaluate the cessation of cocaine-taking once cocaine self-administration has been initiated. The cessation model was similar to a progressive ratio schedule of reinforcement in which the response cost of self-administration increases with each reinforcement (Haney et al., 1998). This procedure, however, attempted to capitalize on the documented relationship between the value of the alternative reinforcer and the choice to take cocaine, rather than employing a work response requirement. Previous research has shown that when the value of an alternative reinforcer (e.g., money) is increased either across sessions (Higgins et al., 1994) or in separate groups of volunteers (Hatsukami et al., 1994), the number of choices for cocaine decreases. In our model, the amount of money available as an alternative choice to cocaine increased within a session to provide incentive for individuals to stop taking cocaine. The dollar amounts were initially low ($1) and increased successively with each of six choice trials within a session (up to $16). The range of monetary reinforcers was chosen to span and surpass the estimated street value of the doses of cocaine available for self-administration. The choice for cocaine was expected to decline as the available alternative dollar amounts increased across trials. A single dose (40 mg) and interchoice interval (15 min) was assessed by Walsh et al. (2001). The results indicated that all eight participants
chose cocaine when the alternative was $1 or 4. Increasing the alternative monetary amount to $7, decreased the number of participants choosing cocaine over money to five; however, there were no further decreases in the number of cocaine choices as the dollar amount increased up to $16. Most participants continued to take cocaine despite increasing alternative reinforcement. In the present study, we extended this work by examining the effects of cocaine dose and inter-choice interval on the choice to take cocaine using the same ascending schedule of alternative reinforcement. Since smaller doses of cocaine have previously been shown to produce lower break points (i.e., largest ratio completed) in both preclinical (Roberts et al., 1989b) and clinical studies (Fischman, 1989; Haney et al., 1998), we hypothesized that choice behavior would be more sensitive to alternative reinforcement at lower cocaine doses. Preclinical work has also shown that the interval between self-administration trials influences operant responding; longer inter-trial intervals and limited holds produced higher break points in rhesus monkeys trained to self-administer cocaine on a progressive ratio schedule of reinforcement (Rowlett et al., 1996). Clinical studies have not systematically varied inter-choice interval. The present study evaluated two fixed interval conditions and a variable interval condition in which the volunteer selected the interval between each trial. Based on similar preclinical studies (Rowlett et al., 1996) we hypothesized that a longer inter-choice interval (e.g., 30 min) would result in a greater preference for cocaine over money at higher dollar values compared with a shorter inter-choice interval (i.e., 15 min). Previous work from our laboratory had demonstrated that moderate to high doses of cocaine could be administered safely at intervals as short as 15 min (Walsh et al., 2001); practical limitations in session duration limited the longer inter-choice interval to 30 min. The variable interval condition was included to allow assessment of whether the volunteer’s control over the timing of cocaine administrations would modify the relative reinforcing value of cocaine and to allow for doserelated shifts in the patterning of self-administration.
2. Methods 2.1. Volunteers Volunteers were recruited through local newspaper advertisements and word-of-mouth. Seven AfricanAmerican males and one African-American female [average age: 34.49/3.7 (S.D.)] completed the protocol. Two additional volunteers were discharged prior to study completion because their response to cocaine challenge in the laboratory exceeded our safety criteria
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(see below). Only the data from the eight volunteers completing the study are presented. Volunteers were required to present with a history of cocaine abuse of at least 6 months duration, have used cocaine by a rapid onset (e.g., smoked or intravenous) route of administration at least three times per week for 4 of the preceding 6 weeks, and provide at least one cocainepositive urine during the screening process. There was no specific criterion for the quantity of cocaine reported per episode of use because it is difficult to quantify accurately illicit doses. During the initial screening process, any participant who described a frequency or intensity of use that was judged to be less than the study doses was excluded. All volunteers completed a standard physical examination, including ECG, blood chemistry, hematology, and routine medical urinalysis, and were determined to be in good health. Potential volunteers were excluded from participation if they were seeking treatment for cocaine dependence, had a history of seizures, cardiovascular disease, diabetes, any current conditions requiring medication, abnormal laboratory values judged clinically significant, were pregnant, had any psychiatric history judged clinically significant (Structured Clinical Interview for DSM-IV; First et al., 1995) or were physically dependent on opioids, benzodiazepines or alcohol. These volunteers reported using cocaine an average of 59.0 months [9/47.0 (S.D.)] and spending $47.59/8.8 on cocaine on 23.99/6.2 of the last 30 days. Three volunteers who smoked ‘‘crack’’ cocaine reported not having used cocaine or other drugs intravenously. Drug and alcohol use was determined by self-report, urinalysis, and/or breathalyzer tests. Volunteers reported an average of 9.39/7.9 days of alcohol use, 4.59/3.7 days of heroin use, and 2.09/2.8 days of cannabis use in the last 30 days. 2.2. Study design The study design and experimental procedures were approved by the Johns Hopkins Bayview Medical Center Institutional Review Board and were in accordance with the 1964 Declaration of Helsinki. Volunteers provided written informed consent to research participation. They were paid for their time and inconvenience. Volunteers remained on the residential research facility for approximately 5 weeks. During this time, participants were not allowed to consume caffeine; smoking was allowed except for 1.5 h before and during experimental sessions. This study used a double-blind, within-subject, crossover, inpatient design to assess the effects of cocaine dose, inter-choice interval, and alternative monetary reinforcement on the choice to take cocaine in a laboratory setting. Volunteers participated in a single
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safety session followed by 12 cocaine self-administration sessions. The dose of cocaine was randomized across choice sessions with one constraint: the first active dose of cocaine was never 50 mg per 70 kg. Inter-choice interval was fully randomized. Sessions were at least 48 h apart. 2.3. Experimental sessions Experimental sessions were conducted in a testing room providing a constant environment. The volunteer was seated in a comfortable chair in front of a personal computer (Apple IIGS, Apple Computer, Cupertino, CA) that recorded subjective and physiological responses. A research assistant, seated behind the computer, initiated the data collection, monitored the volunteer, and provided observer ratings. A slow drip i.v. line was in place throughout each session. Sessions began at 12:00 noon; session length varied according to the inter-choice interval (described below). A physician monitored the ECG for a minimum of 15 min after each injection. The criteria for aborting a session included the occurrence of any of the following: an abnormal ECG, systolic pressure/180 mm Hg, diastolic pressure/120 mm Hg, or heart rate /(220 volunteer’s age) /85 beats per minute (bpm). In addition, it was required that heart rate be B/130 bpm, systolic blood pressure B/165 mm Hg and diastolic blood pressure B/100 mm Hg for the next injection to be administered. If these criteria were not met, the injection was held until the physician judged it safe to proceed. 2.3.1. Safety session During the first experimental session, volunteers received four injections of intravenous cocaine (0, 12.5, 25 and 50 mg per 70 kg) in ascending order with each dose separated by 60 min. Cardiovascular data were used to screen individuals for excessive or idiosyncratic reactions to cocaine. The two volunteers discharged prior to study completion showed no abnormal responses to cocaine during the safety session. In both cases, the safety criteria were exceeded in response to repeated administrations of 50 mg per 70 kg cocaine during a choice session. These cardiovascular responses resolved without incident and the volunteers were medically cleared before discharge. 2.3.2. Choice sessions Volunteers participated in 12 choice sessions during which they were allowed to choose between one of the four doses of cocaine and varying amounts of money. The design of the choice sessions is illustrated in Fig. 1. Sessions began with a 30 min baseline assessment followed by a sampling of the assigned dose for that session at 12:30 PM. The dose of cocaine was constant
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Fig. 1. Schematic representation of the choice sessions. Volunteers (n /8) were administered a sample injection (12.5, 25, 50 mg per 70 kg cocaine or placebo) and then allowed to choose between that dose and money on six subsequent trials. The inter-choice interval varied between sessions (15, 30 min, or an interval selected by the volunteer).
within each session (0, 12.5, 25, or 50 mg per 70 kg). One hour after the sample dose, six choice trials were presented. The volunteer was allowed to choose either the assigned dose of cocaine that was sampled previously or money ($1, 4, 7, 10, 13 or 16 for each trial; Fig. 1). By comparison, the estimated street value of 20 and 40 mg i.v. cocaine in a previous study from our laboratory was approximately $2.90 and 5.00, respectively (Haberny et al., 1995). Thus, we anticipated that the value of the largest test dose would fall approximately in the middle of the range of alternative reinforcer values. The dollar value was increased with each trial (i.e., trial 1 /$1, trial 2 /$4). If the volunteer chose cocaine, an injection was given within 2 min of the choice. If money was chosen, cash was placed in front of the volunteer. All cash was collected at the end of session and the volunteer was given a receipt indicating that their session earnings were added to their account. Session earnings were independent of the compensation for study participation ($24 per night). Compensation for study participation and session earnings were paid to the volunteer after they were discharged. All six choice trials occurred each session regardless of the choices made between money and cocaine. The inter-choice interval varied across sessions. Choice trials were presented every 15, 30 min, or the interval was selected by the volunteer with the imposed constraints of a minimum interval of 15 min (for safety reasons) and a maximum interval of 1 h. Session duration in the self-selected interval condition was limited to 6 h. During self-selected inter-choice interval sessions the volunteer was instructed to make his/her choice at any time within the constraints stated above. Volunteers were given a schematic of the three types of sessions (according to inter-choice interval) and instructed on the timing of the sample injection and the six choice trials prior to the first choice session. The constancy of the dose of cocaine within each session and the increasing order of the monetary alternatives were clearly indicated. In addition, at the start of each choice session volunteers were reminded that the dose of
cocaine available to them during choice session was the same dose they would be sampling at the start of the session. Volunteers were informed of the assigned interchoice interval prior to the start of each session.
2.4. Measures Subjective and physiological data were collected throughout the safety and choice sessions. Only the data collected immediately before (baseline) and for the hour after the sample injection in choice sessions are presented. The purpose of administering the questionnaires during the safety session was to monitor the volunteer’s response to cocaine and provide additional training on the volunteer- and observer-rated measures (see below). Data on the pharmacodynamic effects of cocaine collected during the choice phase of choice sessions are not presented because the pattern of cocaine administration varied between individuals and across conditions according to the choice of the volunteers, yielding an irregular and incomplete data set for choice trials.
2.4.1. Physiological measures Physiological measures included heart rate, systolic blood pressure, diastolic blood pressure, skin temperature, respiratory rate and pupil diameter. Respiratory rate was taken by an observer who visually observed and counted the number of breaths taken by the volunteer for a 30 s period. Pupil diameter was determined from photographs taken in constant room lighting with a Polaroid camera (Polaroid Corp., Cambridge, MA) using a twofold magnification. Pupil diameter and respiratory rate were assessed 15 min before (baseline) and 10, 15, 30, and 45 min after the sample injection. Skin temperature, blood pressure, and heart rate were collected automatically every minute (Noninvasive Patient Monitor model 506; Criticare Systems, Waukesha, WI).
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2.4.2. Volunteer- and observer-rated measures Volunteer-rated measurements included visual analog scales, a street value question and an adjective checklist. The visual analog questions included ‘‘Do you feel any drug effect?, Do you feel a rush?, Does the drug have any good effects?, Does the drug have any bad effects?, How much do you like the drug?’’ and ‘‘How much do you desire cocaine right now?’’ The volunteers responded by positioning an arrow along a 100-point line labeled with ‘‘not at all’’ at one end and ‘‘extremely’’ at the other. These questions were presented at baseline, once each minute for 10 min after the start of the sample injection, and at 15, 30 and 45 min after the sample injection. Street value was measured by asking ‘‘What is the street value of the dose you just received?’’ 10 and 45 min after the sample injection. The volunteer-rated adjective checklist consisted of 22 items rated from 0 (indicating ‘‘not at all’’) to 4 (indicating ‘‘extremely’’). The items were: craving for cocaine, dizzy/lightheaded, drug effect, dry mouth, excited, fearful, feel a thrill, feeling of power, fidgety, irritable, jittery, nervous, numbness, seeing/hearing things, sleepy, stimulated, stomach upset/nausea, suspiciousness, sweating, thirsty, tingling, and tremor. Observer adjectives were rated according to the same 5-point scale, and included drug effect, difficulty concentrating, fidgety, talkative, positive vocalizations, tremor/shaky, sweating, edgy/irritable and moody. Volunteer- and observer-rated adjectives were presented at baseline and 10, 30, and 45 min after the sample injection. 2.4.3. Choice measures Data on the actual choices made were examined as raw data (i.e., discrete choices between injection and money) and then summarized into the following four variables for each session: total number of injection choices, total amount of money earned, the dollar value at which the volunteer first chose money over an injection, and the largest dollar value at which the volunteer chose an injection. The first money choice was scored as $16 if the volunteer chose injections throughout the session, and the largest dollar value at which the volunteer chose an injection was scored as $1 if the volunteer chose money throughout the session. 2.5. Drugs Cocaine powder (Mallinckrodt, Inc., St. Louis, MO) was aseptically prepared under a horizontal laminar flow hood by dissolving it in sterile saline to deliver a dose of 12.5, 25, or 50 mg per 70 kg in 1 ml and filtering the solution through a 0.22 mm Millex-GS Millipore filter (Millipore, Bedford, MA) into a sterile, pyrogenfree vial (Lyphomed, division of Fujisawa USA, Inc., Deerfield, IL). The same volume of sterile saline served as the placebo. Cocaine and placebo were administered
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intravenously at a constant rate by a physician into a venous catheter in the arm over 60 s. During injections, the flow rate of the saline drip was increased to prevent backflow and ensure rapid delivery into the circulatory system. All injections were followed by a 1 ml saline flush through the catheter port. 2.6. Statistical analyses Physiological and subjective data obtained in response to the sample injection were analyzed using both time course and peak score analyses. Time course data were analyzed using a 3-factor within-subject ANOVA (cocaine dose, inter-choice interval, and time) and peak data were analyzed using a 2-factor withinsubject ANOVA (cocaine dose and inter-choice interval). Although, the subsequent inter-choice interval was not expected to produce an effect on the response to the sample injection, it was included as a factor in all analyses since volunteers were informed of the assigned inter-choice interval prior to the start of session. Summary choice data (e.g., total number of cocaine injections) were analyzed using 2-factor ANOVA (cocaine dose and inter-choice interval). All repeated measures data were adjusted for sphericity using Huynh-Feldt corrections. Post hoc comparisons were made using Tukey’s Honestly Significant Difference (HSD). Graphs are presented with error bars representing 1/2 the critical difference value; thus, non-overlapping bars indicate a significant difference. Differences with a probability of P B/0.05 were considered statistically significant.
3. Results 3.1. Sample dose of cocaine: physiological and subjective effects The physiological effects of cocaine were dose-dependent. Time course analyses revealed a significant doserelated increase in heart rate (Fig. 2; P B/0.001), systolic pressure (P B/0.001), diastolic pressure (P B/0.001) and pupil diameter (P B/0.001), and a decrease in skin temperature (P B/0.001) that dissipated over the 1 h period (P B/0.01 for main effect of time). Heart rate is illustrated in Fig. 2 as an example of the cardiovascular effects of cocaine. Pairwise comparisons (Tukey HSD) for heart rate indicated that all doses were significantly different from each other (P B/0.05). The physiological effects of cocaine peaked in the first 10 min postinjection; larger doses of cocaine tended to produce longer-lasting effects that remained elevated compared with placebo throughout the 45 min post-injection period. Analyses of the peak physiological data revealed similar dose-dependent results.
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Fig. 2. Mean (n /8) heart rate, visual analog ratings of ‘‘How much do you like the drug?’’ (upper panel) and ‘‘How much do you desire cocaine right now?’’ (lower panel), and subject ratings of the adjective ‘‘drug effect.’’ 15 min prior to (BL) and for up to 60 min after sampling each of four doses of cocaine. Heart rate data are illustrated as means across the following intervals: 15 min before to 9 min before the injection (BL) and 0 /9, 10 /14, 15 /29, 30 /44, and 45 /59 min post-injection. Data were averaged across the three inter-choice interval conditions for illustration.
Cocaine produced dose-related increases in visual analog ratings of drug effect (P B/0.01), rush (P B/ 0.05), good effect (P B/0.05), liking (P B/0.01; upper panel) and desire for cocaine (P B/0.05; lower panel). Fig. 2 shows mean ratings on the visual analog questions ‘‘How much do you like the drug?’’ and ‘‘How much do you desire cocaine right now?’’ as illustrative examples of subjective measures that may be predictive of choice behavior. Pairwise comparisons (Tukey HSD) indicated that 25 and 50 mg per 70 kg significantly increased ratings of ‘‘liking’’ and ‘‘desire’’ compared with placebo and 12.5 mg per 70 kg (Fig. 2). Significant differences between 25 and 50 mg per kg were restricted to ratings of liking (Fig. 2). Significant effects of cocaine dose (P B/0.05) were also found for the volunteer-rated adjectives dizzy/ lightheaded, craving for cocaine, thirsty, excited, dry mouth, stimulated and drug effect (Fig. 2), and the
observer-rated adjectives drug effect, positive vocalizations, and tremor/shaky. The subject-rated adjective ‘‘drug effect’’ is shown as an example in Fig. 2. Significantly greater ratings of ‘‘drug effect’’ were found for all active doses compared with placebo (P B/0.05) and when 50 mg per 70 kg was compared with 12.5 mg per 70 kg. The subjective effects of cocaine tended to peak at 6/10 min after the injection and then decline over the remainder of the 45 min period. The peak score analyses were concordant with the time course results. The overall street value of the sample injection did not change between the 10 and 45 min post-injection assessments; therefore, only the data from 45 min post-injection are presented. Street value was significantly increased as a function of cocaine dose (P B/ 0.01). Estimated street values for placebo, 12.5, 25, and 50 mg per 70 kg were $0.089/0.05, 2.329/0.40, 3.779/0.49 and 8.259/1.81, respectively.
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3.2. Choice behavior The pattern of choice behavior across all conditions is shown in Fig. 3. The mean inter-choice intervals for the self-selected condition were 15.09/0, 16.69/1.3, 17.39/ 1.0 and 16.89/0.6 min for 0, 12.5, 25 and 50 mg per 70 kg, respectively. Few volunteers chose to take placebo when the alternative was $1 or 4, while none chose placebo over the higher monetary alternatives. When 12.5 mg per 70 kg was available, two of eight volunteers chose money on all six trials for each of the inter-choice intervals. When 25 or 50 mg per 70 kg was available, most volunteers chose cocaine regardless of the value of the alternative reinforcer. There was a tendency for the number of volunteers choosing 50 mg per 70 kg cocaine to decrease during the intermediate trials (e.g., $7 and 10). However, inspection of individual data within each session revealed that, overall, volunteers chose all drug 47% of the time (all when active cocaine was available) and all money 25% of the time (all when either placebo or 12.5 mg of cocaine was available). The total number of injections (Fig. 4, upper left panel) increased with the dose of cocaine [F (3,21) / 27.6, P B/0.001]. When 25 or 50 mg per 70 kg cocaine was available, volunteers chose an average of five to six injections (of a possible six). The 12.5 mg per 70 kg dose, produced an intermediate level of cocaine self-administration, with an average of four injection choices per
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session. The total number of injection choices was not altered by the inter-choice interval. Analysis of the total amount of money chosen (Fig. 4, upper right panel) revealed a dose-dependent decrease in the amount earned (F /30.2, P B/0.001); no effect of inter-choice interval was found. Analysis of the dollar value at which the first choice for money was made (Fig. 4, lower left panel) revealed a significant effect of cocaine dose (F /20.1, P B/0.001), whereby larger doses required a larger dollar value before money was chosen. When choices were presented at 15 min intervals, 25 mg per 70 kg required the largest average dollar value before money was first chosen over cocaine, and this required value tended to decrease when 50 mg per 70 kg was available. In contrast, when choices were presented every 30 min or were under the control of the volunteer (with a mean interval of approximately 17 min), 25 and 50 mg per 70 kg produced near identical results. The drop in value at which volunteers first chose to take money over 50 mg per 70 kg cocaine in the 15 min inter-choice interval condition resulted from five volunteers who took $10 or 13 over cocaine (see Fig. 3). This intermediate money choice lengthened the average inter-infusion interval from 15.45[9/0.47 (S.E.M.)] in the 25 mg per 70 kg condition to 17.349/0.69 in the 50 mg per 70 kg condition. However, all of these volunteers resumed choosing cocaine in subsequent trials after this money choice. In fact, in 82% of the sessions that
Fig. 3. The total number of volunteers (n /8) choosing to take an injection over money during each of six successive choice trials in which the value of the monetary alternative progressively increased with each trial from $1 to 16. The choice between each of four doses of cocaine (represented horizontally) and money was presented every 15 min (upper panels), every 30 min (middle panels), or at a self-selected interval (lower panels).
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Fig. 4. Mean number of injection choices (upper left panel), amount of money earned per session (upper right panel), dollar value at which volunteers first chose to take money instead of cocaine (lower left panel) and the largest amount of money turned down in order to receive an injection (lower right panel). During each session volunteers were allowed to choose between an injection (0, 12.5, 25, 50 mg per 70 kg cocaine) and money ($1 /16) every 15, 30 min, or at a self-selected interval. Error bars represent 1/2 the critical difference; non-overlapping bars indicate a significant difference (P B/0.05; Tukey HSD).
volunteers chose some combination of money and drug, volunteers chose to take at least one more cocaine injection after making a money choice. The remaining 18% of the sessions when volunteers chose an injection and then all money were when placebo was available. There were no sessions in which a volunteer choosing active cocaine transferred to choosing money for the remainder of the session. Similar to the other summary measures of choice, the largest amount of money volunteers turned down in
order to receive an injection (Fig. 4, lower right panel) increased with the dose of cocaine (F /33.7, P B/0.001), but was unaffected by the interval between choices. Volunteers chose to take cocaine over the largest alternative money amount ($16) at both 25 and 50 mg per 70 kg in all but one case when a volunteer chose $16 over 25 mg per 70 kg cocaine. The average maximum amount paid for 0 and 12.5 mg per 70 kg was approximately $1 and 12, respectively, regardless of the inter-choice interval.
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4. Discussion The choice to take cocaine was dose-dependent up to an intravenous dose of 25 mg per 70 kg. The mean number of choices to take an injection instead of the alternative monetary reinforcer increased when active doses of cocaine were available compared with placebo and when 25 and 50 mg per 70 kg were available compared with 12.5 mg per 70 kg cocaine. This dosedependent cocaine self-administration produced a decrease in the total amount of money earned within each session as the dose of cocaine was increased. Larger doses of cocaine increased the average dollar value of the first money choice and the maximum amount of money volunteers were willing to forgo for an injection. These results are similar to those reported in a study in which volunteers could respond on a progressive ratio schedule of reinforcement for either intravenous cocaine or $5 by pressing a computer key (Haney et al., 1998). Higher maximum response outputs (i.e., break points) were obtained with active cocaine compared with placebo and with the two highest doses (16 and 32 mg per 70 kg) compared with the lowest dose (8 mg per 70 kg). Injection choices did not decrease as the value of the alternative reinforcer increased within a session. Most volunteers chose to take either all money or all injections within a session, depending on the cocaine dose. When placebo injections were available, all money choices were made in 75% of sessions. In contrast, the lowest dose of cocaine (12.5 mg per 70 kg) produced all money choices in only 25% of sessions and all cocaine choices in 42% of sessions. When the two highest doses of cocaine (25 and 50 mg per 70 kg) were available, volunteers chose to take some cocaine in all sessions and all cocaine in 88 and 58% of sessions, respectively. Overall, this ascending schedule of alternative reinforcement resulted in some combination of money and drug choices in only 28% of choice sessions. These results resemble previous reports of high cocaine intake in cocaine-dependent participants (Ward et al., 1997), despite the availability of an alternative reinforcer. Similar overwhelming preferences for cocaine have been reported in preclinical studies when the alternative reinforcer was food (e.g., Aigner and Balster, 1978). The point at which money was first chosen over cocaine was conceptualized as similar to a break point. However, in contrast to the standard progressive ratio procedure, the choice to take money did not end the session. This approach was taken in order to keep each choice trial independent and avoid compounding the consequences of eliminating subsequent choice trials (e.g., loss of future money choices). It was hypothesized that, after making a money choice, volunteers would continue to choose money over cocaine during subsequent trials in which the value of the monetary alter-
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native continued to increase. However, examination of the data from individual volunteers that chose money over an active dose of cocaine revealed that in 100% of the cases, volunteers chose at least one subsequent cocaine injection in lieu of an even larger monetary alternative. It is unclear what accounts for the observation that participants returned to choosing cocaine after a money choice was made despite larger alternative reinforcers. One possibility is that the reinforcing value of a given dose of cocaine may increase over time since the last injection. However, longer inter-choice intervals produced little change on any of the choice outcome measures, suggesting that time since last injection was not of critical importance under these schedule conditions. A second possible explanation is that the choice for money at an intermediate trial may represent a transient decrease in the reinforcing efficacy of cocaine related to either acute tolerance or an accumulation of aversive effects following repeated dosing. Acute tolerance following repeated cocaine doses is a well-documented phenomenon in humans (Ambre et al., 1988). However, inspection of the subjective responses to cocaine in this study does not support this hypothesis. Cocaine produced similar effects on visual analog ratings of ‘‘good effect’’ and ‘‘bad effects’’ in trials that preceded a money choice, preceded a cocaine choice, or followed a money choice. A third possibility is that participants titrated their intake of cocaine around some optimal level (i.e., maximizing positive effects and/or avoiding aversive effects) and that the value of the alternative reinforcer was not causally related to either the intermediate money choice or the subsequent choice to take cocaine. The choice to take additional active doses of cocaine was largely independent of the magnitude of the monetary alternative reinforcer. In contrast, previous models of human cocaine self-administration have reported a decrease in cocaine self-administration as the value of the alternative reinforcer was increased (Hatsukami et al., 1994; Higgins et al., 1994). Several differences may account for this discrepancy, including larger cocaine doses in the present study, differences in route of administration, and, importantly, differences in the design used to manipulate the magnitude of alternative reinforcement. The present model increased the value of the alternative reinforcer within each session, while in previous models the monetary alternative was constant within session and either increased across sessions (Higgins et al., 1994) or between participants (Hatsukami et al., 1994). Alternative reinforcers may decrease the likelihood of initiating cocaine self-administration during abstinence, but have little effect once cocaine-taking has been initiated. This is consistent with the report by Walsh et al. (2001) in which the present model of cocaine self-administration was compared with
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a model with two critical differences. The alternative model did not require a sample injection immediately prior to the choice trials and the value of the alternative reinforcer was large on the first choice trial ($16) and decreased with each subsequent trial (i.e., by $3 per trial). This alternative model resulted in fewer cocaine choices than the present model. Furthermore, three times as many individuals chose $16 over cocaine when it was the first as compared with the last choice trial. Moreover, studies employing models in which the alternative reinforcer is constant within a session have found that participants chose either all money or all cocaine in the majority of sessions (79% in Higgins et al., 1994; 58% in Hatsukami et al., 1994), supporting the notion that alternative reinforcement may have only modest effects on cocaine-taking once the behavior has been initiated. Preclinical studies have also indicated that cocaine self-administration may be less affected by increasing response costs than responding maintained by other drugs of abuse (Woolverton et al., 1997; Stafford et al., 1998). The range of monetary alternatives was chosen to span and surpass estimates of the street value of cocaine. However, this amount of money was clearly too low to compete with cocaine in this paradigm. Volunteers overwhelmingly chose cocaine over money at dollar values that far exceeded the estimated street value of that dose of cocaine during the sample session. For example, most volunteers presented with the choice to take either 25 or 50 mg of cocaine or up to $16 chose to take cocaine, despite estimating the value for that dose to be $3.77 and 8.25, respectively. On average, the maximum amount of money volunteers were willing to forgo in order to receive cocaine was 2/4 times greater than their estimated street value of cocaine. This discordance between functional value in the behavioral choice procedure and subjectively reported value on the questionnaire highlights an important distinction between these two methods of assessing reinforcing efficacy. The present study cannot distinguish between several possible explanations for this discrepancy. One is that this discordance between self-report and behavior represents the construct of loss of control over drugtaking behavior that is commonly imputed to be a core feature of drug dependence disorders (APA, 1994). A second possibility is that this discordance reflects the influence of delay discounting, in which the value of a delayed reinforcer is discounted compared with an immediately available reinforcer (Hull, 1943; Mazur, 1987), on choice behavior (as discussed in more detail below). These two explanations may be related. Greater discounting of delayed rewards has been reported in drug-dependent compared with non-dependent individuals (Bickel and Marsch, 2001; Petry, 2001) and may provide a mechanistic explanation of the loss of control construct.
Subjective estimates of street value, as well as other self-report measures of the positive effects of cocaine, were more sensitive to changes in dose than choice behavior. Most volunteers chose to self-administer almost all active doses of cocaine, despite a range of self-administration doses that produced mild to moderate subjective effects. Previous research has demonstrated that when cocaine users are given the choice between two cocaine injections, they prefer higher compared with lower doses (Foltin and Fischman, 1994). However, near-maximal cocaine self-administration is observed across a wide range of active doses of cocaine both when volunteers are allowed to perform an operant response for an active dose of cocaine (Haney et al., 1998) and when they are given a choice between an active dose of cocaine and a constant (Foltin and Fischman, 1996; Haney et al., 2001) or escalating (data shown here) alternative, non-drug reinforcer. This suggests that there may be a relatively low threshold of subjective effects that can initiate cocaine selfadministration, above which cocaine self-administration is robust and largely insensitive to variations in the dose of cocaine. Preclinical research is consistent with this idea; low doses of cocaine can initiate cocaine-seeking (Norman et al., 1999), but the threshold for satiation is high (Tsibulsky and Norman, 1999). The choice to take cocaine in the present study may have been influenced by an array of factors, including priming and the economic conditions of the study (i.e., open vs. closed economies, delay to monetary reward). The intent of this study was to assess the ability of an alternative monetary reinforcer to compete with cocaine self-administration after the volunteer had already initiated taking cocaine. Volunteers were given a ‘‘sample’’ injection and then provided little incentive (e.g., $1) not to take cocaine during the early trials. However, the preference for cocaine over money during subsequent trials (i.e., in the presence of larger alternative reinforcers) may have been enhanced because the previous doses ‘‘primed’’ cocaine self-administration. Priming is the ability of a stimulus (e.g., cocaine) to increase the probability of drug-seeking behavior (de Wit and Stewart, 1981). Preclinical studies have shown that injections of cocaine and pharmacologically related drugs, such as amphetamine, induce cocaine-seeking behavior in abstinent animals (de Wit and Stewart, 1981; Spealman et al., 1999; Sutton et al., 2000) and human experimental studies have demonstrated that alcohol administration increases the choice for alcohol in social drinkers (de Wit and Chutuape, 1993). Similarly, cocaine administration in humans increases selfreported desire for cocaine (present results; Haberny et al., 1995; Haney et al., 1998). Exposure to cocaine when there was little or no cost may have increased the value of subsequent cocaine self-administration. Future studies will attempt to isolate the effect of priming in order
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to determine its contribution to cocaine-taking behavior in the human laboratory. It is also important to recognize two potentially important behavioral economic factors. First, the laboratory constituted a closed economy for cocaine and an open economy for money. Limiting access to cocaine or providing additional sources of monetary reward (e.g., payment for participation) in volunteers residing on a residential unit may greatly increase the value of cocaine relative to money (Carroll et al., 2000). Indirect evidence that this may be an important factor can been seen in choice behavior when volunteers were offered their last opportunity of the session to take cocaine or $16. Despite sometimes choosing money at a lower dollar value, volunteers with access to 25 or 50 mg per 70 kg chose cocaine over money on all but one occasion. Second, because the monetary alternative reinforcer was delayed relative to the immediacy of cocaine administration, the present value of the monetary alternative was likely discounted to some degree (Hull, 1943; Mazur, 1987). Although money was physically presented to the volunteer during session in an attempt to make the monetary reinforcer more salient, the money was collected by the experimenter at the conclusion of the session. The volunteer was unable to retain and spend that money until after discharge from the study, while consumption of cocaine occurred immediately. Manipulating the inter-choice interval had little effect on the choice to take cocaine. Dose-effect functions for cocaine self-administration were nearly identical across the three inter-choice interval conditions; however, because of safety considerations and practical constraints on the session length, the effect of inter-choice interval was examined over a limited range. Further shortening of the inter-choice interval may have reduced cocaine choices, especially at high doses. There was a trend for a small decrease in the total number of injection choices and value of the first money choice as the dose was increased from 25 to 50 mg per 70 kg and this was less evident in the self-selected condition. This decrease was a result of three to five volunteers (depending on condition) making a money choice on an intermediate trial when 50 mg per 70 kg was available. The decrease from 25 to 50 mg per 70 kg was not observed in the self-selected condition because one volunteer chose money on five of six trials when 25 mg per 70 kg was available, producing a decrease in the overall mean at 25 mg per 70 kg; this was not representative of the condition as a whole. The tendency for cocaine self-administration to decrease slightly from 25 to 50 mg per 70 kg suggests an upper limit of cocaine consumption may have resulted in some volunteers making a single money choice during the session. Conversely, if the reinforcing efficacy of cocaine is increased 15 /30 min after a cocaine injection, substantially longer intervals (e.g., 90 min), that allow cocaine’s
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effects to dissipate entirely, may reduce the probability of additional cocaine choices. Participants in the present study were required to have a history of either i.v. or smoked cocaine use prior to investigational administration of i.v. cocaine. The National Advisory Council on Drug Abuse (1997) Guidelines for the Administration of Drugs to Human Subjects stated that the rationale for exposure to ‘‘new routes of administration should be clear and compelling.’’ The Council also emphasized that the ethical responsibility falls upon the investigator and the local Institutional Review Board and that the guidelines are intended ‘‘to encourage a sensitive, ethical approach that is also consistent with the best current practices and experience in the field of drug abuse research.’’ It is important, therefore, to discuss our rationale for including intravenous-naı¨ve participants in the present study. Our recruiting decision was rooted in the principle that participants should not be exposed to routes of administration involving greater abuse liability than those with which they are already experienced. Laboratory assessments of the reinforcing effects of cocaine have found that smoked cocaine has equal or greater abuse liability than intravenous cocaine (Foltin and Fischman, 1992). Furthermore, investigational administration of i.v. cocaine to i.v. inexperienced cocaine users does not appear to increase the risk of recreational i.v. use (Kaufman et al., 2000). This may be, in part, because investigational i.v. cocaine differs considerably from recreational i.v. cocaine use; investigational exposure employs a slower rate of infusion, is injected through an indwelling catheter, is administered by a physician, and occurs in an artificial and controlled environment. Based on the available evidence, we concluded, in partnership with our local Institutional Review Board, that the added risk from the inclusion of both i.v. and smoked cocaine users was minimal and acceptable given the benefits of this approach. These benefits include a history of safe, i.v. cocaine administration in our laboratory (e.g., Nann-Vernotica et al., 2001; Walsh et al., 2001), the ability to employ a doubleblind, placebo-controlled design to evaluate active cocaine without confounding the sensory effects of smoking cocaine, and the inclusion of and consequent generalizability to users of both smoked and i.v. cocaine. In summary, cocaine self-administration was dosedependent in this human laboratory model. The total number of injection choices increased and the total amount of money earned per session decreased when larger doses of cocaine were available. However, most volunteers chose to take either all money or all injections within a session. Increasing the value of an alternative, monetary reinforcer within the session had little effect on the choice to take active doses of cocaine under these conditions. These observations highlight the difficulty in reducing or stopping cocaine self-administration once
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cocaine-taking has been initiated and suggest that the initiation of cocaine-taking may be a critical determinant of subsequent cocaine self-administration (Walsh et al., 2001).
Acknowledgements This research was supported by grants from the National Institute on Drug Abuse R01 DA10753, R01 DA05196, T32 DA07209, and K05 DA00050. The authors thank the staff at BPRU especially Melissa Blank, Heather Cronin, Roxanna Kelly, Tim Mudric, Paul Nuzzo and John Yingling.
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