The dopamine D3 receptor is part of a homeostatic pathway regulating ethanol consumption

We recently identified a homeostatic pathway that inhibits ethanol intake. This protective pathway consists of the scaffolding protein RACK1 and brain-derived neurotrophic factor (BDNF). RACK1 translocates to the nucleus after exposure of neurons to ethanol and increases expression of BDNF (McGough et al., 2004). We also found that increasing the levels of BDNF via systemic administration of RACK1 expressed as a Tat-fusion protein (Tat-RACK1) reduces ethanol consumption, whereas reduction of BDNF levels augments this behavior (McGough et al., 2004). Based on these results, we hypothesized that activation of the BDNF receptor TrkB is necessary for the effects of BDNF on ethanol intake and that gene products downstream of BDNF negatively regulate ethanol consumption. Here, we show that inhibition of the BDNF receptor TrkB increases voluntary ethanol consumption in wild-type mice but not in mice lacking one copy of the BDNF gene (BDNF(+/-)). We also find that increases in the levels of BDNF, mediated by ethanol or RACK1, lead to increased dorsal striatal levels of the dopamine D3 receptor (D3R), a gene downstream of BDNF, via activation of the TrkB receptor. Finally, we show that the Tat-RACK1-mediated reduction of ethanol consumption is attenuated by coinjection with either the Trk inhibitor K252a or the dopamine D3R-prefering antagonist U-99194A [5, 6-dimethoxy-2-(di-n-propylamino)indan], suggesting that activation of the BDNF pathway via RACK1 leads to increased expression of the dopamine D3R, which in turn mediates the attenuation of ethanol consumption.