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Abstract: Rationale: Nicotine increases dopamine (DA) release but its role in nicotine dependence remains unclear. Objective: To assess the role of DA in nicotine craving and self-administration using acute phenylalanine/tyrosine depletion (APTD). Methods: Fifteen nicotine-dependent men ingested, a minimum of 3days apart, a nutritionally balanced amino acid (AA) mixture (BAL), a mixture deficient in the catecholamine precursors, phenylalanine and tyrosine, and APTD followed by the immediate DA precursor, l-DOPA. Beginning 3h after ingestion of the AA mixture, subjects smoked 4 cigarettes. Craving, mood, and other aspects of subjective state were assessed with self-report scales. Smoking puff topography was measured with a computerized flowmeter. Results: APTD did not change smoking puff topography, cigarette craving, or subjective effects of smoking. Conclusions: The findings suggest that in nicotine-dependent smokers craving for cigarettes, subjective effects of nicotine, and the self-administration of freely available cigarettes are largely unrelated to acute changes in DA neurotransmission. [Copyright &y& Elsevier]