Delta-opioid receptor expression in the ventral tegmental area protects against elevated alcohol consumption.
Alcoholism is a complex and debilitating syndrome affecting approximately 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 delta-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-Psi 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 mu-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.
Margolis
Elyssa B
EB
Ernest Gallo Clinic and Research Center, University of California, San Francisco, Emeryville, California 94608, USA.
Fields
Howard L
HL
Hjelmstad
Gregory O
GO
Mitchell
Jennifer M
JM
D020268:Alcohol-Induced Disorders, Nervous System / Q000378:metabolism* / Q000503:physiopathology; D000437:Alcoholism / Q000378:metabolism* / Q000503:physiopathology; D000701:Analgesics, Opioid / Q000494:pharmacology; D000818:Animals; D001008:Anxiety Disorders / Q000139:chemically induced / Q000378:metabolism / Q000503:physiopathology; D002492:Central Nervous System Depressants / Q000494:pharmacology; D004195:Disease Models, Animal; D000431:Ethanol / Q000494:pharmacology*; D018756:GABA Antagonists / Q000494:pharmacology; D058787:GABA-A Receptor Antagonists; D053444:Inhibitory Postsynaptic Potentials / Q000187:drug effects / Q000502:physiology; D008297:Male; D018782:Maze Learning / Q000187:drug effects / Q000502:physiology; D008845:Microinjections; D009292:Narcotic Antagonists / Q000494:pharmacology; D009433:Neural Inhibition / Q000187:drug effects / Q000502:physiology; D009924:Organ Culture Techniques; D051381:Rats; D011917:Rats, Inbred Lew; D011963:Receptors, GABA-A / Q000378:metabolism; D017465:Receptors, Opioid, delta / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism*; D017450:Receptors, Opioid, mu / Q000819:agonists / Q000378:metabolism; D017557:Ventral Tegmental Area / Q000187:drug effects / Q000378:metabolism*
D000701:Analgesics, Opioid; D002492:Central Nervous System Depressants; D018756:GABA Antagonists; D058787:GABA-A Receptor Antagonists; D009292:Narcotic Antagonists; D011963:Receptors, GABA-A; D017465:Receptors, Opioid, delta; D017450:Receptors, Opioid, mu; D000431:Ethanol