The Role of Dopamine D3 Receptors in the Control of Alcohol Intake

Mesolimbic dopamine controls drug and alcohol seeking behavior. Stimulation of dopamine D3 autoreceptor reduces extracellular levels of dopamine. We tested the hypothesis that dopamine D3 receptor (D3R) gene deletion or its pharmacological blockade counteracts alcohol preference and intake in a long-term voluntary ethanol intake paradigm. Mice D3R -/and their wild type (WT) littermates, treated or not with the D3R antagonists U99194A and SB277011A, were tested. The selectivity of the D3R antagonists was further assessed by molecular modeling. Activation of dopamine (DA) transmission and D3R expression was assessed at the end of the experiment. After 8 days, daily ethanol intake was negligible in D3R -/and robust in WT; this behavior was stably maintained for 44 days. Treatment with D3R antagonists counteracted ethanol intake in WT and was associated to increased DA transmission (assessed as phosphorylation of DARPP-32 and GSK3β) in striatum and prefrontal cortex. Forced ethanol intake increased the expression of RACK1 and BDNF in both WT and D3R ; in WT there was also a robust overexpression of D3R. Thus, increased expression of D3R associated with activation of RACK1/BDNF seems to operate as a reinforcing mechanism in voluntary ethanol intake. Taking into account that ethanol intake increases mesolimbic DA, low levels of extracellular DA resulting from D3R overexpression would facilitate ethanol intake, and high levels of extracellular DA, from either gene deletion of D3R blockade, would inhibit ethanol intake. Thus, modulation of DA mesolimbic pathway by selective targeting of D3 receptor might provide a basis for novel weaning treatments in alcoholism.