In vivo ethanol experience increases D(2) autoinhibition in the ventral tegmental area.
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 D(2) 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 D(2) 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, GABA(B) receptor/GIRK-mediated inhibition and its desensitization are not affected. Chelating cytosolic Ca(2+) with BAPTA augments D(2) 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 (IP(3))-induced intracellular Ca(2+) release and Ca(2+)/calmodulin-dependent protein kinase II are selectively involved in the desensitization of D(2), but not GABA(B), receptor signaling. Consistent with this, activation of metabotropic glutamate receptors that are coupled to IP(3) generation leads to cross-desensitization of D(2)/GIRK-mediated responses. We propose that enhancement of D(2) receptor-mediated autoinhibition via attenuation of a Ca(2+)-dependent desensitization mechanism may contribute to the hypodopaminergic state during ethanol withdrawal.
Waggoner Center for Alcohol and Addiction Research, University of Texas at Austin, Austin, TX, USA.
Simona
S
Perra
Michael A
MA
Clements
Brian E
BE
Bernier
Hitoshi
H
Morikawa
D000200:Action Potentials / Q000187:drug effects; D000704:Analysis of Variance; D000818:Animals; D001418:Baclofen / Q000494:pharmacology; D002492:Central Nervous System Depressants / Q000494:pharmacology*; D002614:Chelating Agents / Q000494:pharmacology; D004298:Dopamine / Q000494:pharmacology; D015259:Dopamine Agents / Q000494:pharmacology; D065127:Dopamine D2 Receptor Antagonists; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions / Q000502:physiology; D004533:Egtazic Acid / Q000031:analogs & derivatives / Q000494:pharmacology; D004558:Electric Stimulation / Q000379:methods; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004963:Estrenes / Q000494:pharmacology; D000431:Ethanol / Q000494:pharmacology*; D018756:GABA Antagonists / Q000494:pharmacology; D058786:GABA-B Receptor Agonists / Q000494:pharmacology; D066298:In Vitro Techniques; D007211:Indoles / Q000494:pharmacology; D008297:Male; D008734:Methoxyhydroxyphenylglycol / Q000031:analogs & derivatives / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D009433:Neural Inhibition / Q000187:drug effects / Q000502:physiology*; D009474:Neurons / Q000187:drug effects*; D009943:Organophosphorus Compounds / Q000494:pharmacology; D018408:Patch-Clamp Techniques / Q000379:methods; D011760:Pyrrolidinones / Q000494:pharmacology; D017448:Receptors, Dopamine D2 / Q000819:agonists / Q000378:metabolism*; D013997:Time Factors; D017557:Ventral Tegmental Area / Q000166:cytology* / Q000187:drug effects
D002492:Central Nervous System Depressants; D002614:Chelating Agents; D015259:Dopamine Agents; D065127:Dopamine D2 Receptor Antagonists; D004791:Enzyme Inhibitors; D004963:Estrenes; D018756:GABA Antagonists; D058786:GABA-B Receptor Agonists; D007211:Indoles; D009943:Organophosphorus Compounds; D011760:Pyrrolidinones; D017448:Receptors, Dopamine D2; C060229:1-(6-((3-methoxyestra-1,3,5(10)-trien-17-yl)amino)hexyl)-1H-pyrrole-2,5-dione; C107353:CGP 54626; D000431:Ethanol; D004533:Egtazic Acid; D008734:Methoxyhydroxyphenylglycol; D001418:Baclofen; C025603:1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid; C010117:3,4-dihydroxyphenylglycol; D004298:Dopamine; C000543:cyclopiazonic acid
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