Cocaine In Rhesus Monkeys Research Articles

Selective dopamine D3 receptor partial agonist (±)VK4-40 reduces the reinforcing strength of d-amphetamine but not cocaine in rhesus monkeys responding under a progressive-ratio schedule of reinforcement

Selective dopamine D3 receptor partial agonist (±)VK4-40 reduces the reinforcing strength of d-amphetamine but not cocaine in rhesus monkeys responding under a progressive-ratio schedule of reinforcement

Chronic levetiracetam (Keppra®) treatment increases the reinforcing strength of cocaine in rhesus monkeys

BackgroundDrugs that increase inhibitory neuronal activity in the brain have been proposed as potential medications for stimulant use disorders. ObjectiveThe present study assessed the ability of chronically administered levetiracetam (Keppra®), a clinically available anticonvulsant drug that increases GABA by binding to synaptic vesicle glycoprotein 2A, to modulate the reinforcing strength of cocaine in monkeys. MethodsThree adult male rhesus monkeys (Macaca mulatta) self-administered cocaine intravenously each day under a progressive-ratio (PR) schedule of reinforcement. Two monkeys also responded to receive food pellets under a 50-response fixed-ratio schedule (FR 50) each morning. After determining a cocaine dose-response curve (0.001–0.3 mg/kg per injection, i.v.) in the evening, levetiracetam (5–75 mg/kg, p.o., b.i.d.) was administered for 12–16 days per dose. To model a treatment setting, cocaine self-administration sessions were conducted using the PR schedule every 4 days during levetiracetam treatment. After tapering the dose of levetiracetam over two weeks in the absence of cocaine sessions, cocaine dose-effect curves were re-determined. ResultsLower doses of levetiracetam produced non-systematic fluctuations in numbers of cocaine injections received in each subject, whereas the highest tested dose significantly increased the reinforcing strength of cocaine; no effects on food-maintained responding were observed. After termination of levetiracetam treatment, dose-effect curves for cocaine self-administration were shifted to the left in two monkeys. ConclusionThese data suggest that levetiracetam is not likely to be an efficacious pharmacotherapy for cocaine dependence. Rather, sensitivity to cocaine may be increased during and after levetiracetam treatment.

Effects of the mGluR2/3 receptor agonist LY379268 on the reinforcing strength of cocaine in rhesus monkeys.

Because chronic cocaine exposure produces profound effects on brain glutamate function, this system has been investigated as a target for novel medications for cocaine use disorder. Studies in animal models have provided encouraging results for drugs that target metabotropic glutamate receptors (mGluR), particularly group II mGluRs which includes mGluR2 and mGluR3 receptors. The present study examined the effects of the mGluR2/3 receptor-selective agonist, (-)-2-oxa-4-aminobicylco hexane-4,6-dicarboxylic acid (LY379268), in male rhesus monkeys self-administering cocaine under two procedures that assess the strength of cocaine as a reinforcer. In four monkeys, acute effects of LY379268 on food and cocaine self-administration were characterized using a multiple 10-response fixed-ratio food, progressive-ratio cocaine schedule of reinforcement. Maximum injections were delivered when the available cocaine dose was 0.01-0.1 mg/kg.When monkeys self-administered 0.03 mg/kg per injection cocaine, LY379268 (0.001-0.56 mg/kg, i.v.), increased cocaine injections and disrupted food-maintained responding. Another group of monkeys (n = 3) responded under a food-cocaine choice procedure in which a dose-effect curve for self-administered cocaine (0.0, 0.003-0.1 mg/kg per injection) was generated daily. Acute LY379268 (0.01-0.1 mg.kg, i.v.) produced a shift in allocation of responding towards cocaine without affecting the total reinforcers delivered. When treatment was extended to 5 consecutive days, tolerance developed to LY379268-induced increases in cocaine choice. These data from two complimentary nonhuman primate models of cocaine use disorder are consistently negative with respect to the potential of LY379268 as a pharmacotherapy for reducing ongoing cocaine use.

Effects of Lorcaserin on Cocaine and Methamphetamine Self-Administration and Reinstatement of Responding Previously Maintained by Cocaine in Rhesus Monkeys.

Stimulant abuse is a serious public health issue for which there is no effective pharmacotherapy. The serotonin2C [5-hydroxytryptamine2C (5-HT2C)] receptor agonist lorcaserin decreases some abuse-related effects of cocaine in monkeys and might be useful for treating stimulant abuse. The current study investigated the effectiveness of lorcaserin to reduce self-administration of either cocaine or methamphetamine and cocaine-induced reinstatement of extinguished responding. Four rhesus monkeys responded under a progressive-ratio (PR) schedule in which the response requirement increased after each cocaine infusion (32-320 μg/kg/infusion). A separate group of four monkeys responded under a fixed-ratio (FR) schedule for cocaine (32 μg/kg/infusion) and reinstatement of extinguished responding was examined following administration of noncontingent infusions of cocaine (0.1-1 mg/kg) that were combined with response-contingent presentations of the drug-associated stimuli. Finally, three monkeys responded under a FR schedule for methamphetamine (0.32-100 μg/kg/infusion). Lorcaserin (3.2 mg/kg) significantly decreased the final ratio completed (i.e., decreased break point) in monkeys responding under the PR schedule and reduced the reinstatement of responding for drug-associated stimuli following a noncontingent infusion of cocaine; these effects did not appear to change when lorcaserin was administered daily. The same dose of lorcaserin decreased responding for methamphetamine in two of the three monkeys, and the effect was maintained during daily lorcaserin administration; larger doses given acutely (10-17.8 mg/kg) significantly decreased responding for methamphetamine, although that effect was not sustained during daily lorcaserin administration. Together, these results indicate that lorcaserin might be effective in reducing cocaine and methamphetamine abuse and cocaine relapse at least in some individuals.

Lorcaserin (Belviq®) Reduces the Discriminative Stimulus and Reinforcing Effects of Cocaine in Rhesus Monkeys

Drug abuse and obesity are serious public health problems, and mounting evidence suggests that dopamine and serotonin systems are similarly involved in regulating the consumption of food and drugs. Lorcaserin, a serotonin 2C receptor agonist, was recently approved by the US FDA to help obese individuals lose weight and it might also be effective at reducing cocaine abuse. The current studies sought to (1) characterize the pharmacokinetic and behavioral profile of lorcaserin (I.G.), and (2) determine the effectiveness of lorcaserin to alter the discriminative stimulus and reinforcing effects of cocaine (I.V.) in rhesus monkeys. Administered acutely, lorcaserin dose‐dependently increased the occurrence of yawning and decreased spontaneous activity and operant responding for food. These effects occurred within 30‐60 min of administration and began to dissipate by 240 min, which closely matched plasma levels of lorcaserin. In monkeys discriminating cocaine from saline, lorcaserin alone did not increase cocaine‐appropriate responding. When administered prior to cocaine, lorcaserin shifted the cocaine dose‐response curve to the right and down. Lorcaserin also dose‐dependently decreased the rate of cocaine self‐administration with a dose of 3.2 mg/kg lorcaserin decreasing responding by 50% for the duration of the 14 day treatment. Together, these results provide clear evidence that lorcaserin effectively blunts the discriminative stimulus and reinforcing effects of cocaine following acute and repeated administration suggesting that it might have clinical utility for treating cocaine abuse.Supported by NIH/NIDA grants U01DA034992 and K05DA017918 (CPF).

Repeated Administration of a Mutant Cocaine Esterase: Effects on Plasma Cocaine Levels, Cocaine-Induced Cardiovascular Activity, and Immune Responses in Rhesus Monkeys

Previous studies have demonstrated the capacity of a long-acting mutant form of a naturally occurring bacterial double mutant cocaine esterase (DM CocE) to antagonize the reinforcing, discriminative, convulsant, and lethal effects of cocaine in rodents and reverse the increases in mean arterial pressure (MAP) and heart rate (HR) produced by cocaine in rhesus monkeys. This study was aimed at characterizing the immunologic responses to repeated dosing with DM CocE and determining whether the development of anti-CocE antibodies altered the capacity of DM CocE to reduce plasma cocaine levels and ameliorate the cardiovascular effects of cocaine in rhesus monkeys. Under control conditions, intravenous administration of cocaine (3 mg/kg) resulted in a rapid increase in the plasma concentration of cocaine (n = 2) and long-lasting increases in MAP and HR (n = 3). Administration of DM CocE (0.32 mg/kg i.v.) 10 min after cocaine resulted in a rapid hydrolysis of cocaine with plasma levels below detection limits within 5 to 8 min. Elevations in MAP and HR were significantly reduced within 25 and 50 min of DM CocE administration, respectively. Although slight (10-fold) increases in anti-CocE antibodies were observed after the fourth administration of DM CocE, these antibodies did not alter the capacity of DM CocE to reduce plasma cocaine levels or ameliorate cocaine's cardiovascular effects. Anti-CocE titers were transient and generally dissipated within 8 weeks. Together, these results suggest that highly efficient cocaine esterases, such as DM CocE, may provide a novel and effective therapeutic for the treatment of acute cocaine intoxication in humans.

Effects of chronic methylphenidate treatment on the reinforcing strength of cocaine in rhesus monkeys

Drugs that indirectly stimulate dopamine receptors have been proposed as candidates for pharmacotherapies for stimulant addiction. These studies examined the effects of chronic methylphenidate treatment (MPD; 0.003–0.056 mg/kg/hr, i.v.) on cocaine self‐administration in 3 rhesus monkeys. In an attempt to more closely resemble clinical conditions of cocaine use and medication treatment, during chronic MPD treatment, cocaine self‐administration was examined once weekly in evening sessions under a progressive‐ratio schedule. Food‐reinforced responding was examined each morning under a fixed‐ratio schedule to assess some potential “side‐effects” of MPD treatment. Importantly, as in a treatment setting, decisions regarding dosing were made for individual subjects based on that monkey's response to MPD. In contrast to data obtained with this procedure using d‐amphetamine as a treatment agent (Czoty et al., Neuropsychopharmacology 36:539, 2011), MPD did not produced sustained decreases in cocaine self‐administration up to doses that disrupted food‐maintained responding and/or incerased agitated/aggressive behavior. The data suggest that chronic treatment with MPD under this regimen would not be an effective trteatment for cocaine addiction and, in combination with previous results, indicate that an amphetamine‐like drug may be more effective. Support: DA 06634.

Effects of Varenicline on the Reinforcing and Discriminative Stimulus Effects of Cocaine in Rhesus Monkeys

Varenicline is a low-efficacy, α4β2* subtype-selective nicotinic acetylcholine receptor (nAChR) agonist that has shown success in smoking cessation and promise in preclinical assessments relating to other drugs of abuse. The primary goal of the present study was to examine the effects of varenicline on cocaine self-administration and cocaine discrimination and compare these effects with those of the nAChR agonist nicotine and antagonist mecamylamine. One limitation of agonist treatments is the potential for abuse. Thus, a second goal was to examine the abuse potential of varenicline in rhesus monkeys. In the first experiment, rhesus monkeys (n = 3) were trained to self-administer cocaine (saline, 0.01-0.56 mg/kg) under a progressive-ratio schedule of reinforcement; monkeys also earned all of their food by responding on another lever under a fixed-ratio 50 schedule of reinforcement. Chronic administration of varenicline (0.01-0.56 mg/kg p.o., salt) potentiated the reinforcing effects of cocaine, whereas mecamylamine (0.3-1.7 mg/kg p.o, i.m., i.v., salt) had no significant effects on cocaine self-administration up to doses that disrupted food-maintained responding. Neither varenicline (0.01-0.17 mg/kg, salt) nor nicotine (0.01-0.1 mg/kg, base) functioned as reinforcers when substituted for cocaine. Finally, in monkeys trained to discriminate self-administered 0.3 mg/kg cocaine, varenicline (0.1-0.3 mg/kg i.v.) did not substitute for cocaine but, along with mecamylamine (0.3-1.7 mg/kg i.v.) and nicotine (0.03-0.1 mg/kg i.v.), potentiated the discriminative stimulus effects of cocaine. These results suggest that varenicline has low abuse liability in monkey models of cocaine abuse, but would not be an effective medication for cocaine addiction.

Amelioration of the Cardiovascular Effects of Cocaine in Rhesus Monkeys by a Long-Acting Mutant Form of Cocaine Esterase

A long-acting mutant form of a naturally occurring bacterial cocaine esterase (T172R/G173Q CocE; double mutant CocE (DM CocE)) has previously been shown to antagonize the reinforcing, convulsant, and lethal effects of cocaine in rodents. However, the effectiveness and therapeutic characteristics of DM CocE in nonhuman primates, in a more clinically relevant context, are unknown. The current studies were aimed at (1) characterizing the cardiovascular effects of cocaine in freely moving rhesus monkeys, (2) evaluating the capacity of DM CocE to ameliorate these cocaine-induced cardiovascular effects when administered 10 min after cocaine, and (3) assessing the immunological responses of monkeys to DM CocE following repeated administration. Intravenous administration of cocaine produced dose-dependent increases in mean arterial pressure (MAP) and heart rate (HR) that persisted throughout the 2-h observation period following a dose of 3.2 mg/kg cocaine. Cocaine failed to produce reliable changes in electrocardiograph (ECG) parameters, body temperature, and locomotor activity. DM CocE produced a rapid and dose-dependent amelioration of the cardiovascular effects, with saline-like MAP measures restored within 5-10 min, and saline-like HR measures restored within 20-40 min of DM CocE administration. Although administration of DM CocE produced increases in anti-CocE antibodies, they did not appear to have a neutralizing effect on the capacity of DM CocE to reverse the cardiovascular effects of cocaine. In conclusion, these findings in monkeys provide strong evidence to suggest that highly efficient cocaine esterases, such as DM CocE, can provide a potential therapeutic option for treatment of acute cocaine intoxication in humans.

Acute brain metabolic effects of cocaine in rhesus monkeys with a history of cocaine use

Cocaine addiction involves an escalation in drug intake which alters many brain functions. The present study documented cocaine-induced changes in brain metabolic activity as a function of cocaine self-administration history. Experimentally naive rhesus monkeys (N = 6) were given increasing access to cocaine under a fixed-ratio schedule of intravenous (i.v.) drug self-administration. PET imaging with F-18 labeled fluorodeoxyglucose (FDG) was used to measure acute intramuscular (i.m.) cocaine-induced changes in brain metabolism in the cocaine-naïve state, following 60 sessions under limited-access conditions (1h/day), following 60 sessions under extended-access conditions (4h/day), and following 4weeks of drug withdrawal. In the cocaine-naïve state, cocaine-induced increases in brain metabolism were restricted to the prefrontal cortex. As cocaine exposure increased from limited to extended access, metabolic effects expanded throughout the frontal cortex and were induced within the striatum. Conversely, cocaine-induced activation was far less robust following withdrawal. The results highlight a progressive expansion of the metabolic effects of cocaine to include previously unaffected dopamine innervated brain regions as a consequence of cocaine self-administration history. The identification of brain regions progressively influenced by drug exposure may be highly relevant toward efforts to develop treatments for cocaine addiction.

Effects of chronic d-amphetamine administration on the reinforcing strength of cocaine in rhesus monkeys

Agonist medications have been proven effective in treating opioid and nicotine dependence; results from clinical studies suggest that the indirect dopamine agonist d-amphetamine may reduce cocaine abuse. In preclinical studies, chronic d-amphetamine treatment decreased ongoing cocaine self-administration. The present study extended previous results by determining effects of chronic d-amphetamine treatment on the reinforcing strength of cocaine under conditions in which access to cocaine was suspended during d-amphetamine treatment. Daily operant conditioning sessions consisted of morning access to food pellets delivered under a 50-response fixed-ratio schedule and evening access to cocaine (0.005-0.48 mg/kg per injection, i.v.) under a progressive-ratio schedule. After responding maintained by 0.045 mg/kg per injection cocaine stabilized, self-administration sessions were suspended and d-amphetamine (0.01-0.1 mg/kg per hr, i.v.) was administered continuously for 5 days. On the following day, d-amphetamine treatment was discontinued and daily self-administration sessions resumed. Following termination of d-amphetamine treatment, food- and cocaine-maintained responding was decreased in a dose-related manner. Decreases in the reinforcing strength of cocaine were larger and lasted longer than effects on food reinforcement. However, cocaine self-administration was unaltered if 6 days elapsed between discontinuation of d-amphetamine treatment and the next cocaine self-administration session. The necessity of a self-administration session in the presence of d-amphetamine suggests that the protracted decrease in cocaine self-administration may be a manifestation of behavioral tolerance. Regarding treatment of cocaine dependence, data suggest that prolonged d-amphetamine treatment may be necessary to produce a sustained reduction in the reinforcing effects of cocaine.

Behavioral evaluation of modafinil and the abuse-related effects of cocaine in rhesus monkeys.

Modafinil is a central nervous system stimulant used to promote wakefulness, and it is being evaluated clinically as an agonist medication for treating stimulant abuse. This is the first report of the effects of modafinil on the abuse-related effects of cocaine in nonhuman primates. The behavioral effects of modafinil were examined in three studies. First, the discriminative stimulus effects of modafinil (3.2-32 mg/kg) were evaluated in rhesus monkeys (Macaca mulatta) trained to discriminate either low (0.18 mg/kg, IM) or high (0.4 mg/kg, IM) doses of cocaine from saline. Modafinil dose-dependently substituted for cocaine in 6 of 7 monkeys. In the second study, the effects of chronically administered modafinil (32-56 mg/kg/day, IV) on food- and cocaine-maintained (0.001-0.1 mg/kg/inj) operant responding were examined. Modafinil was administered 3 times/hr for 23 hr/day to ensure stable drug levels. Chronic treatment with 32 mg/kg/day modafinil selectively reduced responding maintained by intermediate and peak reinforcing doses of cocaine, but responding maintained by higher doses of cocaine was unaffected. Food-maintained behavior did not change during chronic modafinil treatment. In a third study, modafinil (32 and 56 mg/kg/day, IV) was examined in a reinstatement model. Modafinil transiently increased responding during extinction. These findings indicate that modafinil shares discriminative stimulus effects with cocaine and selectively reduces responding maintained by reinforcing doses of cocaine. In addition, modafinil reinstated cocaine-seeking behavior, which may reflect its cocaine-like discriminative stimulus effects. These data support clinical findings and indicate that these preclinical models may be useful for predicting the effectiveness of agonist medications for drug abuse treatment.

Effects of varenicline on the reinforcing and discriminative stimulus effects of cocaine in rhesus monkeys

In the CNS, stimulation of nicotinic acetylcholine receptors (nAChR) can directly affect dopaminergic tone and may, therefore, modulate the reinforcing effects of abused drugs. In rhesus monkeys, we examined the nAChR partial agonist varenicline and full agonist nicotine in i.v. drug self‐administration and cocaine discrimination procedures. When substituted for cocaine in monkeys responding under a progressive‐ratio (PR) schedule, nicotine (0.03‐0.3 mg/kg) but not varenicline (0.01‐0.17 mg/kg) functioned as a reinforcer. When administered chronically, varenicline (titrated up to 0.3 mg/kg, BID p.o. by day 30) did not affect cocaine break point under the PR schedule or cocaine intake. In monkeys discriminating 0.3 mg/kg i.v. cocaine from saline, varenicline (0.03‐0.3 mg/kg, i.v.) did not engender cocaine‐like discriminative stimulus effects, but dose‐dependently potentiated the effects of cocaine when administered 60 min prior to testing. These preliminary results indicate low abuse liability for the nAChR partial agonist varenicline but suggest that varenicline may potentiate the subjective effects of cocaine. Future studies will investigate nAChR compounds of varying intrinsic efficacy and subtype specificity to further understand the role of nAChRs in mediating the reinforcing and discriminative stimulus effects of cocaine. All doses are expressed as that of the salt. DA12460.

A within-subject assessment of the discriminative stimulus and reinforcing effects of self-administered cocaine in rhesus monkeys.

Drug discrimination (DD) and drug self-administration (SA) are frequently used preclinical assays. All preclinical studies with cocaine have examined the discriminative stimulus (S(D)) and reinforcing (S(R)) effects in separate groups of subjects. The objective of the study is to train drug-naïve rhesus macaques to discriminate self-administered cocaine from saline and to assess S(D) and S(R) effects using a within-subjects design. Adult male rhesus monkeys (n = 4) were trained to self-administer cocaine (0.1 mg/kg per injection) under a progressive-ratio (PR) reinforcement schedule. Next, they were trained to discriminate self-administered cocaine (0.45 or 0.56 mg/kg) or saline under a fixed-ratio (FR) 50 schedule of food presentation. The final schedule combined DD and SA into a multiple [chained FR 50 SA (cocaine or saline), food-reinforced DD] and PR SA schedule. Each subject acquired SA under a PR schedule with significant differences in breakpoint between saline and cocaine evident by session 5. Self-administered cocaine was established as an S(D), such that 80% of responding before delivery of the first reinforcer and 90% of all responding occurred on the injection-appropriate lever. In all monkeys, there was at least one cocaine dose that did not engender cocaine-appropriate responding during DD (i.e., <20% cocaine-appropriate responding) yet functioned as a reinforcer during PR SA, suggesting that cocaine-like S(D) effects are not necessary for cocaine reinforcement. This within-subject model may provide new information related to the behavioral mechanisms of action leading to the high abuse potential of cocaine; such information may lead to novel pharmacological treatment strategies for addiction.

Chronic d‐amphetamine treatment attenuates the reinforcing strength of cocaine in rhesus monkeys

An agonist approach to pharmacotherapy has been successful in treating abuse of several drugs. Currently, no agonist therapy is available for cocaine addiction. Amphetamine, a schedule II drug used to treat disorders such as attention-deficit disorder and obesity, has shown promise in preclinical and clinical studies. We examined the effects of continuous treatment with d-amphetamine on the subsequent reinforcing strength of cocaine in rhesus monkeys (n=4) responding under a concurrent schedule of food and cocaine presentation. On one lever, monkeys responded under a fixed-ratio 50 schedule of food presentation 24 h per day or until the day’s food ration was earned. On another lever, monkeys responded under a progressive-ratio schedule of cocaine presentation beginning at 3 pm daily. Increasing doses of cocaine (0.01–0.3 mg/kg/injection) resulted in increases in PR responding. Next, access to cocaine was suspended and monkeys were treated with d-amphetamine (0.03 or 0.1 mg/kg/hr) for 5 days. When the 0.03 mg/kg/injection training dose of cocaine was again made available for self-administration, 0.1 mg/kg/hr d-amphetamine significantly reduced cocaine-maintained responding for an average of 6 days post-treatment; d-amphetamine treatment marginally affected food intake. These results provide further support that an agonist therapy, specifically d-amphetamine, can decrease cocaine use. DA 06634.

Dopaminergic responses to self‐administered cocaine in Rhesus monkeys do not sensitize following high cumulative intake

Sensitization of mesolimbic dopamine (DA) systems by administration of psychostimulants has been observed repeatedly in rodents. This phenomenon has been incorporated into theories of neurobiological adaptation underlying addiction, and is believed to be a mechanism whereby drug-associated cues acquire the ability to control behaviour via a conditioned release of DA. However, we have previously demonstrated in nonhuman primates that drug cues that cause cocaine seeking do not promote a conditioned increase in DA release of sufficient endurance to be measured in 2-min samples. In addition, imaging studies in humans and nonhuman primates that have been chronically exposed to psychostimulants have not demonstrated an increase in DA release upon psychostimulant challenge. Here we report that following 32 weeks of self-administration by rhesus monkeys, no increase over time in the DA response to self-administered cocaine was observed in any striatal subregion or individual animal. These results are consistent with clinical imaging studies showing a lack of DA sensitization, and might provide a mechanism to explain our previous observation that the rodent and primate differ in neurochemical response to drug-associated cues.

Effects of memantine, haloperidol, and cocaine on primary and conditioned reinforcement associated with cocaine in rhesus monkeys

The N-methyl-D-aspartate (NMDA) receptor has been implicated in mediating the reinforcing effects of abused drugs. Some reports indicate the uncompetitive NMDA antagonist, memantine, modulates the conditioned and unconditioned effects of stimulants in rats. The objective of this study was to evaluate the effects of memantine on the primary and conditioned reinforcing effects of cocaine in the rhesus monkey. Rhesus monkeys were trained to press levers reinforced with either cocaine-associated stimuli (brief stimuli, BS) or 30-microg/kg cocaine infusion during daily, 75-min experimental sessions in which the reinforcers were independently available in separate components according to identical progressive ratio (PR) schedules. Memantine (0.3-10 mg/kg), and as comparators, haloperidol (0.001-0.1 mg/kg) and cocaine (0.01-1 mg/kg), were administered 5 min before experimental sessions. Memantine (0.3-3 mg/kg) produced decreases in responding maintained by BS presentations at some doses which failed to affect cocaine self-administration when measured during equivalent periods early in the experimental session. Memantine (3 mg/kg) increased cocaine self-administration, however, later in the session. A low dose of haloperidol (0.001 mg/kg) increased the number of BS presentations, whereas higher doses decreased their number. Cocaine self-administration was not significantly affected by haloperidol until a behaviorally suppressant dose (0.1 mg/kg) was administered. Pretreatment with high doses of cocaine (0.3 and 1 mg/kg) decreased responding maintained by both reinforcers. These results suggest that while memantine may attenuate the conditioned reinforcing effects of cocaine-associated stimuli, it may also occasion increase levels of cocaine self-administration. These findings support the hypothesis that the NMDA receptor can play a role in modulating the conditioned and primary reinforcing effects of cocaine.

A comparison of the reinforcing efficacy of 3,4-methylenedioxymethamphetamine (MDMA, “ecstasy”) with cocaine in rhesus monkeys

The purpose of the present study was to compare the reinforcing efficacy of 3,4-methylenedioxymethamphetamine (MDMA, ‘ecstasy’) to cocaine. Rhesus monkeys ( n = 4) responded under a within-session, exponentially increasing, progressive-ratio (PR) schedule of cocaine reinforcement. Breaking point (BP) for the PR schedule was defined as the final response requirement completed before 2 h had elapsed without an injection delivered. Saline and doses of cocaine (0.003–0.3 mg/kg/injection) and MDMA (0.01–0.56 mg/kg/injection) were substituted for the training dose of cocaine for at least five consecutive sessions. Both cocaine and MDMA functioned as reinforcers, but self-administration of MDMA occurred at fewer doses and a significantly lower peak BP was obtained for MDMA. These data demonstrate that MDMA functions as a reinforcer, although its reinforcing efficacy appears to be less than that of cocaine.

Tetrabenazine fails to antagonize a behavioral effect of cocaine in rhesus monkeys

For research and therapeutic purposes, a cocaine antagonist is an important drug development goal. The vesicular monoamine transport inhibitor tetrabenazine was tested for interaction with cocaine using food-reinforced responding in rhesus monkeys as an assay. Both tetrabenazine and cocaine suppressed food-maintained behavior individually. However, a low-dose tetrabenazine pretreatment did not alter the rate-suppressing effects of cocaine and cocaine did not alter the rate-suppressing effects of a high dose tetrabenazine pretreatment. Because tetrabenazine interacts with the monoamine oxidase inhibitor deprenyl in this assay, we conclude that cocaine does not produce an effect through vesicular catecholamines in this assay.

The effects of chronic morphine on behavior reinforced by several opioids or by cocaine in rhesus monkeys

The reinforcing effects of intravenously delivered cocaine, alfentanil, morphine, heroin, nalbuphine, or buprenorphine were evaluated in four rhesus monkeys before, during, and after daily administration of 3.2 mg/kg morphine. Morphine was given 21 h prior to measures of the reinforcing effects of each of the drugs. No changes in the potency of cocaine or the high efficacy mu agonist alfentanil were detectable during the period of chronic morphine administration. Small (1/2–1) log unit decreases in the reinforcing potency of intermediate efficacy mu agonists morphine and heroin occurred during chronic morphine administration. Larger decreases in both the potency and effectiveness of low-efficacy mu agonists nalbuphine and buprenorphine developed during this time. These data suggest that the amount of tolerance that develops to the reinforcing effects of opioids depends on the efficacy of the drugs used to maintain responding.