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The Journal of Neuroscience, November 26, 2008, 28(48):12672-12681; doi:10.1523/JNEUROSCI.4569-08.2008

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Behavioral/Systems/Cognitive
-Opioid Receptor Expression in the Ventral Tegmental Area Protects Against Elevated Alcohol Consumption

Elyssa B. Margolis,¹ Howard L. Fields,^1,2,3 Gregory O. Hjelmstad,^1,2,3 and Jennifer M. Mitchell^1,2

¹Ernest Gallo Clinic and Research Center, University of California, San Francisco, Emeryville, California 94608, ²Department of Neurology, University of California, San Francisco, San Francisco, California 94143-0114, and ³Wheeler Center for the Neurobiology of Addiction, University of California, San Francisco, San Francisco, California 94143-0114

Correspondence should be addressed to Elyssa B. Margolis, Ernest Gallo Clinic and Research Center, 5858 Horton Street, Suite #200, Emeryville, CA 94608. Email: elyssam{at}gallo.ucsf.edu

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%) compared with age-matched nondrinking controls (>70%). Together, our findings demonstrate the protective nature of VTA DORs and identify an important new target for therapeutic intervention for alcoholism.

Key words: ethanol; ventral tegmental area; -opioid; alcoholism; drinking; consumption

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Received Sept. 23, 2008; revised Oct. 14, 2008; accepted Oct. 17, 2008.

Correspondence should be addressed to Elyssa B. Margolis, Ernest Gallo Clinic and Research Center, 5858 Horton Street, Suite #200, Emeryville, CA 94608. Email: elyssam{at}gallo.ucsf.edu

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