-Opioid Receptor Expression in the Ventral Tegmental Area Protects Against Elevated Alcohol Consumption
The Journal of Neuroscience, November 26, 2008, 28(48):12672-1268


Alcoholism is a complex and debilitating syndrome affecting 140 million people worldwide. However, not everyone who consumes ethanol develops abuse, raising the possibility that some individuals have a protective mechanism that inhibits elevated alcohol consumption. We tested the hypothesis that the -opioid receptor (DOR) plays such a protective role.

Here we show that DOR activity in the ventral tegmental area (VTA) robustly decreases ethanol consumption in rats and that these effects depend on baseline ethanol consumption. Intra-VTA microinjection of the DOR agonist DPDPE decreases drinking, particularly in low-drinking animals.

Furthermore, VTA microinjection of the DOR selective antagonist TIPP- increases drinking in low, but not high, drinkers and this increase is blocked by comicroinjection of the GABA_A antagonist bicuculline. Using electrophysiological techniques we found that in VTA brain slices from drinking rats DPDPE presynaptically inhibits GABA_A receptor mediated IPSCs in low drinkers, but not in high drinkers or naive animals, most likely through activation of DORs on GABA terminals. This DOR-mediated inhibition of IPSCs also correlates inversely with behavioral correlates of anxiety measured in the elevated plus maze. In contrast, presynaptic inhibition of VTA GABA_A IPSCs by the µ- opioid receptor agonist DAMGO is significantly reduced in both high- and low-drinking rats (<30%)>70%).

Together, our findings demonstrate the protective nature of VTA DORs and identify an important new target for therapeutic intervention for alcoholism.

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