LOW ENDOGENOUS DOPAMINE FUNCTION IN BRAIN PREDISPOSES TO HIGH ALCOHOLPREFERENCE AND CONSUMPTION - REVERSAL BY INCREASING SYNAPTIC DOPAMINE

Using inbred strains of mice that differ widely in their innate prefer ence for and consumption of ethanol, we demonstrate, in ethanol-prefer ring 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 sugg est that genetically determined hypodopaminergic function in these pat hways plays a role in the predisposition to high voluntary intake of e thanol. DA turnover in these areas was selectively increased by ethano l in C57 mice, which suggests that these DA neurons are among the cent ral substrates of ethanol action in brain. In keeping with this hypoth esis, 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 ma rked decreases in ethanol preference and in the high voluntary consump tion of ethanol in C57 mice. The selegiline-mediated decrease in ethan ol 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. These resu lts suggest that hypodopamine activity of the mesolimbic and mesostria tal systems involving D1 and D2 receptors in C57 mice plays a role in determining the susceptibility for high ethanol preference and consump tion exhibited by these animals and that enhancing endogenous synaptic DA availability or function may serve to reverse the behavioral conse quences, confirming the association between DA and ethanol drinking in this model. These studies suggest that hypodopamine function in criti cal central DA pathways is an important factor predisposing to the lia bility for increased alcohol preference and intake.