DOPAMINE-RECEPTOR AGONIST REDUCES ETHANOL SELF-ADMINISTRATION IN THE ETHANOL-PREFERRING C57BL/6J INBRED MOUSE

This report experimentally examined whether the genetically determined low nigrostriatal/mesolimbic dopaminergic activity in the C57BL/6J (herein referred to as C57) inbred mouse mediated the congenital high risk for ethanol abuse (ethanol consumption and ethanol preference) in this model. C57 mice pretreated with dopamine D-1 receptor agonist ((+)-SKF-38393) or dopamine D-2 receptor agonist (bromocriptine) to augment synaptic dopamine availability exhibited marked 76% and 38% reductions in voluntary ethanol intake in comparison to untreated controls. Dopamine receptor agonist administration resulted in changes in dopamine D-1 and D-2 receptor mRNA in the cell bodies and dopamine D-1 and D-2 receptor densities principally in the afferent targets of nigrostriatal/mesolimbic dopamine neurons. Dopamine receptor agonists promoted a decrease of striatal dopamine D-1 and D-2 receptor densities and corresponding down-regulation of olfactory tubercle dopamine D-1 and D-2 receptor mRNA abundance. Dopamine receptor agonist-induced increases in forebrain dopaminergic activity was compensated with increased dopamine D-2 receptor density and correspondingly higher dopamine D-2 receptor mRNA content in the brain stem. When bromocriptine was administered to ethanol-sensitized mice, it was ineffective in reducing voluntary ethanol abuse. In these mice, treatment with the dopamine D-2 receptor antagonist haloperidol led to a 28% reduction in the absolute amount of ethanol consumed, but not in voluntary ethanol preference. These data indicated that nigrostriatal/mesolimbic dopamine D-1-D-2 receptor mechanism(s) mediating the potential for becoming high ethanol drinking on exposure to ethanol are distinct from factors mediating voluntary ethanol drinking after sensitization to ethanol. These data constitute direct evidence supporting a dopamine hypothesis for ethanol abuse in the genetically ethanol-preferring C57 mouse.