Using inbred strains of mice that differ widely in their innate preference for and consumption of ethanol, we demonstrate, in ethanol-preferring C57BL/6J (C57) mice, decreased dopamine (DA) content and turnover in the terminals of the mesolimbic and mesostriatal dopamine neurons, compared with ethanol-avoiding DBA/2J and BALBc mice. These data suggest that genetically determined hypodopaminergic function in these pathways plays a role in the predisposition to high voluntary intake of ethanol. DA turnover in these areas was selectively increased by ethanol in C57 mice, which suggests that these DA neurons are among the central substrates of ethanol action in brain. In keeping with this hypothesis, augmenting synaptic DA concentrations by enhancing the synthesis by L-3-4-dihydroxyphenylalanine with carbidopa, or by decreasing its degradation by monoamine oxidase-B blockade with selegiline, led to marked decreases in ethanol preference and in the high voluntary consumption of ethanol in C57 mice. The selegiline-mediated decrease in ethanol preference and drinking in C57 mice could be blocked selectively by D1 and D2 DA receptor antagonists, which suggests that DA activity at D1 and D2 receptors plays an important role in this behavior. Indeed, the high preference for ethanol in C57 animals could be attenuated by direct DA receptor activation by either D1 or D2 agonists.(ABSTRACT TRUNCATED AT 250 WORDS)