DRIVE TO SMOKE AND DOPAMINE BLOCKADE

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Nicotine's enhancement of transmission in central dopaminergic pathways may be a primary reinforcing mechanism which drives smoking behavior. To explore this possibility we propose to study a group of individuals, i.e., patients with schizophrenia, who have a prevalence of smoking more than twice that of the general population. Certain symptoms of this disorder are believed due to dysfunction in dopamine pathways. Drugs to treat this disorder block dopamine receptors. We have developed reliable and valid measures of nicotine hunger, including cigarette self-administration sessions in which patients have repeated determinations of expired carbon monoxide during two hours of free access to cigarettes, and a smoke-mixing device which permits patients to select their preferred nicotine concentrations in cigarette smoke. We propose to measure nicotine hunger in 72 newly admitted patients with schizophrenia during a prospective neuroleptic-free washout, and on three subsequent occasions during a 42 day double-blind trial comparing three pharmacologically distinct dose levels of the dopamine receptor blocker, haloperidol. We will examine whether, and how, nicotine hunger changes in relation to haloperidol dose and plasma level, the unfolding of therapeutic response, and the development of extrapyramidal side effects. Two weeks into the double-blind haloperidol dose comparison, we will also determine the effects of four different dose levels of nicotine transdermal patch (O, 7, 14, or 21 mg, administered in a Latin square design balanced for order effects) on positive and negative psychopathology and extrapyramidal side effects. The proposed work will substantially clarify whether the excess of smoking in these patients reflects their efforts to treat their disease or to counteract the unwanted effects of its pharmacotherapy. It will also provide important information about the relationships between nicotine and dopamine systems which could not be obtained in other populations.