Modulation of ethanol reinforcement by conditioned hyperthermia

The present study was designed to determine whether a signal for availability of self-administered ethanol would acquire the ability to elicit a conditioned thermal response and to alter ethanol self-administration. Non-deprived male albino rats (n=8) were exposed to a differential conditioning procedure in which brief (30-min) periods of access to sweetened ethanol on a fixed-ratio operant schedule were either signalled (CS+ trials) or unsignalled (Blank + trials). A different stimulus signalled trials on which barpressing was not reinforced (CS– trials). Body temperature was recorded continuously from implanted telemetry devices. As in previous studies involving experimenter-administered ethanol injections, the stimulus paired with self-administered ethanol (CS+) acquired the ability to elicit a conditioned increase in body temperature. Moreover, barpressing for ethanol was greater on signalled trials (CS+) than on unsignalled trials (Blank +), indicating that ethanol's reinforcing efficacy was altered by CS+. Ethanol self-administration was significantly correlated with the anticipatory increase in body temperature on CS+ trials (Pearsonr=+0.77). When ethanol was removed, leaving sucrose alone as the reinforcer, the signal's effect on barpressing was eliminated. This finding suggests the signal's effect depended on ethanol's pharmacological properties. In general, these data are consistent with theories that attribute the signal's effect to conditioned changes in motivation to obtain ethanol or to an interaction between the conditioned response and ethanol's unconditioned effects. The specific pattern of results appears to support hypotheses linking ethanol's thermal and motivational effects. According to this view, conditioned hyperthermia produced tolerance to an aversive ethanol effect (hypothermia) that normally contributes to termination of an ethanol drinking bout, thereby allowing a longer period of self-administration on signalled trials.     

Environmental context conditioning with ethanol reduces the aversive effects of ethanol in the acquisition of self-administration in rats

RATIONALE: Many recent theoretical approaches to drug-taking behavior feature a role for Pavlovian conditioning. Despite growing evidence for that role, the particular contributions of Pavlovian conditioning to self-administration are not clear. For example, few studies have addressed the effects of Pavlovian conditioning on the acquisition of self-administration. OBJECTIVES: The purpose of this study was to test the effect of Pavlovian conditioning with an environmental conditioned stimulus and an ethanol unconditioned stimulus on the acquisition of self-administration reinforced by ethanol. METHODS: Rats were either given ethanol by gastric gavage in a distinctive context or in their home cage. All animals were then trained to bar press on a variable interval schedule for a sweetened ethanol solution in the distinctive context. RESULTS: Animals that had received ethanol associated with the training context maintained a higher level of bar press behavior for ethanol as the reinforcing solution. This effect developed only after the first session and resulted from differences in response rates, but did not affect the rate of reinforcement. CONCLUSIONS: This study demonstrates that an environmental context signaling the effects of ethanol maintains a higher operant response rate when ethanol is used subsequently as a reinforcer. This finding replicates previous reports of Pavlovian conditioning effects on ethanol consumption. The specific pattern of results suggests that conditioned tolerance modifies the reinforcing impact of ethanol. Context conditioning with ethanol reduces the aversive impact of initial ethanol consumption and maintains the reinforcing value of the ethanol solution.     

Initiation,maintenance and extinction of cocaine self-administration with and without conditioned reward

 Relapse prevention in abstinent cocaine addicts remains a major focus of drug addiction therapy. We used a rat model of cocaine addiction that focused on cocaine-seeking behavior elicited interoceptively and by conditioned stimuli. Each of 18 rats could self-administer a maximum of 20 intravenous cocaine injections (1.5 mg/kg) per session per day. To prevent initiation of responding by cocaine itself priming injections were never administered. Although cocaine was available beginning every session the rats displayed a self-imposed period of abstinence followed by a period of rapid consumption. The abstinence period was variable among rats but consistent for individual rats. In experiment 1 we studied the contribution of a CS⁺ (stimulus light and lever retraction) to the motivation to initiate and maintain a cocaine self-administration episode. We compared the number of responses the rats emitted to receive the first and subsequent injections of the day between a group responding on a fixed-ratio (FR) schedule (n=6) and a group responding on a second-order (SO) schedule (n=5) of reinforcement. For all rats the number of responses per injection was raised daily until a rat failed to consume more than four injections. The SO group was able to emit approximately four times as many responses as the FR group to obtain their first and subsequent injections. In experiment 2 (n=7) responses during extinction were counted with and without the CS⁺. Responding was greater in the presence of the CS⁺ than in its absence. The present model demonstrates that the motivation to self-administer cocaine is variable and greatly enhanced by conditioned stimuli. Received: 25 January 1996 / Final version: 23 May 1996     

Stimuli produced by observing responses make rats' ethanol self-administration more resistant to price increases

Rationale. Observing responses bring sensory receptors into contact with environmental stimuli. In the observing-response procedure, periods in which an operant response (e.g. pressing a lever) is reinforced by drug deliveries alternate with periods in which this response is never reinforced (i.e. extinction). These alternating periods of drug availability versus extinction are not signaled. Observing responses (i.e. presses on a second lever) produce brief stimuli signaling whether drug is available or not for responses on the first lever. Little is known about how parameters of the drug reinforcer affect drug-stimulus observing. Objectives. The effects of changes in the unit price (responses/reinforcer magnitude) of self-administered ethanol on rats' observing were examined. Also, the effects of an observing-response-produced ethanol stimulus on ethanol consumption were examined by comparing consumption during signaled and unsignaled periods of ethanol availability. Methods. Rats self-administered oral ethanol in the observing-response procedure. The unit price of ethanol in the observing-response procedure was increased by increasing the response requirement for ethanol across conditions. Results. Observing and response rates on the ethanol lever increased and then decreased with increases in the unit price of ethanol. However, ethanol-lever responding and ethanol consumption during periods when ethanol was available were less sensitive to increases in price when the observing-response-produced ethanol stimulus was present. Conclusions. Observing varies as an orderly function of unit price of a drug reinforcer, and drug stimuli produced by observing responses can make drug consumption less sensitive to increases in price. This procedure may provide an animal model of both attending to drug stimuli and the resultant effects of these stimuli on drug taking. Electronic Publication     

Regional heterogeneity for the intracranial self-administration of ethanol within the ventral tegmental area of female Wistar rats

Rationale: Because current findings indicate that the selectively bred alcohol-preferring P line of rats self-administers 50–200 mg% ethanol (EtOH) directly into the ventral tegmental area (VTA), whereas the alcohol-nonpreferring NP line does not, it is important to determine whether unselected, common stock rats would self-administer EtOH directly into the VTA. In addition, because neuroanatomical and self-administration studies indicate that the VTA may be functionally heterogeneous, the present study was designed to determine whether there were subregional differences within the VTA for the intracranial self-administration (ICSA) of EtOH. Objectives: The objective of this study was to employ the ICSA technique to determine whether adult female Wistar rats would self-administer EtOH directly into the VTA, and whether regional heterogeneity existed for EtOH self-infusion within the VTA. Methods: Following surgery to implant guide cannulae aimed at either the posterior or anterior VTA, subjects were placed in standard experimental chambers equipped with an ’active lever’ [fixed ratio (FR)1 schedule of reinforcement], which caused the delivery of the infusate, and an ’inactive lever’, which had no programmed consequence. Subjects were assigned to groups that self-administered either artificial cerebrospinal fluid (aCSF) throughout, or 100–400 mg% EtOH for the first four sessions (acquisition), aCSF in sessions 5 and 6 (extinction), and EtOH again during session 7 (reinstatement). Results: During the four acquisition sessions, rats with posterior VTA placements readily self-administered 200 mg% and 250 mg% EtOH and discriminated between the active and inactive levers. These subjects also demonstrated extinction, when aCSF was substituted for EtOH, and reinstatement when EtOH was reintroduced. Rats with posterior VTA placements self-infused 300 mg% and 400 mg% EtOH, and demonstrated lever discrimination only during the initial acquisition sessions. In contrast, rats with anterior VTA placements did not self-administer EtOH. Conclusions: The findings suggest that EtOH is reinforcing within the posterior VTA of Wistar rats, and the VTA is a functionally heterogeneous structure with regard to EtOH reinforcement. Received: 22 March 1999 / Final version: 18 November 1999     

Buprenorphine alters ethanol self-administration in rats: dose-response and time-dependent effects

 Buprenorphine is a partial opioid agonist derived from thebaine and has high affinity for μ and κ opioid receptors. The present study investigated dose-response (0.03, 0.15, 0.3, 3 mg/kg) and time-dependent effects of buprenorphine (1.5 or 4 h post-treatment) on EtOH self-administration in outbred Sprague-Dawley rats. Freely feeding and drinking rats were trained to initiate EtOH self-administration for 1 h daily using the ascending concentration procedure, wherein they were provided with increasing concentrations of EtOH at 2, 5, 7, 9 and 11% (v/v), respectively. Water was concurrently available with each concentration. Animals were maintained on a given concentration of EtOH for 5 days. By day 21, animals began their stabilization on the 11% regimen and remained on this concentration throughout the remainder of the study. EtOH and water consumption were recorded daily at both 10- and 60-min intervals. At 1.5 h post-buprenorphine, all test doses greatly suppressed both EtOH and water intake at the 10-min interval. At the 60-min interval, all but the lowest dose (0.03 mg/kg) significantly suppressed EtOH intake, while only the highest dose (3 mg/kg) suppressed water intake. In contrast to the suppressant profile observed at 1.5 h post-buprenorphine, at 4 h post-buprenorphine the lower doses (0.03 and 0.15 mg/kg) significantly increased EtOH intake while the higher doses (0.3 and 3 mg/kg) continued to suppress intake. None of the doses of buprenorphine altered water intake 4 h post-buprenorphine. The results support previous research demonstrating the utility of low doses of buprenorphine in suppressing behavior rewarded by a non-opioid drug. Received: 11 September 1997 / Final version: 21 February 1998     

Food-deprivation increases cocaine-induced conditioned place preference and locomotor activity in rats

 Food-deprivation increases the reinforcing efficacy of cocaine and other drugs within self-administration experiments. In this study, the effects of food-deprivation on cocaine-induced conditioned place preference were investigated. Male Sprague-Dawley rats were assigned to one of two feeding conditions: satiated (with ad libitum food) or deprived (maintained at 80% of free-feeding body weights). During conditioning trials, on alternate days, rats received IP injections of cocaine (0.0, 2.5, 5.0, or 10.0 mg/kg; n=12 per dose group) and were confined for 30 min in one of two distinct environments. On intervening days, the same rats were injected with saline and confined for 30 min in the opposite environment. After four cocaine and four saline trials, a 15-min choice test (with no injections) was given. During this time, the rats were able to move freely through a passageway between both environments. Relative to the food-satiated rats, the food-deprived rats showed a greater conditioned preference for the cocaine-paired environment during the choice test, greater cocaine-induced locomotor activity during conditioning trials, and a greater degree of sensitization to the activating effects of cocaine across conditioning trials. This study extends the general findings of food deprivation-induced increases in the reinforcing efficacy of cocaine to include the conditioned place preference paradigm. Received: 23 January 1996 / Final version: 4 December 1996     

Naloxone blockade of amphetamine place preference conditioning

Amphetamine and naloxone were examined in place conditioning, in order to study possible interactions between endogenous opioids and catecholamines in reinforcement. After initial preferences were determined, animals were conditioned with amphetamine alone (1.0 mg/kg SC), naloxone alone (0.02, 0.2 or 2.0 mg/kg SC) or combinations of amphetamine plus naloxone. A reliable, long-lasting preference for the compartment associated with amphetamine was observed, reflecting the reinforcing properties of this drug. No preference or aversion was observed in animals that received saline in both compartments. Naloxone (0.02, 0.2 and 2.0 mg/kg) produced a dose-dependent place aversion; while the lowest dose had effects similar to saline, the higher doses produced significant place aversions. Naloxone, at all three doses examined, prevented the ability of amphetamine to produce a place preference. Thus, the lowest dose of naloxone, having no effects alone in place conditioning was still able to block the reinforcing effects of amphetamine. These results suggest that the reinforcing effects of amphetamine are dependent on activation of opiate receptors, and provide further evidence that interactions between endogenous opioids and catecholamines may be important in reinforcement.A preliminary report of this research was presented at the 11th Annual Society for Neuroscience Meeting in Dallas, Texas (Trujillo et al. 1985)     

Oral drug self-administration in the home cage of mice: alcohol-heightened aggression and inhibition by the 5-HT1B agonist anpirtoline

RATIONALE: In order to model heightened aggression after alcohol consumption and to study the inhibitory influence of 5-HT1B receptors on drinking and fighting, an experimental procedure should enable self-administration of precise amounts of alcohol in a limited period of time before an aggressive confrontation. OBJECTIVES: To design a new device that can reinforce operant responding by the delivery of sweet alcohol in the resident mouse home cage, where aggressive behavior toward an intruder can subsequently be examined, and to demonstrate inhibition of alcohol-heightened aggression by 5-HT1B receptor agonist treatment. METHODS: Within one experimental session, all singly housed CFW male mice (n=26) performed a nose-poke response that was reinforced by 0.05 ml sucrose. Using the sucrose fading technique, eventually the mice consumed a 6% ethanol/4% sucrose solution after each fifth nose poke during daily 15-min experimental sessions. The number of ethanol reinforcements was adjusted so that 0.6, 1.0, 1.7, and 3.0-g/kg doses were consumed in 15 min or less. Assays confirmed blood alcohol levels at 68.1 mg/dl for intake of 1.0 g/kg. After consuming a specific dose of ethanol in the form of a fixed number of response-dependent deliveries, the response panel was removed from the home cage and, 15 min later, the resident confronted a male intruder. Anpirtoline was administered either before alcohol self-administration or before the aggressive confrontation. RESULTS: After being reinforced with 1.0 g/kg or 1.7 g/kg sweet ethanol, the mice significantly increased attack and threat behavior relative to their aggressive behavior following sucrose or water consumption only. Treatment with the 5-HT1B receptor agonist anpirtoline (0.125, 0.25, 0.5 mg/kg, i.p.) before the confrontation decreased alcohol-heightened aggression and species-typical aggression in the absence of changes in other elements of the behavioral repertoire. Anpirtoline affected ethanol-reinforced behavior only at doses that were 5-10 times higher than those producing anti-aggressive effects. CONCLUSIONS: Self-administration of alcohol in the home cage of mice is readily accomplished with the aid of a simple, removable panel. The effective inhibition of high levels of aggressive behavior due to alcohol consumption after anpirtoline treatment confirm the 5-HT1B receptor as a critical site in the termination of aggression.     

Nicotine self-administration in animals and humans: similarities and differences

 Studies of nicotine self-administration in animal and human subjects are discussed with respect to the behavioral paradigms employed, the effects of nicotine dose manipulations and nicotinic agonist/antagonist pre-treatment, and the role of neurochemical processes mediating reinforcement. Animal models have focused on intravenous nicotine self-administration, while most studies in human subjects have studied cigarette smoking behavior. Despite procedural differences, data from both animal and human studies show an inverted-U function relating nicotine dose to self-administration behavior, with maximal rates of responding occurring at intermediate doses of nicotine. Moreover, nicotine supplementation via non-contingent nicotine administration suppresses nicotine self-administration behavior in both animal models and human cigarette smokers. Nicotine antagonist treatment also reduces responding, although human studies usually find a transient increase in smoking, which is interpreted as an attempt to compensate for nicotinic receptor blockade. Amongst the neurochemical systems which have been examined, most emphasis has been given to dopamine. The mesolimbic dopamine pathway has been implicated in nicotine reward based on animal studies, and research with humans suggests a role for dopaminergic processes as well. However, dopaminergic blockade appears to increase cigarette smoking behavior in humans, while in animals nicotine self-administration is attenuated. Future research should exploit the complementary aspects of animal models and human paradigms to provide a coherent understanding of nicotine reinforcement. Animal models allow for analysis of anatomical and physiological mechanisms underlying nicotine self-administration; human studies validate the relevance to tobacco dependence and smoking cessation treatment. Received: 29 February 1996 / Final version: 23 September 1996     

Attenuation by haloperidol of place preference conditioning using food reinforcement

The place preference conditioning paradigm was used to examine the reinforcing properties of food in hungry rats. Availability of food in one of two distinctive environments increased the amount of time they spent in the environment associated with food in a test when the animals were no longer food deprived and neither environment contained food. Pretreatment with haloperidol (0.1 or 0.2 mg/kg) during the conditioning phase blocked the establishment of place preference even though the animals consumed the food in the drugged state. The results are interpreted as demonstrating a role for dopamine-containing neurons in mediating the reinforcing properties of food.     

Systemic pretreatment with MK-801 (dizocilpine) increases breaking points for self-administration of cocaine on a progressive-ratio schedule in rats

 The effects of the noncompetitive N-methyl-d-aspartate (NMDA) receptor antagonist, MK-801, on cocaine self-administration were investigated. Forty-six male Wistar rats were trained to intravenously self-administer four unit doses of cocaine (0.19, 0.38, 0.75 and 1.5 mg/kg per injection) on a progressive-ratio schedule of reinforcement. The effects of increasing doses of MK-801 (0.05, 0.1, 0.15 and 0.2 mg/kg, IP, 30 min before test sessions) on breaking point (BP) for cocaine self-administration were investigated. The results showed that pretreatment with MK-801 produced effects on cocaine BPs that fit on an inverted-U function. That is, the 0.05 and 0.1 mg/kg doses of MK-801 produced no effect or a small enhancement of BPs across all doses of cocaine, respectively. The 0.15 mg/kg dose of MK-801 produced a significant treatment effect characterized by increased BPs, relative to baseline BPs, across all doses of cocaine. The 0.2 mg/kg dose of MK-801 produced a nonsignificant decrease in BPs across most doses of cocaine. The dose-dependent effects on cocaine BPs after pretreatment with MK-801 suggest that MK-801 can potentiate, and at higher doses attenuate, the rewarding effects of self-administered cocaine. Received: 3 January 1996 / Final version: 12 June 1996     

Extinction of ethanol-induced conditioned place preference and conditioned place aversion: effects of naloxone

 Four experiments examined the effect of naloxone pretreatment on the expression and extinction of ethanol-induced conditioned place preference (experiments 1, 2, 4) or conditioned place aversion (experiments 1, 3). DBA/2 J mice received four pairings of a distinctive tactile (floor) stimulus (CS) with injection of ethanol (2 g/kg) given either immediately before or after 5-min exposure to the CS. A different stimulus was paired with injection of saline. Pre-CS injection of ethanol produced conditioned place preference, whereas post-CS injection of ethanol produced conditioned place aversion. Both behaviors extinguished partially during repeated choice testing after vehicle injection. Naloxone (10 mg/kg) had little effect on the initial expression of conditioned place preference, but facilitated its extinction. Moreover, repeated naloxone testing resulted in the expression of a weak conditioned place aversion to the CS that initially elicited a place preference. In contrast, naloxone (1.5 or 10 mg/kg) enhanced expression of conditioned place aversion, thereby increasing its resistance to extinction. A control experiment (experiment 4) indicated that repeated testing with a different aversive drug, lithium chloride, did not affect rate of extinction or produce an aversion to the CS previously paired with ethanol. These findings do not support the suggestion that naloxone facilitates the general processes that underlie extinction of associative learning. Also, these data are not readily explained by the conditioning of place aversion at the time of testing. Rather, naloxone’s effects appear to reflect a selective influence on maintenance of ethanol’s conditioned rewarding effect, an effect that may be mediated by release of endogenous opioids. Overall, these findings encourage further consideration of the use of opiate antagonists in the treatment of alcoholism. Received: 4 December 1997 / Final version: 16 February 1998     

Oral ethanol self-administration in the rat: effect of naloxone

Rats responding on a two lever concurrent for ethanol and water, were injected with 5, 10, or 20 mg/kg naloxone hydrochloride 30 min prior to a 30 min session. Only the 20 mg/kg dose had any effect, a decrease in responding for ethanol of up to 50% compared to saline control injection sessions. There were no systematic effects upon water responding. An additional study using sucrose and water as the fluid concurrently available failed to find any effects of naloxone on sucrose responding at the same doses. The effect upon ethanol responding was found not to resemble a pattern of extinction, but rather was best described as a general overall reduction in responding. The relation of these findings to the direct involvement of the endogenous opiate system in ethanol reinforcement is discussed.     

Effects of corticosterone on place conditioning to ethanol

Rationale and objective Effects of corticosterone on place conditioning to ethanol were investigated in mice using two conditioning schedules; the conventional method and a rapid conditioning schedule in which exposure to the CS+ followed immediately on exposure to the CS–.Methods Effects of administration of corticosterone, 10 mg/kg, on the acquisition of place conditioning produced by ethanol, 1–2.5 g/kg, were investigated using the conventional method of conditioning, with exposure to the CS+ and the CS– on alternate days, and also using the rapid conditioning method. Total and free blood corticosterone concentrations were measured after administration of ethanol and corticosterone.Results In the conventional, alternate day, conditioning schedule, ethanol produced significant place preference at 2 and at 2.5 g/kg, but when these alcohol doses were given with corticosterone 10 mg/kg, significant place conditioning was not seen. In contrast, in the rapid, same day, conditioning schedule corticosterone significantly decreased the dose at which ethanol produced an apparent place preference, with significant place conditioning being seen with ethanol at 1 and 1.5 g/kg in combination with corticosterone, 10 mg/kg. Total and free corticosterone concentrations were increased after ethanol, 1.5 g/kg, compared with controls, and administration of corticosterone, 10 mg/kg, caused a significantly greater increase. There were no significant differences in spontaneous locomotor activity or brain alcohol concentrations between any of the treatment groups.Conclusions The effects of corticosterone on ethanol-induced place conditioning are substantially affected by the conditioning schedule used.     

The NMDA receptor antagonist dizocilpine (MK-801) stereoselectively inhibits morphine-induced place preference conditioning in mice

The effect of the non-competitive NMDA receptor antagonist dizocilpine (MK-801) on conditioned place preference induced by morphine was studied in mice. As expected, morphine (1–8 mg/kg, IP) elicited a significant preference for the drug-paired compartment. Pretreatment of mice with (+)-dizocilpine (0.1 and 0.2 mg/kg, IP), the more active dizocilpine enantiomer, dose-dependently reversed the conditioned place preference produced by morphine (4 mg/kg, IP), whereas (–)-dizocilpine (0.2 mg/kg, IP) did not modify morphine-induced effects. In contrast, both enantiomers of dizocilpine (at a dose of 0.2 mg/kg, IP) elicited a conditioned place preference. These data suggest that (1) NMDA receptors play a role in morphine-induced place preference, and (2) dizocilpine-reinforcing properties in the place preference paradigm do not seem to be dependent on NMDA receptor blockade.     

Induction of high voluntary ethanol intake in dependent rats

The experimental conditions under which oral high intake may be induced in previously intoxicated rats have been investigated. Seventeen rats were administered intragastrically with 10 g/kg/day of ethanol for 15 days. At cessation of treatment, they were presented a single bottle of alcoholic solution (10% v/v) during 24 hr. For the following 6 days, they received either an ethyl alcohol solution or water in alternation for 8 hours each. Ethanol treated rats exhibited a high oral intake of ethanol equivalent to the previously injected doses. Controls displayed a significantly lower intake of ethanol. It is concluded that the suppression of the withdrawal state by an initial priming oral intake of ethanol in physically dependent rats is a condition for the development of a conditioned taste preference for ethanol as a basis for the behavioral dependence.     

Enhancement of pavlovian conditioned suppression by mild ethanol intoxication

Rats were trained to bar-press for food and then received aversive Pavlovian conditioning following low doses of ethanol (0–1600 mg/kg in different groups). They were tested for Pavlovian conditioned suppression of barpressing 48 h, 7 days, and 14 days later following no additional differential treatments. The results showed that very low doses of ethanol (approximately 200 mg/kg) during training enhanced later conditioned suppression, whereas more moderate doses (800–1600 mg/kg) disrupted Pavlovian conditioning. These results parallel earlier observations that very low ethanol doses enhance Pavlovian conditioned eyeblink and heart rate responses in rabbits, and suggest that facilitation of Pavlovian conditioning may be a general effect of mild ethanol intoxication.     

Effect of baclofen on cocaine self-administration in rats reinforced under fixed-ratio 1 and progressive-ratio schedules

Rationale: Recent reports have indicated that the γ-aminobutyric acid (GABA)_B agonist baclofen attenuates the reinforcing effects of cocaine. Objectives: To further evaluate the effect of baclofen on cocaine self-administration under a fixed ratio (FR) and progressive ratio (PR) schedule of reinforcement. Methods: In the first series of experiments, three dose–response curves were generated that examined the effect of three doses of baclofen (1.8, 3.2, or 5.6 mg/kg, i.p.) against four unit-injection doses of cocaine (0.19, 0.38, 0.75, and 1.5 mg/kg per injection) reinforced under a FR1 schedule. For comparison, an additional group of rats was pretreated with haloperidol (32, 56, or 100 μg/kg, i.p.). A separate experiment examined the effect of baclofen (1.8, 3.2, or 5.6 mg/kg, i.p.) on responding for concurrently available cocaine or food reinforcement. Results: Under the FR1 schedule, baclofen suppressed intake of low but not high unit injection doses of cocaine. In contrast to haloperidol, baclofen had no effect on the distribution of inter-injection intervals and, instead, produced long pauses in cocaine self-administration. Baclofen dose dependently reduced cocaine- reinforced responding on a PR schedule; concurrent access to a food-reinforced lever demonstrated that the animals retained the capacity to respond at high rates. Conclusion: The effect of baclofen pretreatment on cocaine self-administration is dependent on the unit injection dose of cocaine and on the response requirements of the schedule. Received: 22 July 1999 / Final version: 23 September 1999     

Oral self-administration of ethanol, phencyclidine, methadone, pentobarbital and quinine in rhesus monkeys

Rationale: Simultaneous and sequential drug use among clinical populations is the norm, whereas the pattern of self-administration of multiple drugs among non-human primate populations has not been thoroughly explored. Objectives: To determine the relationship between the preferences and intakes of a large group of rhesus monkeys exposed to various orally available solutions. Methods: Thirteen male and eleven female young adult rhesus monkeys (Macaca mulatta) were exposed to orally available drug solutions using a concurrent choice (drug and water) procedure, where fluid delivery was made contingent upon single spout contacts (fixed ratio one). Results: Ethanol (0.25–16% w:v) produced biphasic effects on the number of fluid deliveries obtained, with peak ethanol preferences over water demonstrated at the 1–2% w:v concentrations. No preferences for the N-methyl-d-aspartate receptor antagonist phencyclidine or water were demonstrated at lower concentrations (0.0078125–0.125 mg/ml) and, at higher concentrations (0.25, 0.5 mg/ml), a preference for water was demonstrated. The μ opioid receptor agonist methadone (0.001–0.3 mg/ml) and the prototypic bitter substance quinine (0.001–0.3 mg/ml) failed to produce preferences for drug or water. A large preference for water over the barbiturate pentobarbital (0.01–3 mg/ml) was also demonstrated. After rank-ordering the subjects based on their drug preferences or intakes, modest to no correlations across drugs were demonstrated. Conclusions: These results reveal that a robust ethanol preference is not predictive of a preference for drugs of abuse from other classes and suggests that fluid intakes were correlated, irrespective of the presence or absence of drug in the solution. Received: 6 October 1998 / Final version: 27 May 1999