Joshua A. Lile

Self-administration of two long-acting monoamine transport blockers in rhesus monkeys

Abstract. Rationale: 2β-propanoyl-3β-(4-tolyl)-tropane (PTT) is a cocaine analog with high affinity at and selectivity for the dopamine transporter (DAT). 2β-propanoyl-3β-(2-naphthyl)-tropane (HD-23), like cocaine, binds with approximately equal affinity to the DAT, the serotonin transporter, and the norepinephrine transporter but has over a 100-fold higher affinity for these monoamine transporters than cocaine. The reinforcing effects of these drugs have not been evaluated in cocaine-naïve non-human primates. Objective: The primary goal of the present study was to examine the reinforcing effects of PTT and HD-23 in rhesus monkeys before and after a history of intravenous cocaine self-administration. Methods: Monkeys (n=4) were initially trained to respond under a fixed-ratio 30 schedule of food presentation. When responding was stable, saline, PTT (0.001–0.03xa0mg/kg per injection), and HD-23 (0.0003–0.0056xa0mg/kg per injection) were made available for self-administration for least five sessions per dose. Next, a cocaine dose-effect function (0.0003–0.3xa0mg/kg per injection) was determined and then PTT and HD-23 dose-effect curves were redetermined. Results: When substituted for food, neither drug maintained responding significantly higher than saline during 3-h (PTT and HD-23) or 22-h (PTT) sessions. After determining the cocaine dose-effect function, PTT and HD-23 functioned as reinforcers in one of four monkeys, when substituted for food during daily 3-h sessions. However, when PTT was made available during 22-h sessions, it had reinforcing effects in three of the four monkeys tested. Conclusions: These results indicate that the reinforcing effects of PTT were slightly modified by a brief history of cocaine reinforcement, and that the weak reinforcing effects were most apparent when the drug was available under unlimited-access conditions.

The effects of eticlopride and the selective D3-antagonist PNU 99194-A on food- and cocaine-maintained responding in rhesus monkeys.

The dopamine D3 receptor is mainly expressed in regions of the brain associated with the limbic system. D3 receptor blockade may antagonize cocaine reinforcement while producing less severe extrapyramidal side effects than blockade of D2 receptors. The purpose of the present studies was to evaluate the effects of a selective D3 receptor antagonist and a non-selective D2/D3 receptor antagonist on food- and cocaine-maintained responding under two schedules of cocaine self-administration. Adult male rhesus monkeys were trained to respond under multiple schedules of food (1.0 g pellets) and cocaine (0.01-0.3 mg/kg/injection) presentation. In one experiment (n=4), the schedule was a fixed-interval (FI) 3-min and a second study (n=6) was conducted using a second-order fixed-ratio 5 (FI 6-min:S) schedule. The D3 antagonist PNU 99194-A (0.3-3.0 mg/kg), which is 14-fold selective for D3 relative to D2 receptors, or the D2/D3 antagonist eticlopride (0.001-0.03 mg/kg) was administered immediately prior to the experimental session for at least 5 consecutive sessions. Under the multiple FI 3-min schedule of food and cocaine presentation, PNU 99194-A and eticlopride decreased food- and cocaine-maintained responding in a dose-dependent manner and irrespective of cocaine dose. Under the multiple second-order schedule of food and cocaine presentation, at least one dose of PNU 99194-A and eticlopride decreased cocaine- and food-maintained responding. These findings indicate that PNU 99194-A can decrease operant responding in monkeys, but not in a manner that would suggest selectivity of cocaine- over food-maintained responding. Future studies with more selective D3 antagonists are needed to better address the role of this receptor subtype in cocaine addiction.

Separate and Combined Effects of Naltrexone and Extended-Release Alprazolam on the Reinforcing, Subject-Rated, and Cardiovascular Effects of Methamphetamine.

Abstract Opioid antagonists (eg, naltrexone) and positive modulators of &ggr;-aminobutyric acid type A receptors (eg, alprazolam) each modestly attenuate the abuse-related effects of stimulants. A previous study demonstrated that acute pretreatment with the combination of naltrexone and alprazolam attenuated a greater number of the subject-rated effects of D-amphetamine than the constituent drugs alone. This study tested the hypothesis that maintenance on the combination of naltrexone and alprazolam XR would attenuate the reinforcing and “positive” subject-rated effects of methamphetamine to a greater extent than the constituent drugs alone. Eight non–treatment-seeking, stimulant-using individuals completed a placebo-controlled, crossover, double-blind inpatient protocol. Participants were maintained on naltrexone (0 and 50 mg), alprazolam XR (0 and 1 mg), and the combination of naltrexone and alprazolam XR (50 mg and 1 mg, respectively) for 6 to 7 days. Under each maintenance condition, participants sampled intranasal doses of methamphetamine (0, 10, and 30 mg), and were then offered the opportunity to work for the sampled dose on a modified progressive-ratio procedure. Subject-rated drug effect questionnaires, psychomotor, and physiology assessments were collected. Intranasal methamphetamine functioned as a reinforcer and produced prototypical stimulant-like “positive” subject-rated and physiological effects. Maintenance on naltrexone significantly decreased the reinforcing, but not subject-rated drug effects of 10-mg methamphetamine. Alprazolam XR and the combination of naltrexone and alprazolam XR did not impact methamphetamine self-administration or subject-rated drug effects. The results support the continued evaluation of naltrexone for methamphetamine dependence, as well as the identification of other drugs that enhance its ability to reduce drug-taking behavior.

Effects of the dopamine reuptake inhibitor PTT on reinstatement and on food- and cocaine-maintained responding in rhesus monkeys

RationaleHigh-affinity, slow-onset, long-acting dopamine transporter (DAT) inhibitors are being considered as potential agonist replacement therapies for cocaine addiction, and therefore the ability of these drugs to reinstate cocaine seeking and to selectively decrease cocaine-maintained responding should be assessed.ObjectivesThe purpose of these experiments was to evaluate the effects of the active enantiomer of a high-affinity, slow-onset, long-acting DAT inhibitor, (−)2β-propanoyl-3β-(4-tolyl)-tropane (PTT), and cocaine on food- and cocaine-maintained responding and on extinguished responding previously maintained by cocaine in non-human primates using a within-subjects design.MethodsRhesus monkeys (n=3) responded under a multiple fixed-ratio schedule of food (1xa0g) and drug reinforcement, and cocaine dose-response curves (saline, 0.003–0.3xa0mg/kg per injection) were determined. The effects of pretreatment with (−)PTT (0.001–0.056xa0mg/kg, IV) and cocaine (0.03–0.3xa0mg/kg, IV) were determined when the dose of cocaine that maintained peak response rates (0.03xa0mg/kg per injection) or saline was available.Results(−)PTT and cocaine reduced cocaine intake; (−)PTT affected cocaine self-administration only at doses that also decreased food-maintained responding. (−)PTT and cocaine reinstated responding that was previously reinforced by cocaine at lower doses than were necessary to decrease cocaine-maintained responding. For all studies, PTT was at least 1.0 log-unit more potent than cocaine. Compared to cocaine, PTT had a longer duration of action in all behavioral measures.ConclusionsThese results suggest that PTT would decrease cocaine use, but only at doses that disrupted other behaviors. It appears that the potency of this class of drugs to reinstate cocaine-seeking is substantially greater than their potency at decreasing cocaine self-administration.

Separate and combined effects of gabapentin and [INCREMENT]9-tetrahydrocannabinol in humans discriminating [INCREMENT]9-tetrahydrocannabinol.

The aim of the present study was to examine a potential mechanism of action of gabapentin to manage cannabis-use disorders by determining the interoceptive effects of gabapentin in cannabis users discriminating [INCREMENT]9-tetrahydrocannabinol ([INCREMENT]9-THC) using a pharmacologically selective drug-discrimination procedure. Eight cannabis users learned to discriminate 30u2009mg oral [INCREMENT]9-THC from placebo and then received gabapentin (600 and 1200u2009mg), [INCREMENT]9-THC (5, 15, and 30u2009mg), and placebo alone and in combination. Self-report, task performance, and physiological measures were also collected. [INCREMENT]9-THC served as a discriminative stimulus, produced positive subjective effects, elevated heart rate, and impaired psychomotor performance. Both doses of gabapentin substituted for the [INCREMENT]9-THC discriminative stimulus and engendered subjective and performance-impairing effects that overlapped with those of [INCREMENT]9-THC when administered alone. When administered concurrently, gabapentin shifted the discriminative-stimulus effects of [INCREMENT]9-THC leftward/upward, and combinations of [INCREMENT]9-THC and gabapentin generally produced larger effects on cannabinoid-sensitive outcomes relative to [INCREMENT]9-THC alone. These results suggest that one mechanism by which gabapentin might facilitate cannabis abstinence is by producing effects that overlap with those of cannabinoids.

The relative reinforcing strength of methamphetamine and D-amphetamine in monkeys self-administering cocaine.

Epidemiological data indicate that rates of methamphetamine misuse surpass those of D-amphetamine, but self-administration research in animals and humans has not typically demonstrated differences in their reinforcing effects. The present study used a within-session, exponentially increasing progressive-ratio schedule and extended-access conditions to assess the relative reinforcing strength of D-amphetamine and methamphetamine in rhesus monkeys (n=5) trained to self-administer cocaine. A range of doses of methamphetamine (0.003–0.1 mg/kg/injection), D-amphetamine (0.003–0.1 mg/kg/injection), and cocaine (0.003–0.3 mg/kg/injection) was tested to capture the ascending and descending limbs of the dose-effect functions. Each drug functioned as a reinforcer, but the peak number of self-administered D-amphetamine injections was significantly lower compared with methamphetamine and cocaine; the peak number of self-administered injections of cocaine and methamphetamine did not differ. Although differences in availability and other social factors likely impact relative rates of abuse, the present data suggest that the greater reinforcing strength of methamphetamine contributes to its increased use compared with D-amphetamine.

First- versus last-session substitution: an evaluation of the reinforcing effects of cocaine and the cocaine analogue 2beta-propanoyl-3beta-(4-tolyl)-tropane.

Research has shown that many variables influence the reinforcing effects of drugs. The purpose of the present study was to compare the reinforcing effects of cocaine and the long-acting cocaine analogue 2beta-propanoyl-3beta-(4-tolyl)-tropane (PTT) in rhesus monkeys during the 1st versus the last day of substitution. When PTT and cocaine were initially substituted for food or the training dose of cocaine, a large number of injections were self-administered. However, when the 1 st day of substitution was compared with the last day, the number of injections obtained with PTT but not cocaine were significantly lower. This effect was observed under different schedule conditions and in cocaine-naive and cocaine-experienced monkeys. These results suggest that when studying long-acting cocaine analogues, unlike cocaine itself, quantitative differences may be seen early in substitution testing compared with stable performance after multiple-session substitution.

Influence of tiagabine maintenance on cannabis effects and related behaviors in daily cannabis users.

No medications are approved for cannabis use disorder (CUD). Gamma-aminobutyric acid (GABA) reuptake is modulated by cannabinoid (CB) receptor agonists, and there are shared effects between CB agonists and the GABA reuptake inhibitor tiagabine. This overlapping neuropharmacology suggested that tiagabine might be useful for CUD. The study determined the ability of tiagabine maintenance to reduce cannabis self-administration using a placebo-controlled, double-blind, counterbalanced, within-subjects design. Nontreatment-seeking daily cannabis users (N = 12; 3 female, 9 male) completed two 12-day outpatient maintenance phases (0 or 12 mg of tiagabine/day). Each phase consisted of a safety session, 7 maintenance days, and 4 experimental sessions. During experimental sessions, maintenance continued and participants completed two 2-day blocks of sampling and self-administration sessions to determine the reinforcing effects of smoked cannabis (0% and 5.9% &Dgr;9-tetrahydrocannabinol). Naturalistic cannabis use, the subjective, performance and physiological response to cannabis, as well as side effects, sleep quality, craving, other self-reported substance use, and observer ratings were also measured. Cannabis functioned as a reinforcer and produced prototypical effects (e.g., increased heart rate and ratings of “high”), but tiagabine generally did not impact the effects of cannabis, or alter naturalistic use. Furthermore, tiagabine produced small, but significant, increases on 2 subscales of a Marijuana Craving Questionnaire, and reductions in both the amount of time slept in the past 24 hr and ratings of positive mood upon awakening. These human laboratory results from a sample of nontreatment-seeking cannabis users do not support the potential efficacy of 12 mg of tiagabine as a stand-alone pharmacotherapy for CUD.

A Prototypical First-Generation Electronic Cigarette Does Not Reduce Reports of Tobacco Urges or Withdrawal Symptoms among Cigarette Smokers.

It is unknown whether first-generation electronic cigarettes reduce smoking urges and withdrawal symptoms following a 24u2009h deprivation period. This study tested whether a first-generation electronic cigarette reduces smoking urges and withdrawal symptoms in cigarette smokers. Following 24u2009h of tobacco deprivation, using a within-subjects design, eight nontreatment seeking tobacco cigarette smokers (3 females) administered 10 puffs from a conventional cigarette or a first-generation electronic cigarette containing liquid with 0, 8 or 16u2009mg/ml nicotine. Conventional cigarettes ameliorated smoking urges and electronic cigarettes did not, regardless of nicotine concentration. First-generation electronic cigarettes may not effectively substitute for conventional cigarettes in reducing smoking urges, regardless of nicotine concentration.