Behavioral effects of the novel tropane analog, 2β-propanoyl-3β-(4-toluyl)-tropane (PTT)

In vitro studies have demonstrated that a novel tropane analog, PTT, in which both of the esters of cocaine have been removed is 20 times more potent than cocaine and more selective than cocaine in binding to dopamine transporters. The present studies compared the ability of PTT and cocaine to stimulate locomotor activity in rats. The intraperitoneal administration of PTT and cocaine to male Fisher-344 rats produced dose-dependent increases in spontaneous locomotor activity and stereotypic behaviors. PTT was 10–20 times more potent than cocaine in this behavioral assay, closely paralleling its potency relative to cocaine in dopamine transporter binding and uptake assays in vitro. PTT, however, elicited a qualitatively different profile of stereotypic behaviors, and PTT had a longer duration of action than cocaine. These results show how changes in kinetics and selectivity of tropanes can affect stimulant-elicited behaviors.     

High affinity stereospecific binding of [3H] cocaine in striatum and its relationship to the dopamine transporter

A high affinity (KD 35 nM) binding site for [3H]cocaine is detected in rat brain striatum present at 2-3 pmol/mg protein of synaptic membranes. This binding is displaced by cocaine analogues with the same rank order as their inhibition of [3H]dopamine ([3H]DA) uptake into striatal synaptosomes (r = 0.99), paralleling the order of their central stimulant activity. The potent DA uptake inhibitors nomifensine, mazindol, and benztropine are more potent inhibitors of this high affinity [3H]cocaine binding than desipramine and imipramine. Cathinone and amphetamine, which are more potent central stimulants than cocaine, displace the high affinity [3H]cocaine binding stereospecifically, but with lower potency (IC50 approximately equal to 1 microM) than does cocaine. It is suggested that the DA transporter in striatum is the putative "cocaine receptor." Binding of [3H]cocaine, measured in 10 mM Na2HPO4-0.32 M sucrose, pH 7.4 buffer, is inhibited by physiologic concentrations of Na+ and K+ and by biogenic amines. DA and Na+ reduce the affinity of the putative "cocaine receptor" for [3H]cocaine without changing the Bmax, suggesting that inhibition may be competitive. However, TRIS reduces [3H]cocaine binding noncompetitively while Na+ potentiates it in TRIS buffer. Binding of [3H]mazindol is inhibited competitively by cocaine. In phosphate-sucrose buffer, cocaine and mazindol are equally potent in inhibiting [3H]mazindol binding, but in TRIS-NaCl buffer cocaine has 10 times lower potency. It is suggested that the cocaine receptor in the striatum may be an allosteric protein with mazindol and cocaine binding to overlapping sites, while Na+ and DA are allosteric modulators, which stabilize a lower affinity state for cocaine.     

Oral vs parenteral drug effects on schedule-controlled behavior in rhesus monkeys

Intramuscular, intravenous, and subcutaneous injections of heroin, methadone, morphine, LAAM, cocaine, d-amphetamine, and phencyclidine produced about equivalent effects on schedule-controlled responding in rhesus monkeys. By the buccal route, potency was reduced by approximately three-fold except with cocaine and heroin; with cocaine, buccal potency was equivalent to the parenteral routes while with heroin, buccal potency was reduced by about 20-fold. By the oral route (gavage), methadone, morphine, heroin, and phencyclidine were at least 50–100 times less potent than by i.m., i.v., or s.c. routes. Cocaine was about sixteen times less potent orally than parenterally, while LAAM and d-amphetamine were only slightly less potent orally than parenterally. Thus, for certain drugs like methadone and phencyclidine, relative potencies by oral vs. parenteral routes in rhesus monkeys differ greatly from those obtained in humans.     

Cocaine and Cocaethylene: Microdialysis Comparison of Brain Drug Levels and Effects on Dopamine and Serotonin

Abstract: Cocaethylene is a pharmacologically active metabolite resulting from concurrent cocaine and ethanol consumption. The effects of cocaine and cocaethylene on extracellular levels of dopamine in the nucleus accumbens, and serotonin in the striatum were characterized in vivo in the anesthetized rat. Both intravenous (3 μmol/kg) and intraperitoneal (44 μmol/kg) routes of administration were used. In addition to monitoring neurotransmitter levels, microdialysate levels of cocaine and cocaethylene were determined at 4-min intervals after intravenous administration, and at 20-min intervals after intraperitoneal administration. Extracellular levels of dopamine in the nucleus accumbens were increased to ∼400% of preinjection value by both cocaine and cocaethylene when administered intravenously. Cocaine caused a significant increase of striatal serotonin to 200% preinjection value, whereas cocaethylene had no effect. Brain levels of cocaine and cocaethylene after intravenous administration did not differ. After intraperitoneal administration, extracellular levels of dopamine in the nucleus accumbens were increased to 400% of preinjection levels by cocaine, but were only increased to 200% of preinjection levels by cocaethylene, the difference being statistically significant. Serotonin levels were increased to 360% of preinjection levels by cocaine, but only to 175% of preinjection value by cocaethylene. Levels of cocaine attained in brain were significantly higher than those for cocaethylene, suggesting pharmacokinetic differences with the intraperitoneal route. These results confirm in vivo that cocaethylene is more selective in its actions than cocaine with respect to dopamine and serotonin uptake. In addition, route-dependent differences in attainment of brain drug levels have been observed that may impact on interpretations of the relative potency of the reinforcement value of these compounds.     

Behavioral sensitization and tolerance to cocaine and the occupation of dopamine receptors by dopamine

Data from the authors’ laboratory on the neural substrates of Pavlovian conditioning and behavioral sensitization to psychomotor stimulants are reviewed. The findings of a recent experiment on the role of occupation of dopamine receptors by dopamine and its association to behavioral sensitization are reported. Daily intermittent injections of cocaine produced behavioral sensitization to the locomotor response in rats, whereas continuous cocaine infusions produced behavioral tolerance. Behavioral sensitization to cocaine was blocked by coadministration of nimodipine, anL-type calcium channel blocker. The increases in locomotion produced by cocaine was associated with an increase in the occupation of striatal dopamine D₁ and D₂ receptors, measured as the density of receptors protected from denaturation byN-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ). This association was not observed when rats were given a challenge injection of cocaine 10 d after withdrawal from similar treatment regimens. Rats given a cocaine challenge after withdrawal from either intermittent or continuous cocaine treatment regimens exhibited increased occupations of striatal D₁ and D₂ receptors. This increase was similar in magnitude to that observed in rats without a history of cocaine treatments after a challenge injection of cocaine. This suggests tnat the differences in occupancy of striatal dopamine receptors by dopamine observed in the prewithdrawal condition are likely the result of differences in brain levels of cocaine achieved by the two treatment regimens. Occupancy of striatals dopamine D₁ and D₂ receptors does not appear to be related to the development of sensitization to the motor-stimulating effects of cocaine.     

Human liver cocaine esterases: ethanol-mediated formation of ethylcocaine

A new, pharmacologically active metabolite of cocaine, ethylcocaine, has been reported in individuals after concurrent use of cocaine and ethanol. Formation of ethylcocaine may contribute to the common coabuse of these two drugs and the apparent danger of this practice. We have identified a nonspecific carboxyl-esterase that catalyzes the ethyl transesterification of cocaine to ethylcocaine in the presence of ethanol. In the absence of ethanol, this human liver esterase catalyzes the hydrolysis of cocaine to benzoylecgonine, a metabolite that is inactive as a psychomotor stimulant. A second human liver esterase is also described. This enzyme catalyzes hydrolysis of cocaine to ecgonine methyl ester, also inactive as a stimulant. These two liver esterases may play important roles in regulating the metabolic inactivation of cocaine.     

Neuroendocrine responses to cocaine do not exhibit sensitization following repeated cocaine exposure.

Cocaine-induced enhancement of motor activity and extracellular dopamine concentrations exhibits sensitization upon repeated exposure. In this study, the neuroendocrine responses to cocaine were examined following cocaine pretreatment regimens which have been shown to produce behavioral sensitization. Adult male rats were injected with cocaine (15 mg/kg, IP) once daily for 14 days, followed by a dose-response challenge with cocaine (1-15 mg/kg, IP) either 18 hours or 7 days after the final pretreatment injection. Blood was collected 15 minutes following injections for radioimmunoassay of ACTH, corticosterone, prolactin, and renin. Cocaine increased plasma ACTH and corticosterone, while it decreased prolactin and renin concentrations. Pretreatment with cocaine for 2 weeks did not alter any of these endocrine responses after either the 18 hour or 7 day interval between pretreatment and challenge injections. In contrast, sensitization to the locomotor stimulant effects of cocaine was observed on the final day of pretreatment injections, and 7 days later. These data suggest that these endocrine effects of cocaine do not exhibit sensitization following repeated cocaine exposure.     

Ethanol/cocaine interaction: cocaine and cocaethylene plasma concentrations and their relationship to subjective and cardiovascular effects.

To investigate the pharmacologic effects of the interaction between ethanol and cocaine, eleven male, paid volunteers familiar with the use of both ethanol and cocaine were tested in a dose-response, placebo-controlled, single-blind, randomly-assigned, cross-over design. Ethanol (0.85 g/kg) or placebo was administered in divided doses over a thirty minute period. Fifteen minutes after the termination of ethanol ingestion, cocaine HCl (1.25 and 1.9 mg/kg) or placebo (lidocaine and mannitol) was given by nasal insufflation (snorting). Cocaine and cocaethylene plasma concentrations, blood ethanol levels, subjective ratings of drug effects, and cardiovascular parameters were measured. Statistical analysis of the results indicate that: 1) cocaine administration did not alter blood ethanol concentrations nor the ratings of ethanol intoxication; 2) ethanol caused a significant increase in cocaine plasma concentrations, ratings of cocaine "high", and heart rate; 3) acute tolerance to the subjective and heart rate effects of cocaine was observed; 4) when combined with cocaine, ethanol led to the slow formation of cocaethylene in amounts much lower than those of its parent compound; and 5) the appearance of cocaethylene in plasma did not alter cocaine's subjective and cardiovascular effects.     

Caffeine-phenylethylamine combinations mimic the cocaine discriminative cue

Twelve male Sprague-Dawley rats were trained in a two-choice, food reinforced, drug discrimination task utilizing 10 mg/kg cocaine and saline as discriminative stimuli. Subjects were tested for stimulus generalization with a wide range of cocaine doses and several dose combinations of caffeine, ephedrine, and phenylpropanolamine (CEP). Caffeine produced only partial generalization. The triple CEP combinations resulted in complete generalization at high doses. All drugs produced response rate decrements at high doses. These data clearly indicate that certain look-alike stimulant products mimic the cocaine cue. The present data parallel human self-report data regarding the similarity in subjective profiles between illicit cocaine and the legal look-alike stimulants.     

Cocaethylene: a neuropharmacologically active metabolite associated with concurrent cocaine-ethanol ingestion

High concentrations of cocaethylene (EC), the ethyl ester of benzoylecgonine, were measured in the blood of individuals who had concurrently used cocaine and ethanol. Since the powerful reinforcing effects of cocaine appear to be dependent on inhibition of dopamine reuptake in brain, we compared the effects of EC on the dopamine uptake system and its behavioral effects with those of cocaine. EC was equipotent to cocaine with respect to inhibition of binding of [3H]GBR 12935 to the dopamine reuptake complex, inhibition of [3H]dopamine uptake into synaptosomes and in its ability to increase extracellular dopamine concentration in the nucleus accumbens following its systemic administration to rats. Moreover, in rats, EC and cocaine each increased locomotor activity and rearing to the same extent following i.p. administration. In self-administration studies in primates, EC was approximately equipotent to cocaine in maintaining responding. The in vivo formation of this active, transesterified ethyl homolog of cocaine may contribute to the effects and consequences of combined cocaine and ethanol abuse.     

Quantitation of cocaine and cocaethylene in canine serum by high-performance liquid chromatography

A reversed-phase high-performance liquid chromatographic procedure for the determination of cocaine and cocaethylene in canine serum has been developed. The compounds were extracted from 1 ml of alkalinized canine serum with hexane. Chromatographic separation was achieved with a cyanopropyl column (250 × 4.6 mm I.D., 5 μm) using a mobile phase of acetonitrile and phosphate buffer, pH 7.40 (38:62, v/v) flowing at 1 ml/min. Eluate was monitored by a variable-wavelength UV detector set to 230 nm. The extraction procedure yields an average recovery of 99 and 96% for cocaine and cocaethylene, respectively. The between-day coefficients of variation, at 2400 ng/ml, for cocaine and cocaethylene were both 8.6% and the within-day coefficients of variation, at 400 ng/ml, for cocaine and cocaethylene were 7.3 and 8.0%, respectively. A concentration-time profile resulting from administration of 3 mg/kg cocaine and cocaethylene to the dog revealed a similar disposition between cocaine and cocaethylene, with a clearance and volume of distribution at steady-state values of 72.8 and 61.0 ml/min/kg and 2.6 and 2.7 1/kg, respectively.     

Relative potencies of two phenylalkylamines found in the abused plant Catha edulis, khat

Cathinone and d-norpseudoephedrine are closely related phenylalkylamines isolated from $\text{Catha edulis}$ (khat), a plant much abused for its stimulant properties. We have compared the potency of these two compounds on an operant behavioral procedure in rats. Both suppress fixed ratio 20 responding for food in a dose related manner. Cathinone was 7–10 times more potent and had a more rapid onset of action than d-norpseudoephedrine, although the duration of action of cathinone was shorter. The ability of these two compounds to produce amphetamine-like stereotyped movements was in concordance with this same relative potency and difference in duration of action. Comparison of the behavioral effects in rats with the pattern of stimulation reported for khat use by man suggests that cathinone may be the major CNS active component of $\text{Catha edulis}$.     

2,3-Disubstituted quinuclidines as a novel class of dopamine transporter inhibitors

There is considerable interest in developing dopamine transporter (DAT) inhibitors as potential therapies for the treatment of cocaine abuse. We report herein our pharmacophore-based discovery and molecular modeling-assisted rational design of 2,3-disubstituted quinuclidines as potent DAT inhibitors with a novel chemical scaffold. Through 3-D-database pharmacophore searching, compound 12 was identified as a very weak DAT inhibitor with K(i) values of 7.3 and 8.9 microM in [3H]mazindol binding and in inhibition of dopamine reuptake, respectively. Molecular modeling-assisted rational design and chemical modifications led to identification of potent analogues (-)-29 and 34 with K(i) values of 14 and 32 nM for both compounds in binding affinity and inhibition of dopamine reuptake, respectively. Behavioral pharmacological evaluations in rodents showed that 34 has a profile very different from cocaine. While 34 is substantially more potent than cocaine as a DAT inhibitor, it is approximately four times less potent than cocaine in mimicking the discriminative stimulus properties of cocaine in rat. On the other hand, 34 (3-30 mg/kg) lacks either the locomotor stimulant or stereotypic properties of cocaine in mice. Importantly, 34 blocks locomotor stimulant activity induced by 20 mg/kg cocaine in mice, with an estimated ED(50) of 19 mg/kg. Taken together, our data suggest that 34 represents a class of potent DAT inhibitors with a novel chemical scaffold and a behavioral pharmacological profile different from that of cocaine in rodents. Thus, 34 may serve as a novel lead compound in the ultimate development of therapeutic entities for cocaine abuse and/or addiction.     

Sensitivity to psychostimulants in mice bred for high and low stimulation to methamphetamine

Methamphetamine (MA) and cocaine induce behavioral effects primarily through modulation of dopamine neurotransmission. However, the genetic regulation of sensitivity to these two drugs may be similar or disparate. Using selective breeding, lines of mice were produced with extreme sensitivity (high MA activation; HMACT) and insensitivity (low MA activation; LMACT) to the locomotor stimulant effects of acute MA treatment. Studies were performed to determine whether there is pleiotropic genetic influence on sensitivity to the locomotor stimulant effect of MA and to other MA- and cocaine-related behaviors. The HMACT line exhibited more locomotor stimulation in response to several doses of MA and cocaine, compared to the LMACT line. Both lines exhibited locomotor sensitization to 2 mg/kg of MA and 10 mg/kg of cocaine; the magnitude of sensitization was similar in the two lines. However, the lines differed in the magnitude of sensitization to a 1 mg/kg dose of MA, a dose that did not produce a ceiling effect that may confound interpretation of studies using higher doses. The LMACT line consumed more MA and cocaine in a two-bottle choice drinking paradigm; the lines consumed similar amounts of saccharin and quinine, although the HMACT line exhibited slightly elevated preference for a low concentration of saccharin. These results suggest that some genes that influence sensitivity to the acute locomotor stimulant effect of MA have a pleiotropic influence on the magnitude of behavioral sensitization to MA and sensitivity to the stimulant effects of cocaine. Further, extreme sensitivity to MA may protect against MA and cocaine self-administration.     

Estradiol: A key biological substrate mediating the response to cocaine in female rats

A consistent finding in drug abuse research is that males and females show differences in their response to drugs of abuse. In women, increased plasma estradiol is associated with increased vulnerability to the psychostimulant and reinforcing effects of drugs of abuse. Our laboratory has focused on the role of estradiol in modulating the response to cocaine. We have seen that ovariectomy increases the locomotor response to a single cocaine injection, whereas estradiol exacerbates the locomotor response to repeated cocaine administration. Cocaine-induced sensitization of brain activity, as measured by fMRI, is also dependent on plasma estradiol. Moreover, we observed that although all ovariectomized rats show conditioned place preference to cocaine, it is more robust in ovariectomized rats with estradiol.Opioid receptors are enriched in brain regions associated with pleasure and reward. We find that in females, the effectiveness of kappa opioid agonists in decreasing the locomotor response to repeated cocaine varies with plasma estradiol. We also find that estradiol regulates the density of mu opioid receptors in brains areas associated with reward. These data hint that in females, estradiol modulates the behavioral effects of cocaine by regulating mu and kappa opioid signaling in mesocorticolimbic brain structures. Identifying the mechanisms that mediate differences in vulnerability to drugs of abuse may lead to effective therapeutic strategies for the treatment and prevention of addiction and relapse. We encourage health practitioners treating persons addicted to drugs to consider gender differences in response to particular pharmacotherapies, as well the sex steroid milieu of the patient.     

Frequency of cocaine administration affects behavioral and endocrine responses in male and female Fischer rats.

Accumulating evidence has shown disparate behavioral responses to cocaine in male and female rats. To date, there is a lack of understanding of how cocaine administration frequency affects sexually dimorphic behavioral responses. In the present study we investigated the behavioral and endocrine responses to single (1 x 15 mg/kg) and "binge" (3 x 15 mg/kg) cocaine administration in male and female Fischer rats. Overall, females showed a more prolonged and robust behavioral response to both acute and "binge" pattern cocaine administration. Furthermore, sex-dependent behavioral topographies emerged during binge-pattern cocaine administration; female rearing activity increased across "binge" injections while ambulatory activity decreased. In contrast, male ambulatory and rearing behaviors remained constant across injections of "binge" cocaine. At the hormonal level, both single and "binge" pattern cocaine administration decreased testosterone levels in male rats. However, cocaine's modulation of testosterone levels was transient since testosterone levels were decreased by cocaine 30 min but not 3 hr following a single injection. In both male and female rats, "binge" cocaine increased plasma progesterone levels. However, acute cocaine administration increased progesterone levels transiently in only female rats. Our results show that pattern of administration affects both cocaine-stimulated behavioral and endocrine responses in male and female rats.     

Methylphenidate and cocaine have a similar in vivo potency to block dopamine transporters in the human brain.

The reinforcing effects of cocaine and methylphenidate have been linked to their ability to block dopamine transporters (DAT). Though cocaine and methylphenidate have similar in vitro affinities for DAT the abuse of methylphenidate in humans is substantially lower than of cocaine. To test if differences in in vivo potency at the DAT between these two drugs could account for the differences in their abuse liability we compared the levels of DAT occupancies that we had previously reported separately for intravenous methylphenidate in controls and for intravenous cocaine in cocaine abusers. DAT occupancies were measured with Positron Emission Tomography using [11C]cocaine, as a DAT ligand, in 8 normal controls for the methylphenidate study and in 17 active cocaine abusers for the cocaine study. The ratio of the distribution volume of [11C]cocaine in striatum to that in cerebellum, which corresponds to Bmax/Kd +1, was used as measure of DAT availability. Parallel measures were obtained to assess the cardiovascular effects of these two drugs. Methylphenidate and cocaine produced comparable dose-dependent blockade of DAT with an estimated ED50 (dose required to block 50% of the DAT) for methylphenidate of 0.07 mg/kg and for cocaine of 0.13 mg/kg. Both drugs induced similar increases in heart rate and blood pressure but the duration of the effects were significantly longer for methylphenidate than for cocaine. The similar in vivo potencies at the DAT for methylphenidate than for cocaine are in agreement with their reported relative in vitro affinities (Ki 390 nM and 640 nM respectively), which is likely to reflect the similar degree of uptake (8-10% of the injected dose) and regional distribution of these two drugs in the human brain. Thus, differences in the in vivo potency of these two drugs at the DAT cannot be responsible for the differences in their rate of abuse in humans. Other variables i.e. longer duration of methylphenidate's side effects may counterbalance its reinforcing effects.     

Marker-assisted dissection of genetic influences on motor and neuroendocrine sensitization to cocaine in rats

This study investigated genetic influences on behavioral and neuroendocrine responses to cocaine sensitization. We used male and female rats of the inbred strains Lewis (LEW) and spontaneously hypertensive rats (SHR), which display genetic differences in stress-related responses. The influence of two quantitative trait loci (QTL; Ofil1 and Ofil2 on chromosomes 4 and 7), which modulate stress reactivity in rats, on the effects of cocaine was also investigated through the use of recombinant lines (derived from a LEW   ×   SHR intercross) selected by their genotype at Ofil1 and Ofil2 . Animals were given repeated cocaine or saline injections and tested for locomotion (induction of sensitization). Two weeks later, all animals were challenged with cocaine, and locomotion and corticosterone levels were measured (expression of sensitization). Results indicated that male SHR rats showed more behavioral sensitization than LEW rats, whereas no strain differences in sensitization were seen among females. When challenged with cocaine, LEW and SHR rats of both sexes pretreated with cocaine showed behavioral sensitization compared with saline pretreated animals; however, only LEW rats displayed an increase in the corticosterone levels. Ofil1 was found to influence the induction of sensitization in males and Ofil2 modulated the locomotor effect of cocaine in females. This study provides evidence of a genotype-dependent relationship between the induction and expression of cocaine sensitization, and between the behavioral and neuroendocrine responses induced by cocaine. Moreover, the Ofil1 and Ofil2 loci may contain one or more genes that control the behavioral effects of cocaine in rats.     

Sensitization enhances acquisition of cocaine self-administration in female rats: Estradiol further enhances cocaine intake after acquisition

Cocaine self-administration in rodents has been used widely as a preclinical model of cocaine use in humans. In laboratory animals, estradiol enhances behavioral sensitization to cocaine and the acquisition of cocaine self-administration in female rats. The rewarding effect of cocaine has been shown to be enhanced following behavioral sensitization in male rats. This experiment examined whether behavioral sensitization to cocaine would promote cocaine-taking behavior in female rats, and whether estradiol could further modulate cocaine-taking behavior in cocaine-sensitized rats. Ovariectomized female rats were pretreated with either cocaine or saline for 4 days per week for 3 weeks. Self-administration sessions started 2 weeks after the last dose of drug. Female Sprague-Dawley rats received either estradiol or oil 30 min prior to the start of each session and self-administration was carried out 5 days per week for 4 weeks. The dose of cocaine self-administered each week was as follows (in mg/kg/infusion): week 1, 0.1; week 2, 0.1; week 3, 0.15; and week 4, 0.4. The rats that received cocaine pretreatment took fewer days to acquire cocaine self-administration and took more cocaine than rats that received saline pretreatment. Estradiol enhanced cocaine intake during the last six self-administration sessions after acquisition but did not affect acquisition of self-administration at the lowest doses of cocaine used. In conclusion, cocaine sensitization promotes the acquisition of cocaine self-administration in female rats. Furthermore, prior cocaine experience is more powerful than estradiol at enhancing acquisition, while estradiol enhances intake of cocaine after acquisition of self-administration.     

Discriminative stimulus properties of stereoisomers of cyclazocine in phencyclidine-trained squirrel monkeys

Squirrel monkeys were trained to discriminate 0.16 mg/kg phencyclidine (PCP) from saline in a two-layer drug discrimination task on a fixed-ratio 32 schedule of food presentation. After reliable discriminative control of lever choice was established, dose-response determinations for generalization to the training dose of PCP were made with several doses of PCP, a racemic mixture of cyclazocine and the pure (+)- and (-)-isomers of cyclazocine. Only PCP and the (+)-isomer produced dose-dependent PCP-appropriate responding. Neither the racemic mixture nor (-)-cyclazocine produced over 25% PCP-appropriate responding at any of the doses tested. (+)-Cyclazocine was eight times less potent than PCP in producing drug-lever appropriate responding. (-)-Cyclazocine was about 30 times more potent than PCP and over 200 times more potent than (+)-cyclazocine in overall response rate suppression. The potency of the racemic mixture for response-rate suppression was consistent with an additive effect of the isomers. Neither the PCP-lever appropriate responding produced by (+)-cyclazocine nor the response-rate suppression produced by (-)-cyclazocine were antagonized by naloxone. Thus, racemic cyclazocine is composed of two isomers with differing behavioral effects. The (-)-isomer is more potent, and the (+)-isomer has more specificity for PCP-like effects.