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Three experiments demonstrated the validity of studying drug reinforcement in humans by using a novel Multiple-Choice Procedure. The distinguishing characteristic of the procedure is that it arranges intermittent reinforcement for choices between pairs of potential reinforcers (e.g., drug vs. money). A series of manipulations was conducted, the outcomes of which were predicted on the basis of a well-established literature on operant behavior maintained by food and drug. Specifically, the experiments manipulated reinforcer availability (i.e., extinction), deprivation versus satiation, and reinforcer magnitude in cigarette smokers and demonstrated the predicted changes in cigarette reinforcement as measured by the Multiple-Choice Procedure. Finally, the reinforcer magnitude manipulation was concurrently studied using a conventional two-option choice procedure and the results were shown to be virtually identical to those with the Multiple-Choice Procedure.

Studies conducted with nonhuman laboratory animals have consistently shown that atypical antipsychotics that are mixed dopamine and serotonin antagonists attenuate the discriminative-stimulus effects of amphetamine. In the present experiment, eight healthy humans learned to discriminate 15 mg of oral d-amphetamine. After acquiring the discrimination (i.e., Ն80% correct responding on four consecutive days), the effects of a range of doses of d-amphetamine (0, 2.5, 5, 10, and 15 mg), alone and after pretreatment with risperidone (0 and 1 mg), a D 2 dopamine and 5-hydroxytryptamine (5-HT) 2 serotonin antagonist, were assessed. d-Amphetamine alone functioned as a discriminative stimulus and produced stimulant-like selfreported drug effects (e.g., increased ratings of "like drug"). These effects were generally a function of dose. Risperidone alone did not occasion d-amphetamine-appropriate responding, but impaired performance. Risperidone pretreatment significantly attenuated the discriminative-stimulus effects of damphetamine, and some of the self-reported drug effects. The results of the present experiment suggest that combining drugdiscrimination and self-reported drug-effect questionnaires may be an effective strategy for assessing the behavioral effects of agonist-antagonist interactions. Future studies should compare the behavioral effects of d-amphetamine after pretreatment with a selective D 2 dopamine (e.g., haloperidol) or 5-HT 2 serotonin (e.g., ritanserin) antagonist to determine the relative contribution of dopamine and serotonin systems in mediating the behavioral effects of stimulants in humans. The results of these studies might guide the development of a pharmacotherapy for the treatment of amphetamine abuse/ dependence. The results of preclinical behavioral pharmacology experiments suggest that atypical antipsychotics such as risperidone, olanzapine, and clozapine consistently attenuate the discriminative-stimulus effects of amphetamine (Kilbey and Ellinwood, 1979;Nielsen and Jepsen, 1985;Meert, 1991Meert, , 1996Arnt, 1992Arnt, , 1996Mechanic et al., 2002). The discriminative-stimulus effects of drugs in animals are thought to be a model of the self-reported effects of drugs in humans. In one experiment, the discriminative-stimulus effects of d-amphetamine (1.0 mg/kg) were tested alone and after pretreatment with risperidone (0.04 -2.5 mg/kg), olanzapine (0.0025-2.5 mg/kg), and clozapine (0.08 -2.5 mg/kg) in rats trained to discriminate 1.0 mg/kg d-amphetamine (Arnt, 1996). Risperidone, olanzapine, and clozapine dose dependently decreased

Individual differences that may contribute to vulnerability to abuse drugs have been identified. Sensation-seeking status has been shown to influence both vulnerability to drug use and response to acute drug administration. The purpose of the present experiment was to examine the reinforcing effects of d-amphetamine in high and low sensation-seeking subjects using a modified progressive-ratio procedure. A battery of subject-rated, performance, and cardiovascular measures was also included to better characterize the effects of d-amphetamine in these groups. Ten high sensation seekers and ten low sensation seekers that were matched for education, age, drug use, height, and weight, first sampled doses of d-amphetamine (0, 8, and 16 mg). In subsequent sessions, subjects were offered the opportunity to work for the sampled dose on a modified progressive-ratio procedure. d-Amphetamine functioned as a reinforcer and produced prototypical stimulant-like effects (e.g., increased subject-ratings of Like Drug, enhanced performance, and increased heart rate). High sensation seekers were more sensitive than low sensation seekers to the reinforcing and some of the subject-rated effects of d-amphetamine. The results of the present experiment extend those of previous findings by demonstrating that the reinforcing effects of damphetamine vary as a function of the biologically based sensation-seeking personality trait. These results suggest that increased stimulant drug use and abuse among high sensation seekers may be related, in part, to increased sensitivity to the reinforcing effects of stimulants among these individuals.

Rationale-While the personality dimensions of novelty seeking and sensation seeking are associated with drug abuse vulnerability, the mechanisms associated with this vulnerability remain obscure.Objective-This study examined the behavioral effects of d-amphetamine in healthy volunteers scoring in the upper and lower quartiles based on age-and gender-adjusted population norms on the impulsive Sensation-Seeking Scale (SSS) of the Zuckerman-Kuhlman personality questionnaire (ZKPQ).Method-Participants completed 7-day outpatient studies examining the subjective, performance, and cardiovascular effects of d-amphetamine (0, 7.5, and 15 mg/70 kg, p.o.) under double-blind conditions according to a randomized block design. Performance tasks included behavioral measures of impulsivity, including attention, inhibition, and risk-taking behavior.Results-No differences in baseline performance or d-amphetamine effects on measures of attention, inhibition, and risk-taking behavior were observed. High impulsive sensation seekers

The discriminative-stimulus and participate-rated effects of a range of doses of d-amphetamine (2.5-20 mg), methylphenidate (5-40 mg), bupropion (50-400 mg), and triazolam (0.0625-0.5 mg) were tested in 5 humans trained to discriminate between oral d-amphetamine (20 mg) and placebo. d-Amphetamine and methylphenidate generally dose dependently increased drug-appropriate responding. Bupropion and triazolam on average occasioned less than or equal to 40% drug-appropriate responding. d-Amphetamine, methylphenidate, and bupropion produced stimulant-like participant-rated effects, while triazolam produced sedative-like effects. These results further demonstrate that the acute behavioral effects of d-amphetamine and methylphenidate overlap extensively in humans, which is concordant with preclinical studies. Bupropion produced some d-amphetamine-like, participant-rated drug effects but did not occasion significant levels of d-amphetamine-appropriate responding. These findings are concordant with previous findings of a dissociation between the discriminative-stimulus and participant-rated effects of drugs.

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