Decreased Cocaine Choice Research Articles

THE EFFECTS OF THE DOPAMINE TRANSPORTER LIGANDS JJC8-088 AND JJC8-091 ON COCAINE VS. FOOD CHOICE IN RHESUS MONKEYS.

While there are no FDA-approved treatments for cocaine use disorder (CUD), several modafinil analogs have demonstrated promise in reducing cocaine self-administration and reinstatement in rats. Furthermore, the range of dopamine transporter (DAT) compounds provides an opportunity to develop pharmacotherapeutics without abuse liability. This study extended the comparison of JJC8-088 and JJC8-091, the former compound having higher DAT affinity and predicted abuse liability, to rhesus monkeys using a concurrent cocaine-food schedule of reinforcement. First, binding to striatal DAT was examined in cocaine-naïve monkey tissue. Next, i.v. pharmacokinetics of both JJC compounds were evaluated in cocaine-experienced male monkeys (n=3/drug). In behavioral studies, acute and chronic administration of both compounds were evaluated in these same monkeys responding under a concurrent food vs. cocaine (0, 0.003-0.1 mg/kg/injection) schedule of reinforcement. In nonhuman primate striatum, JJC8-088 had higher DAT affinity compared to JJC8-091 (14.4 {plus minus} 9 vs. 2,730 {plus minus} 1,270 nM, respectively). Both JJC compounds had favorable plasma pharmacokinetics for behavioral assessments, with half-lives (t1/2) of 1.1 h and 3.5 h for JJC8-088 (0.7 mg/kg, i.v.) and JJC8-091 (1.9 mg/kg, i.v.), respectively. Acute treatment with both compounds shifted the cocaine dose-response curve to the left. Chronic treatment with JJC8-088 decreased cocaine choice in two of the three monkeys, while JJC8-091 only modestly reduced cocaine allocation in one monkey. Differences in affinities of JJC8-091 DAT binding in monkeys compared to rat, may account for the poor rodent-to-monkey translation. Future studies should evaluate atypical DAT blockers in combination with behavioral interventions that may further decrease cocaine choice. Significance Statement Cocaine use disorder (CUD) remains a significant public health problem with no FDA-approved treatments. The ability of drugs that act in the brain in a similar manner to cocaine, but with lower abuse liability, has clinical implications for a treatment of CUD.

Effects of Dopamine D1-Like Receptor Ligands on Food-Cocaine Choice in Socially Housed Male Cynomolgus Monkeys

Although dopamine plays a prominent role in mediating cocaine's abuse-related effects, the specific roles of dopamine receptor subtypes are not fully understood. Whereas the effects of drugs acting at dopamine D2-like receptors (D2Rs) have been characterized, less is known about dopamine D1-like receptors (D1Rs). The present experiments examined the effects of drugs with varying intrinsic efficacy at D1R on the relative reinforcing strength of cocaine in male cynomolgus monkeys. Use of socially housed monkeys permitted the assessment of whether social status influenced the behavioral effects of D1R-acting drugs. The high-efficacy D1R agonist SKF 81297, low-efficacy D1R agonist SKF 38393, and D1R antagonist SCH 23390 were administered acutely to monkeys self-administering cocaine under a food-cocaine choice procedure in which a cocaine-choice dose-effect curve was determined daily. To assess selectivity of behavioral effects on cocaine choice, effects of doses that did not disrupt responding (indicated by a ≥35% decrease in total reinforcers delivered) were analyzed. Neither SKF 81297 nor SCH 23390 affected cocaine choice in dominant or subordinate monkeys. However, the low-efficacy agonist SKF 38393 selectively decreased cocaine choice; this effect was larger and only reached statistical significance in subordinate monkeys. Increasing the time between D1-acting drug administration and the cocaine choice session did not affect these results. The results indicate that, like D2R-acting drugs, the behavioral effects of D1R-acting drugs on cocaine choice can vary according to intrinsic efficacy and social status. Moreover, they demonstrate that D1R-acting drugs affect behavior under a narrower range of conditions than D2R-acting drugs. SIGNIFICANCE STATEMENT: Cocaine use disorder represents an insidious public health concern with no Food and Drug Administration-approved medications. Although dopamine receptors have been strongly implicated in mediating the abuse-related effects of cocaine, the roles of dopamine receptor subtypes are incompletely understood. The present study in nonhuman primates found that cocaine choice was decreased only by a low-efficacy D1R agonist, and that this effect depended on the social status of the monkey.

Effects of the α-2 Adrenergic Receptor Agonists Lofexidine and Guanfacine on Food-Cocaine Choice in Socially Housed Cynomolgus Monkeys.

Although norepinephrine (NE) does not appear to play a prominent role in mediating the abuse-related effects of cocaine, studies have indicated that NE α-2 receptor agonists can attenuate reinstatement of extinguished cocaine self-administration in rats and monkeys and can decrease cocaine craving in humans. In the present studies, we examined the effects of two α-2 receptor agonists, lofexidine and guanfacine, on choice between food and cocaine (0.0-0.1 mg/kg per injection) in cynomolgus monkeys. Male and female subjects were housed in stable same-sex social groups of four; social rank did not influence the effects of lofexidine and guanfacine. When administered acutely, lofexidine (0.03-3.0 mg/kg, i.v.) significantly decreased cocaine choice in females (n = 7) but not males (n = 8). However, in males, the same lofexidine doses produced dose-dependent decreases in core body temperature (n = 7), and acute guanfacine (0.003-1.0 mg/kg, i.v.) significantly decreased cocaine choice (n = 11). When lofexidine was administered for five consecutive days to a subset of the monkeys in whom lofexidine acutely decreased cocaine choice, tolerance to this effect developed to varying degrees of completeness in three of three males and two of four females. Taken together, these data suggest that α-2 receptor agonists can produce small decreases in the reinforcing strength of cocaine relative to food and that, even when efficacy is observed after acute administration, tolerance to the decreases in cocaine choice are apparent and more likely in males compared with females. SIGNIFICANCE STATEMENT: Cocaine use disorder remains a significant public health problem with no US Food and Drug Administration-approved treatments. Although cocaine elevates dopamine, serotonin, and norepinephrine (NE), the latter target has received less research. The present study noted modest effects of NE agonists on the relative reinforcing strength of cocaine with greater efficacy in female compared with male monkeys.

Cannabinoid Modulation of Food-Cocaine Choice in Male Rhesus Monkeys.

Marijuana and other cannabinoid compounds are widely used by cocaine users. Preclinical animal studies suggest that these compounds can increase the reinforcing effects of cocaine under some schedules of cocaine self-administration and reinstatement, but not in all cases. To date, no studies have used a food-cocaine concurrent choice procedure, which allows for assessment of drug effects on response allocation, not just changes in cocaine self-administration. The goal of the present study was to examine the effects of compounds differing in their efficacy at the cannabinoid receptor (CBR) on cocaine self-administration using a food-drug choice procedure in monkeys. Four adult male rhesus monkeys were trained to self-administer cocaine in the context of an alternative food (1.0-g banana-flavored pellets) reinforcer, such that complete cocaine dose-response curves (0, 0.003-0.1 mg/kg per injection) were determined each session. Monkeys were tested acutely with the CBR full agonist CP 55,940 (0.001-0.01 mg/kg); the CBR partial agonist Δ9-tetrahydrocannabinol (THC; 0.03-0.3 mg/kg), which is also the primary active ingredient in marijuana and the CBR antagonist rimonabant (0.3-3.0 mg/kg). Cocaine choice increased in a dose-dependent manner. Acute treatment with CP 55,940 decreased cocaine choice, whereas THC and rimonabant enhanced the reinforcing effects of cocaine. Chronic (7-day) treatment with CP 55,940 resulted in tolerance to the decreases in cocaine choice. These findings with Δ9-THC provide support for a potential mechanism for co-abuse of marijuana and cocaine. Additional research with chronic treatment with full CBR agonists on attenuating the reinforcing strength of cocaine is warranted. SIGNIFICANCE STATEMENT: Co-abuse of tetrahydrocannabinol and cocaine is a significant public health problem. The use of animal models allows for the determination of how cannabinoid receptor stimulation or blockade influences the reinforcing strength of cocaine.

Effects of the mGluR2/3 agonist LY379268, alone and in combination with monoamineenhancing drugs, on cocaine self‐administration in rhesus monkeys

Cocaine addiction persists as a major public health problem but still lacks any FDA‐approved pharmacotherapies. Wake Forest's Center for the Neurobiology of Drug Abuse Treatment (CNAT) has demonstrated the effectiveness of ‘agonist medications’ such as the monoamine releaser phenmetrazine (PM) and its pro‐drug phendimetrazine (PDM) to decrease cocaine use in animal models. CNAT investigators have hypothesized that combination of a dopamine‐enhancing drug like PM/PDM with a drug with a different pharmacological and/or behavioral mechanism may display enhanced effectiveness and represent a promising pharmacotherapeutic approach to treating cocaine use disorder. The present studies characterized the effects of the mGluR2/3 receptor agonist LY379268, alone and in combination with daily PDM or the dopamine transporter inhibitor methylphenidate (MPD) on cocaine reinforcement in rhesus monkeys. In one experiment (n=4), a multiple schedule was used in which food reinforcers were available in the first component under a fixed‐ratio schedule of reinforcement and cocaine self‐administration was studied under a progressive‐ratio schedule. A second study (n=4) used a food‐cocaine choice procedure in which a complete cocaine dose‐effect curve was generated each day. Effects of acute and chronic LY379268 were studied. Under the multiple schedule, acute LY379268 decreased food‐but not cocaine‐maintained responding; when administered chronically (as an i.v. injection) during chronic oral PDM treatment, a drug combination that persistently decreased cocaine self‐administration was found in only one of four subjects. Under the choice procedure, LY379268 increased the reinforcing strength of cocaine relative to food. After 5 days of treatment, tolerance developed to this effect in a dose‐related manner but at no point were decreases in cocaine choice observed. Finally, when chronic LY379268 was administered in combination with chronic oral PDM or chronic MPD (via subcutaneous osmotic pump), dose combinations were observed that modestly decreased cocaine choice in two of four monkeys. Although some results were positive, taken together these studies, which used highly translational nonhuman primate models of cocaine use disorder, do not support the effectiveness of LY 279638 alone or in combination with agonist medications.Support or Funding InformationP50 DA06634This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Modafinil decreases cocaine choice in human cocaine smokers only when the response requirement and the alternative reinforcer magnitude are large

This study examined how response effort (pressing a keyboard button) for cocaine and the value of an alternative reinforcer (opportunity to play a game of chance for money) combined with ‘free’ cocaine (with no response effort) affected cocaine choice when participants were maintained on modafinil or placebo. Nontreatment-seeking current cocaine smokers were enrolled in a placebo-controlled, double-blind, within-subject study comprising both inpatient and outpatient phases. Participants were maintained on placebo capsules (0mg/day) during one inpatient phase and modafinil (300mg/day) capsules during another inpatient phase in counter-balanced order. A minimum of 8 medication-free days separated the two 15-day inpatient phases to allow for medication clearance. Under each medication condition participants had the opportunity to self-administer smoked cocaine (25mg) when the response effort for cocaine was low (500responses/dose) and had a low value alternative (2 game plays for money) or when the response effort for cocaine was large (2500responses/dose) and had a more valuable alternative (4 game plays for money). Under both conditions, participants received one free dose of cocaine (0, 12, 25 or 50mg) prior to making their first choice of the session. Fifteen individuals began the study and 7 completed it. Participants chose fewer cocaine doses when the response effort for cocaine and the alternative value was high (4.4±0.19) compared to when the response effort for cocaine and the alternative value was low (5.3±0.14). Providing individuals a free “priming” dose of cocaine prior to making their cocaine choice did not alter cocaine taking. Modafinil decreased cocaine choice only when the response effort for cocaine and the alternative value was high. These results suggest that modafinil may be most effective when combined with therapy emphasizing the large personal costs of using cocaine.

Development of a translational model to screen medications for cocaine use disorder I: Choice between cocaine and food in rhesus monkeys

BackgroundHomologous cocaine self-administration procedures in laboratory animals and humans may facilitate translational research for medications development to treat cocaine dependence. This study, therefore, sought to establish choice between cocaine and an alternative reinforcer in rhesus monkeys responding under a procedure back-translated from previous human studies and homologous to a human laboratory procedure described in a companion paper. MethodsFour rhesus monkeys with chronic indwelling intravenous catheters had access to cocaine injections (0, 0.043, 0.14, or 0.43mg/kg/injection) and food (0, 1, 3, or 10 1g banana-flavored food pellets). During daily 5h sessions, a single cocaine dose and a single food-reinforcer magnitude were available in 10 30-min trials. During the initial “sample” trial, the available cocaine and food reinforcer were delivered non-contingently. During each of the subsequent nine “choice” trials, responding could produce either the cocaine or food reinforcer under an independent concurrent progressive-ratio schedule. ResultsPreference was governed by the cocaine dose and food-reinforcer magnitude, and increasing cocaine doses produced dose-dependent increases in cocaine choice at all food-reinforcer magnitudes. Effects of the candidate medication lisdexamfetamine (0.32–3.2mg/kg/day) were then examined on choice between 0.14mg/kg/injection cocaine and 10 pellets. Under baseline conditions, this reinforcer pair maintained an average of approximately 6 cocaine and 3 food choices. Lisdexamfetamine dose-dependently decreased cocaine choice in all monkeys, but food choice was not significantly altered. ConclusionsThese results support utility of this procedure in rhesus monkeys as one component of a platform for translational research on medications development to treat cocaine use disorder.

Development of translational preclinical models in substance abuse: Effects of cocaine administration on cocaine choice in humans and non-human primates

Human drug use involves repeated choices to take drugs or to engage in alternative behaviors. The purpose of this study was to examine how response cost for cocaine and the value of an alternative reinforcer (opportunity to play a game of chance) and how ‘free’ doses (with minimal response cost) affected cocaine choice. Two laboratory studies of cocaine self-administration were conducted in a group of humans who were habitual cocaine smokers and in a group of rhesus monkeys that intravenously self-administered cocaine. Nine human cocaine smokers who were not seeking treatment for their cocaine were repeatedly presented with the choice to smoke 25mg cocaine base or play a game of chance for a monetary bonus paid at study completion. The response cost for choosing cocaine varied (up to 4000 responses/dose) and the number of game plays varied (up to 8). In this sample of humans, increasing either the response cost for cocaine or increasing the value of the alternative reinforcer did not significantly affect cocaine choice, while increasing both simultaneously slightly decreased cocaine choice and increased choice of the alternative. In monkeys, the dose–response function for cocaine self-administration (10 choices of 0.0125–0.1mg/kg/infusion vs. candy coated chocolate) was steep and we failed to achieve a 50/50 cocaine/candy choice even after substantially manipulating cost and number of candies available. Providing a large ‘free’ self-administered cocaine dose to humans did not significantly affect cocaine choice, whereas in monkeys, a large free dose of cocaine decreased cocaine choice when higher doses of cocaine were available for self-administration. The present results demonstrate that in the laboratory, it is difficult to modify on-going cocaine self-administration behavior in both humans and non-human primates.

Differences between recent quitters and current smokers during pregnancy

Differences between recent quitters and current smokers during pregnancy

Effects of quetiapine treatment on cocaine self-administration and behavioral indices of sleep in adult rhesus monkeys.

Clinical literature suggests a link between substance abuse and sleep disturbances. Quetiapine, an atypical antipsychotic, has shown efficacy in treating sleep disturbances, with clinical studies showing promise for quetiapine as a treatment for cocaine abuse. The goal of this study was to examine the effects of quetiapine on cocaine self-administration and behavioral indices of sleep in monkeys. Seven adult male rhesus monkeys, fitted with Actical® activity monitors, were trained to respond under a choice paradigm of food (1.0-g pellets) and cocaine (0.003-0.3 mg/kg per injection) presentation. First, monkeys received acute pretreatment (45 min) with quetiapine (25-75 mg, p.o.) prior to choice sessions; three cocaine doses were studied in combination with quetiapine. Next, the effect of chronic (14-16 days) quetiapine treatment (25-250 mg, p.o., BID) was examined in combination with the lowest preferred cocaine dose (≥80 % cocaine choice). Behavioral indices of sleep, based on activity measures obtained during lights-out, were recorded throughout the study. Acute quetiapine decreased cocaine choice in four of the seven monkeys. Chronic quetiapine treatment resulted in initial decreases in cocaine choice, but tolerance developed to these effects. Acute doses of quetiapine did not improve sleep efficiency the following night nor did chronic quetiapine. The first night after discontinuing quetiapine treatment resulted in significant decreases in sleep efficiency and increases in nighttime activity. These findings do not offer support for the use of quetiapine as a monotherapy for treatment of cocaine abuse nor as an adjunct therapy to treat sleep disturbances associated with stimulant abuse.

Effect of experimental analogs of contingency management treatment on cocaine seeking behavior

BackgroundContingency management (CM) treatment is effective for treating cocaine dependence but further mechanistic studies of its efficacy are warranted. This study aimed to determine whether: (a) higher vs. lower predictable money amounts ($3 vs. $1; analogs of standard voucher-based CM) increase cocaine demand elasticity; and (b) probabilistic amounts matched for expected value with the $3-predictable amount (50% chance of $6; 25% chance of $12; and 12.5% chance of $24; analogs of prize CM) similarly affect cocaine choice. MethodsEach of 15 cocaine-dependent participants first completed a qualifying session to ensure that intranasal cocaine functioned as a reinforcer, then completed a 10-session, within-subject, randomized crossover study. During each of the 10 sessions, the participant responded on a progressive ratio schedule to earn units of cocaine (5-mg or 10-mg) and/or money (five monetary conditions above). ResultsDuring the reinforcement qualifying session (10-mg vs. 0-mg units; no money alternative), cocaine choice was high. The $3-predictable amount significantly decreased cocaine choice relative to both the $1-predictable amount and the qualifying session. Cocaine-choices in the probabilistic conditions were similar to the $3 predictable condition. ConclusionsThese findings indicate that CM interventions targeted at reducing cocaine self-administration are more likely to succeed with higher value non-drug reinforcement.

Effects of 14-day treatment with the schedule III anorectic phendimetrazine on choice between cocaine and food in rhesus monkeys

BackgroundThe clinical utility of monoamine releasers such as phenmetrazine or d-amphetamine as candidate agonist medications for cocaine dependence is hindered by their high abuse liability. Phendimetrazine is a clinically available schedule III anorectic that functions as a prodrug for phenmetrazine and thus may have lower abuse liability. This study determined the effects of continuous 14-day treatment with phendimetrazine on cocaine vs. food choice in rhesus monkeys (N=4). MethodsResponding was maintained under a concurrent schedule of food delivery (1-g pellets, fixed-ratio 100 schedule) and cocaine injections (0–0.1mg/kg/injection, fixed-ratio 10 schedule). Cocaine choice dose–effect curves were determined daily before and during 14-day periods of continuous intravenous treatment with saline or (+)-phendimetrazine (0.32–1.0mg/kg/h). Effects of 14-day treatment with (+)-phenmetrazine (0.1–0.32mg/kg/h; N=5) and d-amphetamine (0.032–0.1mg/kg/h; N=6) were also examined for comparison. ResultsDuring saline treatment, food was primarily chosen during availability of low cocaine doses (0, 0.0032, and 0.01mg/kg/injection), and cocaine was primarily chosen during availability of higher cocaine doses (0.032 and 0.1mg/kg/injection). Phendimetrazine initially decreased overall responding without significantly altering cocaine choice. Over the course of 14 days, tolerance developed to rate decreasing effects, and phendimetrazine dose-dependently decreased cocaine choice (significant at 0.032mg/kg/injection cocaine). Phenmetrazine and d-amphetamine produced qualitatively similar effects. ConclusionsThese results demonstrate that phendimetrazine can produce significant, though modest, reductions in cocaine choice in rhesus monkeys. Phendimetrazine may be especially suitable as a candidate medication for human studies because of its schedule III clinical availability.

Effects of Dopamine D2/D3 Receptor Ligands on Food-Cocaine Choice in Socially Housed Male Cynomolgus Monkeys

Dopamine D2/D3 receptor partial agonists have been suggested as medications for cocaine dependence. The present experiments examined the effect of acute and repeated administration of drugs with varying intrinsic efficacy at D2/D3 receptors on the relative reinforcing strength of cocaine. Use of socially housed cynomolgus monkeys permitted the assessment of whether social status, known to alter D2/D3 receptor availability, influenced the behavioral effects of D2/D3 receptor compounds. The high-efficacy agonist R(-)-norpropylapomorphine [(-)-NPA], low-efficacy agonist aripiprazole (ARI), and antagonist eticlopride (ETIC) were administered acutely to monkeys self-administering cocaine under a food-cocaine choice procedure in which a cocaine self-administration dose-effect curve was determined daily. The effects of 5-day treatment with ARI and (-)-NPA were characterized under conditions in which monkeys did (ARI) or did not [ARI and (-)-NPA] self-administer cocaine during treatment. When administered acutely, ARI and ETIC increased the choice of low cocaine doses, and only (-)-NPA decreased the choice of higher cocaine doses and cocaine intake; effects were similar across social ranks. When administered repeatedly while self administration occurred only on days 1 and 5 of treatment, ARI, but not (-)-NPA, decreased cocaine choice in dominant monkeys, whereas (-)-NPA, but not ARI, did so in subordinates. When dominant monkeys self-administered cocaine on all five days of ARI treatment, however, these effects were not observed. The results indicate that the behavioral effects of D2/D3 receptor agonists can differ according to intrinsic efficacy and subject characteristics. Moreover, these results suggest that exposure to cocaine during treatment can counteract treatment-induced reductions in the reinforcing effects of cocaine.

Individual differences in the effects of environmental stimuli on cocaine choice in socially housed male cynomolgus monkeys

Studies in laboratory animals have demonstrated an influence of environmentally derived stress and enrichment on the reinforcing effects of stimulants. To characterize the effects of acute exposure to ethologically valid environmental stimuli on the reinforcing strength of cocaine relative to food in socially housed monkeys. Choice between cocaine and food was assessed in subsets of 16 socially housed (4/pen) male cynomolgus monkeys immediately after the following manipulations: (1) treats placed in home cage, (2) a 10-min exposure to a rubber snake, or (3) 3 to 7 days of living in a larger environment without cage mates. Placing treats in the home cage shifted the cocaine dose-response curve to the left in five monkeys tested and to the right in 4 of 12 animals. The rubber snake significantly shifted the cocaine choice curve to the left in dominant monkeys. Exposure to an enlarged environment decreased cocaine choice in 9 of 15 monkeys; this effect was transient and not related to social rank. Repeated testing did not affect cocaine choice. Brief exposure to environmental events hypothesized to be stressors or enrichment altered cocaine choice, although not all individuals were affected and the effects were transient. Importantly, the data suggest that implementing positive changes in the environment produced effects that are clinically desirable. Understanding the behavioral and neurobiological mechanisms mediating sensitivity to environmental events in socially housed animals will lead to better treatment strategies for drug addiction.

Effects of chronic administration of dopamine D2‐like receptor agonists aripiprazole and (−)‐N‐propyl‐norapomorphine on food/cocaine choice in socially housed monkeys

Dopamine D2‐like receptor partial agonists have been suggested as treatments for substance abuse. The goal of this study was to characterize the effects of D2‐like receptor agonists on the relative reinforcing strength of cocaine using a food‐drug choice procedure in socially housed cynomolgus monkeys. In daily self‐administration sessions, monkeys chose between food pellets and cocaine injections (0.003–0.1 mg/kg). The available cocaine dose increased during the session to generate a full dose‐effect curve each day. The high‐efficacy agonist (−)‐N‐propyl‐norapomorphine [(−)‐NPA; 0.001–0.0056 mg/kg] or the lower‐efficacy agonist aripiprazole (ARI; 0.01–0.1 mg/kg) was administered for 5 days; self‐administration was examined on Day 1 and Day 5. At least one ARI dose decreased cocaine choice in most dominant monkeys, but did not affect or increased cocaine choice in subordinates. In contrast, (−)NPA was more effective in decreasing cocaine choice in subordinate monkeys, although increases in cocaine choice were observed in most monkeys. Tolerance was rarely observed across days; in general effects of both drugs were maintained or exacerbated over 5 days. Results suggest that ARI and (−)‐NPA produce qualitatively different effects on the reinforcing strength of cocaine, perhaps due to differing intrinsic efficacies, and that the effects are modulated by social rank. Support: DA12460, DA10584.

Response to cocaine, alone and in combination with methylphenidate, in cocaine abusers with ADHD

Attention deficit hyperactivity disorder (ADHD) is prevalent in adult cocaine abusers. Yet, it remains to be determined how the response to cocaine differs in cocaine abusers with ADHD compared to cocaine abusers without ADHD. Further, since ADHD is commonly treated with stimulants, such as methylphenidate (MPH), it is important to examine whether MPH maintenance alters the response to cocaine in cocaine abusers with ADHD. Thus, the first phase of this study compared the response to cocaine in adult cocaine abusers with ADHD to those without ADHD. The second phase assessed the effects of oral sustained-release methylphenidate (MPH-SR) maintenance (40 and 60 mg) on the response to cocaine only in those with ADHD. Cocaine abusers with ADHD ( N = 7) and without ADHD ( N = 7) who were not seeking treatment remained inpatient initially for 1 week, when the effects of cocaine alone were tested (Phase 1). Cocaine abusers with ADHD remained inpatient for an additional 3 weeks, during which the effects of cocaine during oral MPH-SR maintenance were tested (Phase 2). During cocaine fixed dosing sessions, participants received four injections of i.v. cocaine (0, 16 or 48 mg/70 kg), spaced 14 min apart. During cocaine choice sessions, participants had a choice between receiving i.v. cocaine (16 or 48 mg/70 kg) or two tokens, each exchangeable for US$ 2. Subjective effects related to ADHD symptoms (e.g. ratings of “Able to Concentrate”) were significantly lower in cocaine abusers with ADHD compared to those without ADHD when placebo cocaine was administered. Active cocaine produced similar increases in cardiovascular and positive subjective effects in both groups and there was no difference in cocaine choice between the two groups. These data suggest that the response to cocaine is not different between cocaine abusers with ADHD compared to those without ADHD. When the cocaine abusers with ADHD were maintained on MPH-SR, cardiovascular effects were increased, however, this did not warrant termination of any test session. Maintenance on MPH-SR decreased some of the positive subjective effects of cocaine. Further, maintenance on a high dose of MPH-SR decreased cocaine choice. Thus, oral MPH-SR is safe in combination with repeated cocaine doses and decreases some of the positive and reinforcing effects of cocaine in cocaine abusers with ADHD.

Effects of punishment on choice between cocaine and food in rhesus monkeys

Punishment is widely used in an effort to control drug-taking behavior; however, only a few preclinical studies have investigated the effects of punishment on drug self-administration. Such studies may contribute to more rational use of punishment to control drug use. To evaluate the effects of punishment on choice between cocaine and food in rhesus monkeys. Rhesus monkeys were trained under a concurrent-choice schedule of food delivery (1 g pellets, fixed-ratio 100 schedule) or cocaine injections (0-0.1 mg/kg per injection, fixed-ratio 10 schedule). Full cocaine choice dose-effect curves were determined under baseline conditions and under test conditions in which a putative punisher (intravenous histamine injection; 0.0032-0.032 mg/kg per injection) was paired with either food or cocaine delivery. Under baseline conditions, cocaine produced a dose-dependent increase in cocaine choice. Histamine functioned as a punisher of both food- and cocaine-maintained responding. Pairing histamine with food delivery reduced food choice, increased cocaine choice, and produced left shifts in the cocaine choice dose-effect curve. Conversely, pairing histamine with cocaine decreased cocaine choice, increased food choice, and produced right shifts in the cocaine choice dose-effect curve. The magnitude of histamine's punishing effects was directly related to histamine dose and probability of histamine delivery, and inversely related to the magnitude of the reinforcer. These results demonstrate that a primary effect of punishment in the context of food vs cocaine choice is not only a decrease in the behavior being punished, but also an increase in the unpunished alternative behavior.