PHARMACOLOGICAL SUBSTRATES OF AMPHETAMINE ADDICTION

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The primary goal of this ongoing study is to evaluate the role of dopamine (DA) in the subjective and behavioral effects of d-amphetamine in normal volunteers. Data from this study will be compared to a parallel study exploring the effects of dopaminergic pretreatments on responses to d- amphetamine in cocaine abusers, as well as on responses to nicotine in cigarette smokers. This study will be conducted according to a 2 (Agonist: d-amphetamine [AMP] or placebo [PLAC]) x 2 (Antagonist: haloperidol [HAL] or PLAC) x 2 (Challenge drug: AMP or PLAC) mixed within- and between subjects design. The pretreatment drugs will be a within- subjects manipulation, whereas the challenge drug condition will vary between subjects. All drugs will be administered under double-blind conditions, with the order of conditions counterbalanced across subjects. Each subject will attend four laboratory sessions, conducted once per week. We hypothesize that both haloperidol and d-amphetamine will attenuates subjective (e.g., euphorigenic) responses to the challenge dose of d- ampheatmine, but that combined pretreatment with haloperidol and d- amphetamine will attenuate responses to the challenge dose to a significantly greater extent. Furthermore, we expect the combined pretreatment condition to produce a better side effects protocol than either pretreatment drug alone. Studies with laboratory animals have consistently demonstrated a role for dopamine (DA) in the effects of amphetamine related to its abuse, but to date no dopaminergic agents have proven effective in treating stimulant abuse. The lack of efficacy of dopaminergic agents may relate to differences in the role of DA in animals as compared to humans, or to limitations in the doses of the treatment drugs that can be tested. This study will directly address both issues. We will determine whether the effects of a dopaminergic agonist and antagonist on responses to amphetamine in humans suggest a significant role for DA in humans. In addition, we will explore the effects of an agonist/antagonist combination on responses to amphetamine. To date, DA agonists and antagonists have not been well tolerated at the doses required for treatment of stimulant addiction; DA agonists can produce unpleasant side effects and may have abuse potential of their own, and DA antagonists are aversive and can produce long lasting and permanent motor side effects after prolonged use. Based on previous work with nicotinic agonist/antagonist combinations and smoking cessation, the combined drug treatment would be expected to have less abuse liability and to produce fewer side effects than either drug alone, and should block the positive rewarding effects (e.g., euphoria) of d-amphetamine. The potential usefulness of this treatment approach for stimulant drug abuse cannot be underestimated since no effective treatments are available at this time.