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High Dose Pimozide Does Not Block Amphetamine-Induced Euphoria in Normal Volunteers

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Abstract

Studies with laboratory animals have shown that dopamine antagonists block the rewarding and interoceptive effects of amphetamine. However, studies using dopamine antagonists with humans have not consistently shown blockade of amphetamine-induced euphoria. The unexpected results in humans may relate to the low doses of dopamine antagonists tested. The purpose of this study was to evaluate the effects of a relatively high acute dose (8 mg) of the dopamine receptor antagonist, pimozide, on responses to d-amphetamine (10 and 20 mg) in normal volunteers. Male and female volunteers (N = 12) attended six sessions on which they received pimozide or placebo (7:30 am) followed by d-amphetamine or placebo (9:30 am). Subjective, physiological and behavioral measures were obtained at baseline (7:15 am) and hourly over a 5 h period. d-Amphetamine and pimozide, when administered alone, produced significant and opposite effects on ratings of Elation and Vigor, as well as on psychomotor performance and physiological measures. However, there were few significant interactions between pimozide and d-amphetamine. Thus, pimozide failed to consistently antagonize the effects of d-amphetamine, even at doses of pimozide that had behavioral and physiological effects when administered alone. Possible reasons for lack of robust dopamine antagonism of amphetamine-induced euphoria in humans are discussed.

Section snippets

Subjects

Fifteen normal, healthy males (N = 6) and females (N = 9) between the ages of 21 and 35 were recruited from the University of Chicago community. Non-smokers who consumed at least one alcoholic beverage per week came to the laboratory for a physical examination, electrocardiogram (ECG), and face-to-face psychiatric interview. Cigarette smokers were excluded from the study to minimize potential interactions between nicotine and the study drugs, and to eliminate the possibility that smoking

Subject Characteristics

Three of the original 15 subjects (2 males and 1 female) experienced unpleasant side effects from pimozide and dropped out of the study (see below). The remaining 12 subjects (5 males and 7 females) were a mean age of 24.7 years old, and drank an average of 4.1 alcoholic beverages per week (range = 1-10). In general, subjects were only occasional users of recreational drugs, typically marijuana.

d-Amphetamine

d-Amphetamine produced robust and dose-related effects on a number of measures when administered

Discussion

The results of the study suggest that the lack of effect of pimozide in our previous studies was not due to the doses of pimozide tested. Even though the dose of pimozide used in this study (8 mg) produced significant effects when administered alone (e.g., decreases in Elation, Positive Mood, and Vigor, and increases in Confusion), it did not consistently antagonize responses to d-amphetamine. Therefore, even a clearly behaviorally active dose of pimozide did not attenuate responses to a low or

Acknowledgements

This research was funded by a grant from the National Institute on Drug Abuse (DA02812). The authors wish to thank Sara Hartman for her help in subject recruitment and Matthew Clark and Angela Justice for their diligence in data entry and preparation. The authors are also grateful to Dr. Jed E. Rose for his suggestions regarding data analysis.

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