Andrea R. Vansickel

Aripiprazole Attenuates the Discriminative-Stimulus and Subject-Rated Effects of D -Amphetamine in Humans

The results of animal research suggest that the use of partial agonists at dopamine (DA) D2 receptors may be an effective strategy for the treatment of stimulant dependence. Aripiprazole is an atypical antipsychotic that has partial agonist activity at D2 receptors. In this experiment, seven human participants with a history of nontherapeutic stimulant use learned to discriminate 15 mg oral D-amphetamine. After acquiring the discrimination (ie ⩾80% correct responding on four consecutive sessions), the effects of a range of doses of D-amphetamine (0, 2.5, 5, 10, and 15 mg), alone and in combination with aripiprazole (0 and 20 mg), were assessed. D-Amphetamine alone functioned as a discriminative stimulus, produced prototypical subject-rated drug effects (eg increased ratings of Active, Alert, Energetic) and elevated cardiovascular indices. These effects were generally a function of dose. Aripiprazole alone did not occasion D-amphetamine-appropriate responding or produce subject-rated effects, but modestly impaired performance. Administration of aripiprazole significantly attenuated the discriminative-stimulus and cardiovascular effects of D-amphetamine, as well as some of the subject-rated drug effects. These data are consistent with previous preclinical findings and suggest that DA partial agonists deserve further evaluation as potential pharmacotherapies in the management of stimulant dependence. Future studies should investigate the ability of aripiprazole or related compounds to attenuate the behavioral effects of stimulants associated with a greater degree of dependence, such as methamphetamine or cocaine, in dependent individuals.

Discriminative-stimulus, subject-rated, and physiological effects of methamphetamine in humans pretreated with aripiprazole.

Methamphetamine is thought to produce its behavioral effects by facilitating release of dopamine, serotonin (5-HT) and norepinephrine. Results from animal studies support this notion, whereas results from human laboratory studies have not consistently demonstrated the importance of monoamine systems in the behavioral effects of methamphetamine. Human drug-discrimination procedures are well suited to assess neuropharmacological mechanisms of the training drug by studying pharmacological manipulation. In this human laboratory study, 6 participants with a history of recreational stimulant use learned to discriminate 10 mg oral methamphetamine. After acquiring the discrimination (ie, ≥80% correct responding on 4 consecutive sessions), the effects of a range of doses of methamphetamine (0, 2.5, 5, 10, and 15 mg), alone and in combination with 0 and 20 mg aripiprazole (a partial agonist at D2 and 5-HT1A receptors), were assessed. Methamphetamine alone functioned as a discriminative stimulus, produced prototypical stimulant-like subject-rated drug effects (eg, increased ratings of Good Effects, Talkative-Friendly, and Willing to Pay For) and elevated cardiovascular indices. These effects were generally a function of dose. Aripiprazole alone did not occasion methamphetamine-appropriate responding or produce subject-rated effects but modestly impaired performance. Administration of aripiprazole significantly attenuated the discriminative-stimulus and cardiovascular effects of methamphetamine, as well as some of the subject-rated drug effects. These results indicate that monoamine systems likely play a role in the behavioral effects of methamphetamine in humans. Moreover, given the concordance between past results with d-amphetamine and the present findings, d-amphetamine can likely serve as a model for the pharmacological effects of methamphetamine.Abbreviations: A - Amphetamine Scale, ANOVA - analysis of variance, ARCI - Addiction Research Center Inventory, BG - benzedrine group, DA - dopamine, DAST - Drug Abuse Screening Test, DSST - Digit-Symbol-Substitution Test, LSD - Lysergic acid diethylamide, MAST - Michigan Alcohol Screening Test, MBG - morphine-benzedrine group, PCAG - pentobarbital, chlorpromazine, alcohol group, 5-HT - serotonin, THC - tetrahydrocannabinol

Human Sex Differences in d-Amphetamine Self-Administration

UNLABELLED Women and men may respond differently to the effects of stimulants such as amphetamine and cocaine. AIM In order to assess potential sex differences in the reinforcing effects of d-amphetamine, a retrospective-analysis was conducted on data collected from three studies that employed similar d-amphetamine self-administration procedures and used identical subject-rated drug-effect measures. METHODS Data from 10 women and 15 men were included in the analysis. In all studies, participants sampled placebo, low (8-10 mg) or high (16-20 mg) dose oral d-amphetamine. Following sampling sessions, participants worked for capsules containing one eighth of the previously sampled dose on a modified progressive-ratio schedule of reinforcement. We hypothesized that women and men would be differentially sensitive to the reinforcing effects of d-amphetamine. A two-way mixed-model analysis of variance (sex and dose) and planned comparisons were used in the statistical analyses. RESULTS The low dose of d-amphetamine functioned as a reinforcer in women, but not men, whereas the high dose of d-amphetamine functioned as a reinforcer in men, but not women. Men self-administered significantly more capsules under the high dose condition than women. CONCLUSION The results of this study suggest that men are more sensitive to the reinforcing effects of a high dose of d-amphetamine than women. Future research is needed that determines prospectively the reinforcing effects of weight-adjusted doses of d-amphetamine in women and men while controlling for menstrual cycle phase.

Similar discriminative-stimulus effects of D-amphetamine in women and men.

The results of controlled non-human animal and human laboratory studies are mixed regarding whether women and men respond differently to stimulant drugs. In order to assess potential gender differences in the effects of D-amphetamine, we conducted a retrospective analysis of six studies conducted in our laboratory that used identical procedures and measures. Thirteen women and fourteen men learned to discriminate 15 mg oral D-amphetamine. After acquiring the discrimination (i.e., >or=80% correct responding on 4 consecutive sessions), the effects of a range of doses of D-amphetamine (0, 2.5, 5, 10, and 15 mg) alone and in combination with other drugs, were assessed. Only data from sessions in which D-amphetamine was administered alone were included in this analysis. D-amphetamine functioned as a discriminative stimulus and dose-dependently increased drug-appropriate responding. Women and men did not differ in their ability to discriminate D-amphetamine. Women and men differed on participant-ratings of high (women<men), nausea (women>men) and sluggish (women<men), women also experienced greater increases in diastolic pressure than men. Because the results of this study may have been confounded by the training procedures, future research should use other behavioral arrangements (e.g. drug self-administration) to determine if women and men respond differently to the effects of D-amphetamine.

Acute d-amphetamine pretreatment does not alter stimulant self-administration in humans.

Recent clinical research indicates that d-amphetamine is effective in treating cocaine and methamphetamine dependence. There is concern, however, with the use of d-amphetamine as a pharmacotherapy because acute administration of d-amphetamine decreases inhibition in cocaine-using individuals and may increase drug-taking behavior. The purpose of the present experiment was to determine whether acute d-amphetamine pretreatment would alter the reinforcing, subject-rated, and cardiovascular effects of d-amphetamine. To this end, 7 human volunteers first sampled doses of oral d-amphetamine (0, 8, and 16 mg). These doses engender moderate drug taking and were selected to avoid a ceiling or floor effect. Volunteers were then allowed to self-administer these sampled doses using a modified progressive-ratio procedure in two sessions in which they received pretreatment with either 0 or 15 mg oral d-amphetamine 2 h prior to completing the modified progressive-ratio procedure. d-Amphetamine produced prototypical stimulant-like effects (e.g., increased ratings of stimulated, elevated blood pressure) and maintained responding on the modified progressive-ratio schedule. Pretreatment with 15 mg oral d-amphetamine also produced prototypical stimulant-like effects, but failed to alter break points for d-amphetamine on the modified progressive-ratio procedure relative to placebo pretreatment. These results indicate that acute d-amphetamine pretreatment does not increase stimulant self-administration.

Effects of Potential Agonist-Replacement Therapies for Stimulant Dependence on Inhibitory Control in Cocaine Abusers

Two experiments were conducted to determine whether methylphenidate or modafinil, two potential pharmacotherapies for stimulant dependence, would impair inhibitory behavior in cocaine users. Eleven cocaine abusers were administered methylphenidate (0, 15, 30, and 45 mg) or modafinil (0, 150, 300, and 450 mg) across four experimental sessions. A cued go–no-go task was used to measure response execution and inhibition. Subjective and cardiovascular measures were collected. Neither methylphenidate nor modafinil impaired inhibitory control, but produced prototypical subject-rated and cardiovascular effects. The results of these studies may have implications for the use of these drugs as agonist-replacement therapies for stimulant dependence.

The influence of acute varenicline administration on smoking and eating behavior in humans

Varenicline (Chantix) is a novel smoking-cessation agent that acts at a number of nicotinic acetylcholine receptors. The aim of this study was to determine the behavioral effects of acute varenicline administration in human subjects. The effects of doses of varenicline (0.5, 1 and 2 mg), methylphenidate (40 mg; positive control) and placebo were assessed in 8 (7 males, 1 female) cigarette smokers. Staggered, double blind dosing was used to examine eating and smoking behavior during the peak effects of varenicline and methylphenidate. Starting at the published time to peak plasma levels of these drugs, subjects were allowed to smoke and eat ad libitum for 4 h. Acute varenicline was devoid of behavioral effects. Methylphenidate produced prototypical stimulant-like effects (e.g., increased smoking behavior; decreased caloric intake). The present results indicate that acute varenicline administration does not alter smoking behavior although the low number of subjects limits the ability to detect small effects. Future research should examine the effects of chronic varenicline on smoking and eating behavior in humans, particularly using operant techniques to determine whether varenicline alters the reinforcing effects of cigarettes and food in humans.

Stimulant-induced changes in smoking and caloric intake: influence of rate of onset.

Rate-of-onset modulates the subject-rated effects of stimulants. Results of two studies from our laboratory demonstrate that immediate-release methylphenidate increases smoking and decreases caloric intake. Whether rate-of-onset influences the effects of methylphenidate on smoking and eating is unknown. The present experiment examined the influence of a range of doses of immediate- (7.5-30 mg) and sustained-release (18-72 mg) methylphenidate as well as placebo on smoking and eating. Eight cigarette smokers participated. A double-dummy drug administration procedure was used to maintain the double blind because immediate-release methylphenidate produces peak plasma concentrations 1.5-2 h and the sustained-release formulation produces peak plasma concentrations 6-8 h after oral administration. Smoking and eating were assessed for 4 h across the predicted peak effects of both methylphenidate formulations. Measures of smoking included total cigarettes, puffs, and carbon monoxide levels. Snacks and decaffeinated beverages were available ad libitum and caloric intake was monitored during the four-hour smoking session. Immediate- and sustained-release methylphenidate increased smoking and decreased caloric intake. The effects of methylphenidate generally did not vary as a function of formulation. The results of this study may have important implications for the treatment of disorders that require stimulant medications. Smoking should be monitored in patients that are prescribed stimulant medications, regardless of the formulation type.

Discriminative-stimulus effects of triazolam in women and men.

Benzodiazepines are among the most commonly prescribed therapeutics. Women seem to be more likely than men to be prescribed a benzodiazepine and to use benzodiazepines for nonmedical reasons; they also appear to be at higher risk for benzodiazepine dependence. The aim of the present investigation was to assess the acute behavioral effects of a benzodiazepine in women and men. To accomplish this, 13 volunteers (6 women, 7 men) first learned to discriminate 0.375-mg triazolam, a triazolobenzodiazepine hypnotic. After acquiring the discrimination, (i.e., >80% correct responding on 4 consecutive sessions) a range of doses of triazolam (0, 0.0625, 0.125, 0.25, and 0.375 mg) were tested in each participant. Triazolam dose dependently increased drug-appropriate responding and subject ratings of sedation and impaired performance (i.e., significant effect of dose). The women and men did not differ significantly on any measure. The results of the present experiment suggest that women and men are not differentially sensitive to the behavioral effects of triazolam.