The purpose of this ongoing study is twofold: First, we will explore the role of dopamine in the subjective rewarding effects of nicotine. We will assess the role of dopamine by investigating the effects of pretreatment with a dopamine agonist and an antagonist on acute responses to smoking in a laboratory study. In a separate study that is part of the same protocol, we will explore the effects of these same pretreatment agents on responses to dextroamphetamine, a drug known to exert its abuse potential via the dopamine system. We will compare the apparent role of dopamine in the effects of nicotine to those of dextroamphetamine, which will serve as a positive control. The second purpose of this study is to explore the effects of a novel pharmacotherapeutic approch to treating substance abuse, the use of an agonist in combination with an antagonist. Previous studies have shown that the nicotine patch in combination with the nicotine antagonist, mecamylamine, blocks smoking satisfaction and reduces rates of ad lib smoking to a significantly greater extent than either nicotine alone or mecamylamine alone. The extent to which this promising strategy applies to other neurotransmitter systems (i.e., dopamine) and to other drugs of abuse (i.e., dextroamphetamine) is not known. As a first step, we will explore the effects of a dopamine agonist in combination with an antagonist on responses to nicotine and to dextroamphetamine in the laboratory. We hypothesize that the combined agonist and antagonist will block the rewarding effects of both nicotine and dextroamphetamine to a greater extent than either agonist alone or antagonist alone treatments. Initially, we proposed to test bromocriptine as the agonist and haloperidol as the antagonist. Because bromocriptine produced some expected but unpleasant side effects, we will use dextroamphetamine as the dopamine agonist for the remainder of the study. Subjects in each study attend four laboratory sessions during which they smoke nicotine- containing and denicotinized cigarettes after receiving treatment with dextroamphetamine, haloperidol, dextroamphetamine plus haloperidol, or placebo. Subejcts will rate each cigarette type in terms of smoking satisfaction, craving reduction, and reduction of smoking withdrawal symptoms. In addition, heart rate, blood pressure, mood and cognitive performance will be assessed at regular intervals during the session. The procedures are identical in the study in which dextroamphetamine is the challenge drug; Subjects will attend four sessions on which they will receive each of the pretreatment conditions and will rate responses to a challenge dose of dextroamphetamine on dimensions of mood, and heart rate, blood pressure, and cognitive performance will be measured. In both studies, blood samples will also be collected periodically to assess plasma levels of the study drugs.
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