Dopamine D3 Receptor Is Necessary for Ethanol Consumption: An Approach with Buspirone

Mesolimbic dopamine (DA) controls drug- and alcohol-seeking behavior, but the role of specific DA receptor subtypes is unclear. We tested the hypothesis that D(3)R gene deletion or the D(3)R pharmacological blockade inhibits ethanol preference in mice. D(3)R-deficient mice (D(3)R(−/−)) and their wild-type (WT) littermates, treated or not with the D(3)R antagonists SB277011A and U99194A, were tested in a long-term free choice ethanol-drinking (two-bottle choice) and in a binge-like ethanol-drinking paradigm (drinking in the dark, DID). The selectivity of the D(3)R antagonists was further assessed by molecular modeling. Ethanol intake was negligible in D(3)R(−/−) and robust in WT both in the two-bottle choice and DID paradigms. Treatment with D(3)R antagonists inhibited ethanol intake in WT but was ineffective in D(3)R(−/−) mice. Ethanol intake increased the expression of RACK1 and brain-derived neurotrophic factor (BDNF) in both WT and D(3)R(−/−); in WT there was also a robust overexpression of D(3)R. Thus, increased expression of D(3)R associated with activation of RACK1/BDNF seems to operate as a reinforcing mechanism in voluntary ethanol intake. Indeed, blockade of the BDNF pathway by the TrkB selective antagonist ANA-12 reversed chronic stable ethanol intake and strongly decreased the striatal expression of D(3)R. Finally, we evaluated buspirone, an approved drug for anxiety disorders endowed with D(3)R antagonist activity (confirmed by molecular modeling analysis), that resulted effective in inhibiting ethanol intake. Thus, DA signaling via D(3)R is essential for ethanol-related reward and consumption and may represent a novel therapeutic target for weaning.