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Abstract: Objective: To clarify dopamine''s role in alcohol self-administration in a heterogeneous sample of drinkers using acute phenylalanine/tyrosine depletion (APTD). Methods: Sixteen men with variable drinking histories were characterized on their ethanol-induced cardiac response, a marker previously proposed to index dopamine system reactivity and vulnerability to alcohol abuse. During separate sessions participants were administered (i) a nutritionally balanced (BAL) amino acid (AA) mixture, (ii) a mixture lacking the dopamine precursors, phenylalanine and tyrosine, and (iii) APTD followed by the dopamine precursor, l-DOPA. Five hours after AA administration, participants could earn units of alcohol using a progressive ratio breakpoint task. Results: Alcohol self-administration was reduced in the APTD and APTD+ l-DOPA conditions relative to the BAL condition. In both cases the changes were predicted by ethanol-induced cardiac change. Conclusions: The motivation to drink is likely regulated by more than one neurobiological mechanism. Individual differences in cardiac responsivity to ethanol might provide a peripheral marker of responsiveness to pharmacological manipulations of dopamine. [Copyright &y& Elsevier]