Parametric analysis of cocaine self-administration under a progressive-ratio schedule in rhesus monkeys

The present study was designed to investigate parameters and quantitative analysis of cocaine self-administration under a progressive-ratio (PR) schedule of reinforcement, with the goal of enhancing the resolution of PR schedules for measuring reinforcing efficacy. Six rhesus monkeys were prepared with chronic intravenous catheters and trained to self-administer cocaine under a PR schedule. The schedule consisted of five components, each made up of four trials (i.e., 20 trials total). Each trial within a component had the same response requirement. Three initial response requirements were tested: fixed-ratio (FR) 60, FR 120 and FR 240. The response requirements doubled in successive components to a maximum of FR 960, FR 1920 or FR 3840, respectively, in the fifth component. A trial ended with an injection or the expiration of a 12- or 24-min limited hold (LH). The inter-trial interval (ITI) was 15 or 30 min. Four dependent measures were assessed: break point (last FR completed), injections/session, responses/session and response rate (responses/s). For the three initial FRs, the break point, number of injections/session, responses/session and rate increased with dose of cocaine (0.013–0.1 mg/kg per injection) at both ITI/LH values. At the ITI15/LH12, responding decreased at higher doses, i.e., the dose-response functions were biphasic. In contrast, at the ITI30/LH24, responding reached an asymptote at higher doses. In general, cocaine maintained significantly higher break points, injections/session, responses/session and rate at ITI30/LH24 than at ITI15/LH12. However, at both ITI/LHs, as initial FR was increased, injections/session at the higher doses decreased while break point, total responses/session and rate did not change. A ceiling on performance, as assessed by break point, total responses/session and response rate, may have limited the number of cocaine injections an animal could take in a session. The results of this study indicate that optimal conditions for measuring the reinforcing efficacy of cocaine were obtained at the longer ITI/LH and at initial FRs above 60.     

Self-administration of cocaine and heroin combinations by rhesus monkeys responding under a progressive-ratio schedule

 The present study examined the reinforcing effects of cocaine and heroin, alone and combined, in rhesus monkeys (n=4) responding under a progressive-ratio (PR) schedule. The PR schedule consisted of five components, each made up of four trials (i.e., 20 trials total), with each trial in a component having the same response requirement. The initial response requirement was fixed-ratio (FR) 120, which doubled across components to a maximum of FR1920. A trial ended with an injection or the expiration of a 15-min limited hold and the inter-trial interval was 30 min. Cocaine dose-response functions (13–400 μg/kg per injection) for injections/session were monophasic, i.e., increased with dose until responding reached an asymptote or a peak. Heroin dose-response functions (1.6–100 μg/kg per injection) for injections/session were biphasic functions, i.e., increased to a peak and then decreased, whereas heroin dose-response functions for response rate were monophasic and reached an asymptote. When cocaine (1.6–200 μg/kg per injection) was combined with heroin (0.4–6.4 μg/kg per injection), low doses of cocaine (3.2–25 μg/kg per injection) and heroin (0.4–1.6 μg/kg per injection) that did not maintain behavior when tested alone did so when tested in combination. Combination with heroin resulted in a leftward shift in the cocaine dose-response functions, indicating that heroin increased the potency of cocaine as a reinforcer. This heroin-induced increase in cocaine′s reinforcing potency may be a contributing factor to abuse of cocaine and heroin combinations (i.e., ”speedballs”) in humans. However, maximum injections/session for cocaine combined with heroin were not different from cocaine alone, suggesting that the reinforcing efficacy of combinations of cocaine and heroin were not higher than that of cocaine alone. Received: 14 January 1997 / Final version: 25 March 1997     

Reinforcing properties of intravenous procaine in rhesus monkeys.

The lever pressing behavior of rhesus monkeys was maintained by a fixed ratio 10 schedule of intravenous cocaine (3 monkeys) or codeine (2 monkeys) injections during 2 hour sessions. Saline or various doses of procaine hydrochloride were substituted for the baseline reinforcer for 6 consecutive sessions. Each substitution was separated by 3 or more days of cocaine or codeine reinforced responding. At one or more doses, procaine substitution resulted in response rates higher than saline control in all 5 animals. High response rates (greater than 30 injections per session) were obtained in 4 of the 5 monkeys. In addition, procaine self-administration was studied in two naive monkeys given 23 hour per day access to procaine following an initial 10 days of saline contingent operant level responding. At a dose of 0.3 mg/kg/injection, both animals initiated responding for procaine reinforcement. Drug intake varied widely from day to day, however each animal took over 1200 injections per day (over 360 mg/kg) at least once during the 30 days of access. With the exception of decreased food intake, there was little evidence for behavioral toxicity from these doses. Following a second 10 days of saline self-administration, both animals were given access to 3.0 mg/kg/injection procaine. A substantially greater intake of procaine was observed which was associated with marked toxicity.     

The reinforcing properties of procaine,chloroprocaine and proparacaine in rhesus monkeys

Responding was maintained under a fixed ratio 10 schedule of intravenous cocaine (six monkeys) or pentobarbital (two monkeys) delivery during a daily 3 h session. When responding was stable, intravenous doses of procaine (0.05–3.2 mg/kg), chloroprocaine (0.05–3.2 mg/kg), proparacaine (0.01–0.4 mg/kg), or saline were substituted for the cocaine or pentobarbital for six to ten sessions. Between each substitution, responding was again maintained by cocaine or pentobarbital. Procaine and chloroprocaine maintained rates of responding exceeding saline levels in all monkeys tested, with maximum rates generated by 0.2 mg/kg. Daily intake in mg/kg increased 3–10 times a dose was increased from 0.1 to 3.2 mg/kg per infusion. Within each session, there were periods of continuous responding resulting in multiple infusions, separated by intervals of no responding of varying duration. Nevertheless, the number of infusions occurring in each of the six 30 min periods was relatively constant for both drugs. Responding maintained by proparacaine was similar or slightly above that maintained by saline except at one dose (0.025 mg/kg) in one monkey. No signs of toxicity were observed with any of the drugs. These results indicate that procaine and chloroprocaine are strong positive reinforcers but that proparacaine has minimal reinforcing properties.     

Reinforcing properties of some local anesthetics in rhesus monkeys.

The reinforcing properties of several local anesthetics were determined in rhesus monkeys experienced in the intravenous self-injection of cocaine. Intravenous procaine and, occasionally, tetracaine maintained response rates higher than did vehicle injections in most monkeys. In contrast, lidocaine, procainamide and diethylaminoethanol (a metabolite of procaine) failed to maintain responding resulting in their intravenous delivery. These results demonstrate that not all local anesthetics are positive reinforcers in the rhesus monkey when delivered intravenously. Furthermore, the reinforcing properties of procaine probably cannot be attributed to its metabolite diethylaminoethanol. The data suggest that short-acting, esteratic local anesthetics are most likely to have reinforcing properties in the rhesus monkey.     

Pharmacokinetics of repeated doses of intravenous cocaine across the menstrual cycle in rhesus monkeys

Numerous studies in rodents suggest that there are sex differences in response to cocaine that are related to fluctuations in the ovarian hormones of females. Given that female rhesus monkeys have menstrual cycles that are remarkably similar to those of humans, they provide an ideal laboratory animal model for assessing the effects of cocaine across the menstrual cycle. The present study assessed the effects of 4 injections of intravenous (i.v.) cocaine (0.00, 0.25 or 0.50 mg/kg), spaced 15 min apart, in 4 female rhesus monkeys. Each monkey was tested with each dose during 4 phases of the menstrual cycle: menses, midfollicular, periovulatory and midluteal. Estradiol and progesterone levels were measured each session before cocaine administration to verify phase of the menstrual cycle. Cocaine and cocaine metabolite levels were measured 5 min after each cocaine dose and 5, 15, 30, 45, 60 and 120 min after the last cocaine dose. Similarly, levels of luteinizing hormone (LH) and prolactin levels were measured before, 5, 15, 30, 45, 60 and 120 min after the last cocaine dose. Cocaine and metabolite levels increased as a function of dose, but there were minimal differences across the menstrual cycle following repeated injections of cocaine. With a few exceptions, LH levels decreased as a function of time within the session, with no differences as a function of cocaine dose. Cocaine produced transient increases in LH levels during the luteal phase, with maximal levels occurring after the second cocaine injection. Lastly, cocaine substantially decreased prolactin levels across all menstrual cycle phases. Taken together, these data indicate that any behavioral differences observed either across the menstrual cycle or between males and females, are probably not related to alterations in the pharmacokinetics of cocaine across the menstrual cycle.     

Cocaine-base smoking in rhesus monkeys: reinforcing and physiological effects

Four rhesus monkeys were trained to smoke cocaine-base under a progressive ratio (PR) schedule, with ten smoking trials available each day. Unit dose was varied from 0.25 to 3 mg/kg, and lidocaine (2 mg/kg) was substituted for cocaine. Number of responses and break-point on the PR schedule increased with dose while the number of smoke deliveries increased only slightly. Maximum daily smoke deliveries ranged from six to nine across monkeys. When lidocaine (2 mg/kg) was substituted for cocaine-base, responding decreased to approximately half of that maintained by cocaine, and when cocaine was reinstated, higher response rates returned. Cardiovascular changes associated with cocaine smoking were monitored with an indwelling radio transmitter. There was an initial decrease in heart rate (30 s) followed by a rapid rise and decline by the end of the 15-min trials. Blood pressure increased rapidly after trial onset and returned to pretrial baseline by 15 min. Over the eight trials completed during a session, heart rate and blood pressure steadily increased over presession baselines during the first four trials, but there was then a decline suggesting acute tolerance development. Observations of the monkeys after each trial revealed dilated pupils and slightly agitated, hyperactive behavior. These findings indicated that smoked cocaine-base was rapidly established as a reinforcer for monkeys, and the physiological effects were similar to those reported in studies of human subjects.     

Choice between cocaine and food by rhesus monkeys: effects of conditions of food availability

The present experiment was designed to examine the effects of the conditions of food availability on choice between cocaine and food in rhesus monkeys. Monkeys (n = 3), maintained at approximately 90% of their free-feeding weights, were trained in a discrete-trials choice procedure and allowed to choose between intravenous injections of cocaine (0.03-1.0mg/kg/injection) and food delivery (4 pellets; 1g/pellet) during daily 7-h sessions. When food was available both within the session and by supplemental post-session feeding, the frequency of cocaine choice increased in a dose-related manner for all monkeys. When supplemental post-session feeding was eliminated (i.e. food was only available within the session) the cocaine dose-response function was shifted to the right and down relative to that found initially. However, changes in the frequency of cocaine choice did not vary consistently with changes in body weight. Thus, these results suggest that the reinforcing efficacy of cocaine can be modified by changing the conditions of availability of an alternative non-drug reinforcer.     

Intravenous self-administration of 4-methylaminorex in primates

The reinforcing effects of (+/-)-cis-2-Amino-4-methyl-5-phenyl-2-oxazoline (4-methylaminorex) were determined in two models of intravenous drug self-administration in primates. In baboons, lever pressing was maintained under a fixed-ratio (FR) 80- or 160-schedule of intravenous cocaine delivery (0.32 mg/kg per injection). Each drug injection was followed by a 3-h time-out allowing a maximum of 8 injections per day. Vehicle or 4-methylaminorex doses were substituted for cocaine for a period of 15 or more days. One of the two 4-methylaminorex doses evaluated (0.32 mg/kg per injection) maintained self-administration behavior above vehicle control levels in all four animals. This dose of 4-methylaminorex maintained cyclic patterns of self-injection behavior across days and produced signs of psychomotor stimulant toxicity. In rhesus monkeys, 4-methylaminorex (0.0003-0.1 mg/kg per injection) was made available to animals trained to self-administer cocaine (0.01 or 0.033 mg/kg per injection) under an FR 10 schedule of reinforcement during daily 1-h sessions. Each of the three monkeys self-administered at least two doses of 4-methylaminorex at rates exceeding those maintained by vehicle injections. Taken together with reports of recreational abuse of 4-methylaminorex, the present results indicate that this drug has a potential for abuse similar to that of other psychomotor stimulants.     

Effects of chronic methadone treatment on cocaine- and food-maintained responding under second-order, progressive-ratio and concurrent-choice schedules in rhesus monkeys

The effects of chronic infusion with saline or methadone (0.032-1.0 mg/kg/h) were examined on cocaine- and food-maintained responding in rhesus monkeys using three procedures. In one procedure, cocaine injections (0.0032-0.032 mg/kg per injection) and food pellets were available under a second-order schedule during alternating daily sessions. During saline treatment, cocaine maintained a dose-dependent increase in the number of cocaine injections per day, and monkeys usually responded for the maximum number of pellets. Methadone dose-dependently decreased cocaine self-administration, and methadone doses that decreased cocaine self-administration had variable effects on food-maintained responding. In the second procedure, 0.032 mg/kg per injection cocaine or food pellets were available under a progressive-ratio schedule. During saline treatment, cocaine and food maintained similar break points. Methadone produced a dose-dependent and non-selective decrease in break points maintained by both cocaine and food. In the third procedure, cocaine injections (0-0.1 mg/kg per injection) and food pellets were available under a concurrent-choice schedule. During saline treatment, increasing unit doses of cocaine produced a dose-dependent increase in cocaine choice. Methadone had little effect on the cocaine choice dose-effect curve up to doses that eliminated responding. These results provide little evidence to suggest that chronic methadone altered the reinforcing effects of cocaine; rather methadone appeared to non-selectively decrease rates of operant responding.     

Effect of time-out duration on the reinforcing strength of cocaine assessed under a progressive-ratio schedule in rhesus monkeys

Progressive-ratio (PR) schedules of reinforcement have provided valuable information regarding the reinforcing strength of cocaine and the underlying neurobiological mechanisms. Parametric manipulations, such as altering time-out (TO) values, can affect the shape of the cocaine dose-response curve. Earlier studies have used PR schedules with widely varying parameters, thus complicating comparisons across experiments. This study evaluated the reinforcing strength of cocaine (0.005-0.9 mg/kg) as a function of post-reinforcement TO duration (5, 10, 30, or 60 min) under a PR schedule in rhesus monkeys. Daily sessions ended when 2 h elapsed without an injection; the breakpoint value was defined as the total number of injections. When the TO was 10 min, the relationship between cocaine dose and the number of injections received (i.e. BP) was characterized by an inverted U-shaped curve in all monkeys. Increasing the TO to 30 min resulted in a rightward shift of the ascending limb of the dose-response curve, but did not affect self-administration of higher doses. The number of injections received of a low cocaine dose was not further increased when the TO was shortened to 5 min, nor did increasing the TO to 60 min alter self-administration of the highest tested dose. These results suggest that drug accumulation plays a role in determining the reinforcing strength of low and intermediate cocaine doses under PR schedules. However, the reinforcing strength of higher cocaine doses was unaffected by manipulating TO, suggesting that the BP value is a useful measure of reinforcing strength.     

Effects of haloperidol and physostigmine on self-administration of local anesthetics

Four rhesus monkeys were maintained under a FR 10 schedule of cocaine (0.1 mg/kg) or procaine (0.4 or 1.6 mg/kg) delivery. Haloperidol (0.01–0.08 mg/kg), physostigmine (0.0125–0.1 mg/kg) or saline treatments were administered prior to sessions in which responding was maintained by each of these drugs. Haloperidol produced dose-related increases in the self-administration of cocaine and dose-related decreases in the self-administration of both doses of procaine. Physostigmine produced dose-related decreases in the self-administration of both cocaine and procaine. These results suggest that the reinforcing properties of cocaine are specifically modified by drugs which interact with catecholamines. On the other hand, it seems unlikely that the reinforcing properties of procaine are mediated by the same mechanism. While the results of this experiment indicate that cholinergic mechanisms may not play a major role in mediating the reinforcing properties of either drug, additional studies with other cholinergic agonists and particulary antagonists as well as additional procedures are needed.     

Self-administration in baboons and the discriminative stimulus effects in rats of bupropion,nomifensine, diclofensine and imipramine

The behavioral effects of the antidepressants nomifensine, diclofensine, bupropion, and imipramine were examined using a cocaine substitution drug self-administration procedure in baboons and a cocaine drug discrimination procedure in rats. Intravenous self-administration of the antidepressants was examined in baboons under conditions in which baseline responding was maintained by intravenous injections of cocaine HCl (0.32 mg/kg/injection). Drug was available under a fixed-ratio 80-response or 160-response schedule of intravenous injection. Each drug injection was followed by a 3-h time-out allowing a maximum of eight injections per day. The antidepressants or their vehicles were substituted for cocaine for a period of 15 days, followed by a return to the cocaine baseline. Nomifensine, diclofensine, and bupropion all maintained self-administration behavior at levels above those maintained by their respective vehicles. Some doses of nomifensine, diclofensine, and bupropion maintained levels of behavior similar to those maintained under baseline cocaine conditions. High doses of imipramine maintained levels of behavior above those maintained by its vehicle, but the amount of behavior maintained under these conditions was extremely small. In a second experiment rats were trained to discriminate 32 µmol/kg cocaine (IP 10 min presession) from no drug in a two-lever food reinforced drug discrimination procedure in which responding on one lever was reinforced following ten consecutive responses when the session was preceded by cocaine administration, while responding on the other lever was similarly reinforced in the absence of cocaine pretreatment. Cocaine, nomifensine, diclofensine, and bupropion all dose-dependently occasioned cocaine-appropriate responding. Imipramine did not occasion cocaine-appropriate responding over a range of behaviorally active doses.     

Further evaluation of the reinforcing effects of the novel cocaine analog 2β-propanoyl-3β-(4-tolyl)-tropane (PTT) in rhesus monkeys

 2β-Propanoyl-3β-(4-tolyl)-tropane (PTT) is a cocaine analog which has been shown in rhesus monkeys to have cocaine-like discriminative stimulus effects and a long duration of action (>8 h), yet does not function as a reinforcer when substituted for cocaine in monkeys responding under a fixed-interval 5-min schedule (Nader et al. 1997). The purpose of the present study was to evaluate the reinforcing effects of PTT under a fixed-ratio (FR) schedule and to determine if decreasing the inter-injection interval would influence the reinforcing effects of PTT. Male rhesus monkeys (n=3) were trained to respond under a multiple FR 30 food-drug-food schedule. When responding was stable, cocaine (0.003–0.3 mg/kg per injection) or PTT (0.001–0.03 mg/kg per injection) was available during the drug component for at least five consecutive sessions and until stable responding was observed. To investigate whether the inter-injection interval would influence PTT-maintained response rates, the time-out (TO) following PTT injections was reduced from 180 or 300 s to 10 s for at least five consecutive sessions. Cocaine-maintained response rates were characterized as an inverted-U shaped function of dose, with peak rates maintained by 0.03 mg/kg per injection cocaine. PTT (0.001–0.03 mg/kg per injection) maintained response rates significantly higher than rates maintained by the PTT vehicle, but significantly lower than cocaine-maintained response rates; PTT intake increased with dose. A reduction of the TO following PTT injections to 10 s did not alter PTT-maintained response rates or total session intake. Self-administered PTT was more potent than cocaine at decreasing food-maintained responding. These results suggest that for long-acting compounds like PTT, reinforcing effects are more likely to be observed when the drug is available under a ratio-based schedule, compared to an interval-based schedule. Received: 3 May 1997 / Final version: 11 October 1997     

Effects of cocaine,chlordiazepoxide, and chlorpromazine on responding of squirrel monkeys under second-order schedules of IM cocaine injection or food presentation

Lever pressing by squirrel monkeys was maintained under second-order schedules of either food presentation or IM cocaine injection. Under one second-order schedule, every tenth response produced a brief (1-s) visual stimulus and the first brief stimulus presented after 30 min had elapsed was followed either by ten 300 mg food pellets or by a 3.0 mg IM injection of cocaine. Under another second-order schedule, the first response after 3 min produced the brief stimulus and the tenth brief stimulus was followed either by food or by cocaine. The two types of second-order schedules generated distinctly different patterns of responding. Furthermore, the temporal distribution of responding maintained by food presentation or cocaine injection sometimes differed slightly under the same schedule. Food presentation or cocaine injection occurred only at the end of each daily session, thereby allowing assessment of the effects of presession administration of cocaine, chlorpromazine (CPZ), and chlordiazepoxide (CDP) on responding at times when the direct effects of consequent cocaine injections were minimal or absent. Presession treatment with suitable doses of cocaine increased low rates of food- or cocaine-maintained responding under both types of second-order schedules, whereas CPZ only decreased responding. CDP increased responding in some monkeys, whereas in other monkeys it had little or no effect. Individual differences in the effects of CDP were not related to the schedule of reinforcement, the maintaining event, or the control rate of responding. Thus, the behavioral effects of cocaine, CDP, and CPZ were largely independent of whether responding was maintained by food or by cocaine.     

Influence of abstinence and conditions of cocaine access on the reinforcing strength of cocaine in nonhuman primates

The development of addiction is marked by a transition from recreational to uncontrolled drug use. Investigators modeling this phenomenon in rodents observed increases in cocaine self-administration when conditions of drug access were altered as well as after abstinence. The present studies were designed to extend this research to nonhuman primates by examining whether the reinforcing strength of cocaine could be altered by changing conditions of cocaine availability or by introducing abstinence periods. Rhesus monkeys self-administered cocaine (0.03-0.3 mg/kg per injection) under a progressive-ratio (PR) schedule of reinforcement in evening sessions, with the number of injections earned serving as a measure of reinforcing strength. Alterations in the reinforcing strength of cocaine were assessed after additional access to cocaine under a fixed-ratio (FR) schedule was provided in morning sessions and following various periods of abstinence (3, 7 and 14 days) from regimens of self-administration that resulted in a range of cocaine intakes. Under baseline PR conditions, the maximum number of cocaine injections increased dose-dependently, peaking when 0.3 mg/kg per injection cocaine was available. No increases in the reinforcing strength of cocaine were observed under any condition. In contrast, a statistically significant decrease in the reinforcing strength of cocaine was observed following 14 days of abstinence under one condition. These results fail to support the views that increasing access to cocaine or abstinence enhances the reinforcing strength of cocaine.     

Effects of cocaine under concurrent fixed ratio schedules of food and IV drug availability: a novel choice procedure in monkeys

Abstract Rationale. The relative reinforcing strength of cocaine can be characterized by the distribution of operant behavior during the availability of other reinforcing stimuli. Objective. To develop a procedure to rapidly evaluate the relative reinforcing strength of cocaine in monkeys. Methods. Monkeys were trained to respond on two levers under concurrent fixed-ratio 30 (FR30) schedules of reinforcement. Responding on one lever resulted in food delivery, responding on the alternative lever resulted in delivery of IV saline or cocaine (0.032 or 0.1 mg/kg per injection). Daily sessions consisted of three 30-min components separated by 10-min timeout periods. The availability of saline, 0.032, or 0.1 mg/kg per injection cocaine varied across components, and only in an ascending order. The relative reinforcing strength of 0.0032–0.32 mg/kg per injection cocaine was examined by substituting different unit doses for the training doses of cocaine. Effects of cocaine pretreatment on response distribution were determined by giving IM injections of 0.1–1.8 mg/kg cocaine 10 min prior to sessions of saline availability. Results. Increasing unit doses of cocaine monotonically increased the distribution of responding on the injection-lever and monotonically deceased response rates. Responding occurred predominantly on the food-lever during availability of saline or 0.0032 mg/kg per injection cocaine, whereas availability of 0.032–0.32 mg/kg per injection produced >90% of responding on the injection-lever. Availability of 0.01 mg/kg per injection cocaine resulted in approximately equal levels of responding on the food- and injection-levers. Presession IM cocaine injections dose-dependently increased responding on the injection-lever. Conclusions. Stable behavior can be maintained under concurrent FR schedules of food and cocaine presentation in monkeys, and the distribution of behavior on food- and injection-levers is dependent on the available dose of cocaine. Electronic Publication     

The effects of a D1 and a D2 dopamine antagonist on behavior maintained by cocaine or food

The purpose of the present experiment was to determine whether a D1 or a D2 dopamine antagonist could alter responding maintained by cocaine at doses that did not affect responding maintained by food. Rhesus monkeys were trained to press a lever in daily experimental sessions under a 3 component multiple schedule of reinforcement. In the first and third components, food was available under a fixed-ratio 30/time-out 2 min (FR30/TO 2) schedule. In the second component, cocaine was available under identical schedule conditions. Each component lasted 15 minutes and there was a 15-minute TO between components. When behavior was stable, rates of responding for injections of saline or several doses of cocaine were determined by making each of these solutions available in the second component for at least 4 sessions. After dose-response determinations for cocaine had been determined, a dose of cocaine that maintained maximal rates of responding was available in daily sessions. When behavior was again stable in all 3 components, monkeys were injected daily before the session with each of several doses of the D1 antagonist SCH 23390 or the D2 antagonist pimozide for the same number of sessions that had been required for responding to decline to low levels when the monkeys were allowed to self-administer saline. Both antagonists caused a dose-related decrease in responding for both cocaine and food. Each antagonist decreased responding for food at the same doses that decreased responding for cocaine. Thus both a D1 and a D2 dopamine antagonist decreased behavior maintained by cocaine but only at doses that also decreased behavior maintained by another reinforcer, food.     

Comparison of the intravenous reinforcing effects of propofol and methohexital in baboons

Propofol is a widely used intravenous anesthetic that can directly activate and positively modulate the GABA(A)-receptor. Propofol is not currently regulated under the USA Controlled Substances Act. The present study evaluated the intravenous reinforcing effects of propofol compared to the intravenous barbiturate anesthetic methohexital in baboons using a procedure in which doses of the test drug were substituted for a standard cocaine dose. Drug or vehicle was available for self-injection during daily 5.5-h sessions under a fixed-ratio 120 or 160 schedule of reinforcement. A 40-min timeout after each injection limited the maximum of injections per session to eight. Food pellets were available continuously during the session under a fixed ratio 10 schedule of reinforcement. Self-injection of cocaine (0.001-0.32 mg/kg/injection) and vehicle was characterized first. Cocaine maintained self-injection in a dose-dependent manner, with peak injections maintained by 0.32 mg/kg. Vehicle and each dose of propofol (0.1-1.0 mg/kg/injection) and methohexital (0.01-1.0 mg/kg/injection) were substituted for 0.32 mg/kg cocaine for at least 10 sessions. Propofol and methohexital maintained self-injection greater than vehicle in all three baboons, and these effects were dose dependent. Methohexital maintained peak mean levels of self-injection that were >6 injections/day at doses of 0.56 and 1.0 mg/kg, and did not alter food intake systematically. Propofol maintained peak mean levels of self-injection at 1.0 mg/kg that ranged from 2.2 to >6 injections/day across the baboons. Food intake was increased slightly above vehicle levels by propofol self-injection in two baboons, and was decreased in the third baboon. These data indicate that propofol, like methohexital, can function as a positive reinforcer.     

Effects of increasing the magnitude of an alternative reinforcer on drug choice in a discrete-trials choice procedure

Rhesus monkeys were trained in a discretetrials choice procedure and allowed to choose between food delivery (1–16 pellets; 1 g/pellet) and intravenous injections of cocaine (0.03–0.56 mg/kg/injection;N=4) or procaine (1.0–10 mg/kg/injection;N=4) during daily 3-h sessions. Injections were available as the alternative to food. When the amount of food available as the alternative to drug was held constant and dose of drug was varied, the frequency of drug choice and total drug intake increased in a dose-related fashion for both cocaine and procaine. For both drugs, when the amount of food available as the alternative to drug was increased and the dose of the drug was held constant, the frequency of drug choice and total drug intake decreased. Thus, increases in the magnitude of an alternative non-drug reinforcer decreased cocaine and procaine self-administration. Further, the results suggest that while increasing the magnitude of the alternative reinforcer decreased the potency of cocaine as a positive reinforcer, the reinforcing efficacy of procaine was decreased. Because drug use by humans typically occurs in a context in which other reinforcers are available, the present results are consistent with the hypothesis that drug self-administration by humans can be decreased by increasing the value of alternative positive reinforcers. In addition, these results suggest that the extent to which drug self-administration is sensitive to this manipulation varies across drugs.