Intracerebroventricular naltrexone treatment attenuates acquisition of intravenous cocaine self-administration in rats

The influence of centrally administered naltrexone, an opiate antagonist, on acquisition of intravenous cocaine self-administration behaviour in rats was examined. On five consecutive days, three hours per day, they could self-administer a cocaine solution (30 μg per infusion) through an indwelling cannula. Treatment consisted of daily injections of naltrexone (2 or 5 μg) or placebo into the lateral ventricle 30 minutes before testing. Naltrexone treatment dose dependently attenuated the rate of cocaine self-infusion. Both self-infusion rate and rate of responding on the reinforcement lever in the group treated with 5 μg naltrexone differed from placebo, whereas rate of responding on a dummy lever did not. These findings a) support the notion that opioid systems play a role in cocaine reinforcement, and b) suggest that naltrexone exerts its effect on cocaine reinforcement through action in the central nervous system.     

Effects of intracerebroventricular administration of methyl naloxonium chloride on heroin self-administration in the rat

A quaternary derivative of naloxone, methyl naloxonium chloride (MN), was administered intracerebroventricularly (ICV) to rats trained to self-administer heroin intravenously. MN produced a dose-dependent (0.5-4.0 micrograms) increase in responding for heroin. Since MN is unlikely to reach the peripheral circulation in these doses, these results were viewed as strongly supporting the hypothesis that central opiate receptors are solely responsible for mediating the reinforcing properties of heroin during self-administration. In addition, the present study suggests that intracerebral MN injections may prove to be a useful technique in the search for central substrates of heroin reward.     

Testosterone affects food intake and body weight of weanling male rats

The effects of testosterone propionate (TP) on food intake and body weight were investigated using castrated prepubertal male rats. Regardless of dose (1 mg, 0.2 mg or 0.1 mg), daily injections of TP increased body weight gain and food intake during the prepubertal period (from 22 to 40 days to age). Considering previous results, the present observations suggest that in the male rat sensitivity to the effects of gonadal hormones on feeding develops earlier than in females.     

Environmental enrichment decreases intravenous self-administration of amphetamine in female and male rats

RATIONALE: Previous work has shown that environmental enrichment alters amphetamine-induced locomotor activity and conditioned place preference. OBJECTIVE: The present study examined the effect of environmental enrichment on amphetamine self-administration. METHODS: Female and male rats were raised from 21 days of age in one of three different conditions: an enriched condition (EC) containing novel objects and social partners, a social condition (SC) containing social partners only, or an isolated conditioned (IC) without objects or social partners. Beginning at 51 days of age, rats were then tested for operant responding for a sucrose reinforcer using an incremental fixed ratio (FR) requirement across four sessions. Rats were then implanted with a chronic indwelling intravenous catheter and were allowed to self-administer amphetamine (0.03 or 0.1 mg/kg per infusion) for five FR1 sessions, followed by a progressive ratio (PR) session. RESULTS: EC rats initially showed an increase in sucrose-reinforced responding relative to IC rats and this environment-induced difference was greater in females than in males. However, in both sexes, the environment-induced difference in sucrose-reinforced responding dissipated completely across repeated sessions. With amphetamine self-administration, both EC and SC rats earned fewer infusions than IC rats across repeated FRI sessions using the low dose of amphetamine (0.03 mg/kg per infusion), but not using the higher dose of amphetamine (0.1 mg/kg per infusion). EC rats also earned fewer self-infusions of the low amphetamine dose on the PR session relative to IC rats. The effects of environmental enrichment on amphetamine self-administration were similar in both females and males. CONCLUSION: These results suggest that environmental enrichment may serve as a protective factor for reducing amphetamine self-administration.     

Binge cocaine self-administration in humans: intravenous cocaine

Cocaine is frequently used in intermittent cycles of repeated dosing, or “binges.” This pattern of cocaine use has been difficult to study in humans because currently available laboratory models use only one daily session during which a single dose or multiple doses are administered. In the present study, seven adult male IV cocaine users completed a protocol investigating changes in cardiovascular and subjective responses during the repeated self-administration of cocaine. Volunteers participated in a 2-day and a 3-day access condition. On each day of access, they participated in two 2.5-h sessions, one at 1200 and another at 1600 hours. In the 2- and 3-day conditions, participants had access to cocaine on 2 or 3 consecutive days, respectively. During sessions, participants could self-administer up to six doses of IV cocaine (32 mg/70 kg) every 14 min. Participants chose not to self-administer cocaine on only 10% of the 420 trials. Acute tolerance developed to the cardiovascular and several subjective effects of cocaine. Heart rate was the only measure that tended to decrease across days of repeated cocaine self-administration. Ratings of “I want cocaine” decreased at the end of the last self-administration session during both 2- and 3-day conditions. There was no difference between the 2- and 3-day conditions for any measure. The laboratory model of “binge” cocaine use established in this study can be used to describe changes in cardiovascular and subjective effects of cocaine within and between bouts of repeated cocaine use. Received: 14 November 1996/Final version: 8 March 1997     

Effects of ketoconazole on the acquisition of intravenous cocaine self-administration under different feeding conditions in rats

RATIONALE: Ketoconazole, an inhibitor of corticosterone synthesis, has been reported to decrease the self-administration of low doses of cocaine and prevent stress-induced reinstatement of cocaine-reinforced behavior in rats. OBJECTIVES: The effects of ketoconazole were extended to the acquisition of i.v. cocaine self-administration during food restriction, a form of stress. Food restriction accelerates the acquisition of cocaine self-administration, and the purpose of this experiment was to determine whether ketoconazole would block the food-restriction effect. As control conditions, the effects of ketoconazole on the acquisition of cocaine self-administration in food-satiated rats and acquisition of food-reinforced responding were also evaluated. METHODS: Six groups of rats (groups 1-6) were trained to self-administer i.v. cocaine (0.2 mg/kg; groups 1-4) or food pellets (45 mg; groups 5 and 6) under a fixed-ratio 1 (FR 1) schedule. Food availability was restricted to 20 g per day in groups 1, 2, 5, and 6, while groups 3 and 4 were fed ad libitum. Daily sessions included a 6-h autoshaping component followed by a 6-h self-administration component. During autoshaping, 10 infusions or food pellets were delivered each h under a random interval 15-s schedule after extension and retraction of a lever. During self-administration, the lever remained extended and infusions or food pellets were available under an FR 1 schedule. The criterion for acquisition was a 5-day period during which a mean of 100 cocaine infusions or 150 food pellets was obtained during the self-administration component. Rats were given 30 days to reach this criterion. They were pretreated with ketoconazole (25 mg/kg, i.p.; groups 1, 3, and 5) or vehicle (i.p.; groups 2, 4, and 6) 30 min prior to the autoshaping and self-administration components. RESULTS: Pretreatment with ketoconazole decreased both the rate of acquisition of cocaine self-administration and the percentage of rats meeting the acquisition criterion but only under food-restricted conditions. Ketoconazole had no effect on the acquisition of food-reinforced responding. CONCLUSIONS: These results extended previous findings of the suppressant effects of ketoconazole on cocaine-reinforced responding in rats to the acquisition of cocaine self-administration using food restriction as a stressor.     

Sex differences in the acquisition of IV methamphetamine self-administration and subsequent maintenance under a progressive ratio schedule in rats

Rationale Previous work indicates that female rats initiate cocaine use sooner than male rats and reach significantly higher break points (BPs) for a single injection of cocaine under a progressive ratio (PR) schedule compared to male rats.Objectives The present study extends previous work examining sex differences to the acquisition of methamphetamine (METH) (0.02 mg/kg) and maintenance of METH-maintained responding under a PR schedule.Methods An automated priming procedure that has previously been shown to be sensitive to sex differences was used for the acquisition of drug self-administration. A PR schedule that has been shown to be sensitive in detecting sex differences in maintenance levels of cocaine-reinforced responding was used for the maintenance phase of the experiment.Results A greater percentage of female rats met the acquisition criterion for METH (0.02 mg/kg) self-administration compared to male rats (55.6% versus 11.1%, respectively), and they did so at a significantly faster rate. Under stable fixed-ratio 1 (FR1) conditions (after acquisition and 5 days before the PR schedule) female rats responded for significantly more METH (0.02 mg/kg) infusions compared to males. Dose-response curves obtained under the PR schedule during maintenance indicated that female rats self-administered significantly more METH infusions compared to male rats.Conclusions These data suggest that female rats are more vulnerable to the acquisition of METH self-administration, and they are more motivated to self-administer METH compared to male rats under a PR schedule during the maintenance phase.     

Evaluation of a suspension system for intravenous self-administration studies of water-insoluble compounds in the rhesus monkey

A suspension system for water-insoluble drugs was evaluated using the mouse tail-flick test for analgesia and schedule-controlled responding in rhesus monkeys. One group of monkeys was trained to respond for food reinforcement under a chain fixed-interval 9 min fixed-ratio 10 schedule of reinforcement (chain FIFR). Another group of monkeys was trained to respond for intravenous cocaine injections (100 μg/kg/inj) under an FR-10 schedule. Water-insoluble compounds were suspended in emulphor:ethanol:saline. The bioavailability of these drug suspensions was demonstrated to be equivalent to water-soluble compounds by comparing the activity of the water-soluble and water-insoluble salts of (+)-propoxyphene in the mouse tail-flick test. The behavioral effects of these drug suspension were also determined in the group of monkeys which was trained to respond for food under the chain FI-FR schedule. Dose-related decreases in responding were produced by (+)-propoxyphene HCl (water-soluble), (+)-propyxyphene napsylate (water-insoluble), and a cannabinoid, (±)-9-nor-9β-OH-hexahydrocannabinol (β-HHC) (water insoluble). Doses of (+)-propoxyphene HCl (in saline) and (+)-propoxyphene napsylate (in the emulphor suspension system) were equi-effective in disrupting food-reinforced responding. In addition, these two salts of propoxyphene were equi-effective as reinforcers of self-administration behavior in rhesus monkeys. β-HHC was more potent than (+)-propoxyphene in producing decreases in food-reinforced responding but failed to maintain self-administration behavior in the monkey.     

Anti -addiction effects of agmatine against heroin self-administration in rats

Rationale： Drug abuse is serious and costly health problems. Present understanding that drug addiction is a chronic brain disease paves the way for pharmacotherapy. Unfortunately, few medications have proven effective for the treatment of addiction and dependence. Searching novel strategies of pharmacotherapy against drug addiction are challenging. Agmatine （ decarboxylated L - arginine）, an endogenous imidazoline receptor ligand, with multiple pharmacological profiles including its NMDA antagonistic properties, attracts the attention for its potential therapeutic efficacy for drug addiction.     

The mGluR5 antagonist MPEP decreased nicotine self-administration in rats and mice

Rationale. Nicotine increases glutamate release in the ventral tegmental area and the nucleus accumbens, and thus enhances dopamine neurotransmission in the mesolimbic system that has been implicated in mediating the rewarding effects of drugs. Metabotropic glutamate receptors 5 (mGluR5) are found in the nucleus accumbens and may play a role in modulating the post-synaptic response to both glutamate and dopamine. Objectives. The present study investigated the effects of the mGluR5 antagonist 2-methyl-6-(phenylethynyl)-pyridine (MPEP) on intravenous nicotine self-administration in Wistar rats and DBA/2J mice. Methods. Rats were allowed to self-administer nicotine (0.01, 0.03 mg/kg per infusion) or respond for food on one of two fixed-ratio 5 schedules of reinforcement. Drug-naive mice were acutely exposed, in pairs, to nicotine (0, 0.016, 0.048, 0.16, 0.48 μg per infusion) self-administration under a fixed ratio 1 schedule of reinforcement, with one subject controlling the delivery of nicotine to both subjects in each pair. Results. MPEP (1–9 mg/kg) dose-dependently reduced nicotine self-administration with no effect on food-maintained responding in the rats. Self-administration of nicotine was obtained only at the 0.048 μg per infusion dose by the mice, and administration of MPEP (5–20 mg/kg) decreased nicotine self-administration response rates in the mice. Conclusions. These results indicate that blockade of mGluR5 decreased nicotine self-administration in both rats and mice, and are consistent with findings showing a role of mGluR5 in cocaine self-administration. It is postulated that mGluR5 plays an essential role in mediating the reinforcing effects of nicotine, possibly but not exclusively, via modulation of mesolimbic dopaminergic neurotransmission. Electronic Publication     

Nicotine reinforcement in rats with histories of cocaine self-administration

Few reports have described conditions under which nicotine self-administration occurs in rats. In this study, rats which initially lever pressed for cocaine infusion (0.05 mg/kg) during 1 h experimental sessions continued to obtain similar infusion numbers when nicotine (0.03 mg/kg) was available. When saline was substituted for nicotine, infusions decreased from 11.8±4.5/h to 5.4±1.1/h but returned to pre-saline levels when it was reintroduced (12.0±5.5/h). These results indicate that nicotine can serve as a positive reinforcer for rats under the historical and schedule conditions described.     

Magnesium-maintained self-administration responding in cocaine-trained rats

Magnesium chloride (MgCl₂) produces behavioral effects similar to those of psychomotor stimulants in a variety of behavioral situations. Because MgCl₂ appears to have stimulant properties, the ability of MgCl₂ to maintain responding in a rat self-administration paradigm was examined in seven experiments under different access and schedule conditions in cocaine-trained rats. These varied from the availability of MgCl₂ for a single day's test session subsequent to 1 h availability of cocaine, to the availability of MgCl₂ for 10 or 20 days after cocaine availability was totally discontinued. Fixed ratio 1, fixed ratio 5, and progressive ratio 1, 2 and 3 schedules of drug delivery were used. The results demonstrate that MgCl₂ may substitute for self-administered cocaine because it maintained responding; it did so dose dependently to maintain a constant level of MgCl₂ intake; and it did so over a 10-day period of time both with and without access to cocaine on test days. Responding maintained by MgCl₂ when cocaine was no longer available was similar under fixed ratio 1 and 5 schedule conditions. The progressive ratio breakpoints for MgCl₂ were significantly higher than those for saline, but significantly lower than those for cocaine. These data indicate that MgCl₂ has some reinforcing efficacy in cocaine-trained rats, particularly under fixed ratio 1 and 5 schedules, but has a low abuse potential compared to cocaine.     

Heroin self-administration: I. Incubation of goal-directed behavior in rats

This study used heroin self-administration to investigate incubation of goal-directed heroin-seeking behavior following abstinence. Male Sprague-Dawley rats self-administered heroin on a fixed ratio 10 (FR10) schedule of reinforcement with licking of an empty spout serving as the operant behavior during 14 daily 3 h sessions. After this acquisition period, all rats received a 90 min extinction session following either 1 day or 14 days of home cage abstinence. When the extinction session occurred after only 1 day of home cage abstinence, rats with a history of heroin self-administration divided their responses equally between the previously "active" and "inactive" spouts. However, when the extinction session occurred following 14 days of home cage abstinence, the rats exhibited marked goal-directed heroin-seeking behavior by licking more on the previously "active" than "inactive" spout. These findings demonstrate that heroin-seeking behavior incubates over time, resulting in goal-directed heroin-seeking behavior in rats following 14 days but not 1 day of abstinence. Moreover, this facilitatory effect occurred in response to a different training schedule, lower total drug intake, and shorter periods of daily access than previously reported with heroin.     

Reinstatement of cocaine self-administration in rats: sex differences

Rationale: Results obtained with both humans and animals suggest that rates of relapse, or levels of reinstatement responding, may differ between males and females. However, the results obtained with humans are equivocal, and few studies have compared male and female animals on reinstatement responding. Objectives: The present experiment was designed to compare male (n=8) and female (n=8) rats on reinstatement of extinguished cocaine-reinforced responding. Methods: Reinstatement of responding was examined using a priming model in which lever pressing for cocaine (0.2 mg/kg) was extinguished by replacing cocaine infusions (2 h) with saline infusions (5 h). After responding extinguished during hour 3, reinstatement of responding was tested by administering one of several priming injections of cocaine (0.32, 1.0 and 3.2 mg/kg) or an equal volume of saline. Results: Although males and females did not differ in the number of saline infusions self-administered after either saline or 0.32 mg/kg cocaine-priming injections, female rats self-administered significantly more saline infusions than males after 1.0 mg/kg and 3.2 mg/kg cocaine-priming injections. Additionally, the effects of 0.32 mg/kg cocaine-priming injections were significantly different from those of saline-priming injections for female, but not male, rats. There was no significant difference between males and females in total cocaine self-administered during hours 1 and 2. Conclusions: These findings indicate that female rats are more sensitive than males during the reinstatement phaseof drug abuse. Received: 14 June 1999 / Final version: 13 August 1999     

Heroin self-administration in rats under a progressive ratio schedule of reinforcement

Heroin self-administration behavior under a progressive ratio (PR) schedule of reinforcement was evaluated in rats. The schedule was designed to restrict drug intake, minimize opiate dependency, and quantify the number of responses emitted (final response ratio) in order to receive a limited number of heroin infusions. Final ratios were found to be stable and did not increase with chronic (31 days) PR reinforcement. The ability of the PR schedule to detect changes in heroin reinforcement was demonstrated by evaluating the effect of naltrexone pretreatment and unit dose alteration on final ratios. Naltrexone (0.4 mg/kg) reduced final ratios and an inverted U dose-response relationship was established for the unit heroin doses 12.5–100 µg/injection. Maximal final ratios occurred with 50 µg/injection heroin reinforcement. This PR schedule may provide a useful method for evaluating the effects of pharmacological manipulations or lesions on opiate reinforcement.     

Heroin self-administration under a second-order schedule of reinforcement: acquisition and maintenance of heroin-seeking behaviour in rats

RATIONALE: Second-order schedules of heroin self-administration provide a method of measuring heroin-seeking behaviour independently of the effects of the drug on motor behaviour and of investigating the role of heroin-associated stimuli in such heroin-seeking behaviour. OBJECTIVES: These experiments aimed to establish a second-order schedule of heroin self-administration in rats, similar to that already established in this laboratory for cocaine self-administration and to investigate the role of discrete heroin-associated stimuli in the maintenance of heroin-seeking behaviour under a second-order schedule of reinforcement. METHODS: Heroin i.v. self-administration (0.04 mg/infusion) was initially contingent upon a lever press, and each infusion was paired with presentation of a 20-s light-conditioned stimulus (CS). Following acquisition of heroin self-administration, the response requirement was progressively increased so that, ultimately, responding was maintained under a fixed interval (FI) 15 min [fixed ratio (FR)5:S] second-order schedule. The effects of varying the dose of heroin (0.01 mg and 0.08 mg/infusion) and pre-treatment with the mu-opiate receptor antagonist, naloxone, on responding under a FI15(FR5:S) schedule were investigated. In addition, the role of the heroin-associated CS on responding was assessed by measuring the effects of omitting the CS during heroin-seeking behaviour and during extinction of responding, as well as the effect of CS presentation on the reinstatement of heroin-seeking behaviour following extinction. RESULTS: A second-order schedule of heroin self-administration was established. There were no clear effects on heroin-seeking behaviour of increasing or decreasing the dose of heroin. Although no effect of naloxone pre-treatment was seen on heroin-seeking behaviour during the first, drug-free interval of responding, an extinction-like pattern of responding was seen in that interval during subsequent sessions. Omission of the light CS resulted in a reduction in levels of responding for i.v. heroin, indicating its role in maintaining heroin-seeking behaviour. However, under extinction conditions, response-contingent CS presentations did not affect the rate of extinction, nor did non-contingent presentations of the CS following extinction reinstate heroin-seeking behaviour. CONCLUSIONS: These experiments have established a method of measuring heroin-seeking behaviour in rats by adopting a second-order schedule of i.v. heroin self-administration. The results indicate a relatively weak impact of discrete, heroin-associated cues on heroin-seeking behaviour relative to cocaine-seeking behaviour studied under similar conditions.     

Fluctuations in nucleus accumbens dopamine concentration during intravenous cocaine self-administration in rats

Fluctuations in extracellular dopamine and DOPAC levels in nucleus accumbens septi (NAS) were monitored in 1-min microdialysis samples taken from rats engaged in intravenous cocaine self-administration. For four rats the dose per injection was fixed at 2.0 mg/kg; for four others the dose per injection was varied irregularly, from one response to the next, between three levels (0.5, 1.0 and 2.0 mg/kg). Regardless of the dosing regimen, extracellular dopamine levels were tonically elevated by 200–800% within the cocaine self-administration periods, fluctuating phasically within this range between responses. In the fixed dose condition, the phasic increases following each injection (and the phasic decreases preceding them) averaged approximately 50% of the mean tonic elevation. Phasic fluctuations in dopamine levels remained time-locked to lever-presses even when response rate was irregular, because of the variable dose condition. In the variable dose condition greater increases in dopamine and longer inter-response times followed injections of the higher doses; dopamine fluctuations were consistent with the multiple-infusion pharmacokinetics of cocaine. DOPAC levels showed a slow tonic depression during cocaine self-administration, but individual injections were not associated with discernible phasic fluctuations of DOPAC. These data are consistent with the hypothesis that falling dopamine levels trigger successive responses in the intravenous cocaine self-administration paradigm, but inconsistent with the notion that extracellular dopamine levels are depleted at the times within sessions when the animal initiates drug-seeking responses.     

Nicotine self-administration and reinstatement of nicotine-seeking in male and female rats

Background

Tobacco addiction is a relapsing disorder that constitutes a substantial worldwide health problem, with evidence suggesting that nicotine and nicotine-associated stimuli play divergent roles in maintaining smoking behavior in men and women. While animal models of tobacco addiction that utilize nicotine self-administration have become more widely established, systematic examination of the multiple factors that instigate relapse to nicotine-seeking have been limited. Here, we examined nicotine self-administration and subsequent nicotine-seeking in male and female Sprague-Dawley rats using an animal model of self-administration and relapse.

Methods

Rats lever pressed for nicotine (0.03 and 0.05 mg/kg/infusion, IV) during 15 daily 2-h sessions, followed by extinction of lever responding. Once responding was extinguished, we examined the ability of previously nicotine-paired cues (tone + light), the anxiogenic drug yohimbine (2.5 mg/kg, IP), a priming injection of nicotine (0.3 mg/kg, SC), or combinations of drug + cues to reinstate nicotine-seeking.

Results

Both males and females readily acquired nicotine self-administration and displayed comparable levels of responding and intake at both nicotine doses. Following extinction, exposure to the previously nicotine-paired cues or yohimbine, but not the nicotine-prime alone, reinstated nicotine-seeking in males and females. Moreover, when combined with nicotine-paired cues, both yohimbine and nicotine enhanced reinstatement. No significant sex differences or estrous cycle dependent changes were noted across reinstatement tests.

Conclusions

These results demonstrate the ability to reinstate nicotine-seeking with multiple modalities and that exposure to nicotine-associated cues during periods of a stressful state or nicotine can increase nicotine-seeking.     

Plasma nicotine and cotinine levels following intravenous nicotine self-administration in rats

  Rationale: The route of nicotine administration between animal models and humans is very different and further investigation by determining levels of nicotine entering into the circulatory system is warranted. Objective: The present study addresses the validity of the rat self-administration procedure by comparing plasma levels of nicotine in the rat with levels reported in smokers following cigarette consumption. Methods: Plasma levels of nicotine and its metabolite cotinine were measured in 17 rats following intravenous self-administration of a range of nicotine doses (0.015, 0.03 and 0.06 mg/kg per infusion). Results: The two larger unit doses supported reliable self-administration behaviour with no overall difference in the patterns of nicotine intake. However, the total nicotine intake over the 2-h session was related to unit dose and this correlated highly with nicotine and cotinine levels measured in blood collected from the tail vein. On average, cotinine levels (50–200 ng/ml) were approximately 2-fold higher than nicotine levels (40–120 ng/ml) in plasma. Following an extinction test for one session in which saline was substituted for nicotine, no change in behaviour was observed in the two groups, while plasma levels of nicotine and cotinine dropped to nominal levels. Conclusions: The concentrations of nicotine attained following nicotine self-administration appear to be similar to levels reported in smokers after cigarette consumption, providing further validation of this procedure as an animal model of nicotine dependence. Received: 14 November 1998 / Final version: 4 January 1999     

Effects of fixed ratio size and dose on phencyclidine self-administration by rats

Female Sprague-Dawley rats were trained to self-administer phencyclidine (PCP; 0.125, 0.25, or 0.5 mg/kg/injection) on a fixed ratio (FR) schedule of reinforcement under limited access conditions (3 h). Initial training began with cocaine, which was later replaced with ketamine and then one of the three unit doses of PCP. Baseline rates of injection were determined at RF 10. The size of the ratio was then incremented geometrically every fifth daily session. Increasing the ratio resulted in a decrease in the number of injections per session. Furthermore, this decrease was greater for the 0.25 mg/kg dose than for the 0.5 mg/kg unit dose. The self-administration of the 0.125 mg/kg dose was variable and rapidly extinguished upon the increase in fixed ratio. The results indicate that PCP is self-administered by rats under the conditions imposed in this study. Furthermore, the relative reinforcing efficacy of the different unit doses of PCP could be discriminated using this type of response cost procedure.