Alcoholism is characterized by compulsive alcohol intake after a history of chronic consumption. A reduction in mesolimbic dopaminergic transmission observed during abstinence may contribute to the negative affective state that drives compulsive intake.
Although previous in vivo recording studies in rodents have demonstrated profound decreases in the firing activity of ventral tegmental area (VTA) dopamine neurons after withdrawal from long-term ethanol exposure, the cellular mechanisms underlying this reduced activity are not well understood. Somatodendritic dopamine release within the VTA exerts powerful feedback inhibition of dopamine neuron activity via stimulation of D2 autoreceptors and subsequent activation of G protein-gated inwardly rectifying K+ (GIRK) channels.
Here, by performing patch-clamp recordings from putative dopamine neurons in the VTA of mouse brain slices, we show that D2 receptor/GIRK-mediated inhibition becomes more potent and exhibits less desensitization after withdrawal from repeated in vivo ethanol exposure (2 g/kg, i.p., three times daily for 7 days).
In contrast, GABAB receptor/GIRK-mediated inhibition and its desensitization are not affected.
Chelating cytosolic Ca2+ with BAPTA augments D2 inhibition and suppresses its desensitization in control mice, while these effects of BAPTA are occluded in ethanol-treated mice.
Furthermore, inositol 1,4,5-trisphosphate (IP3)-induced intracellular Ca2+ release and Ca2+/calmodulin-dependent protein kinase II are selectively involved in the desensitization of D2, but not GABAB, receptor signaling. Consistent with this, activation of metabotropic glutamate receptors that are coupled to IP3 generation leads to cross-desensitization of D2/GIRK-mediated responses.
We propose that enhancement of D2 receptor-mediated autoinhibition via attenuation of a Ca2+-dependent desensitization mechanism may contribute to the hypodopaminergic state during ethanol withdrawal.
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