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In vivo ethanol experience increases D(2) autoinhibition in the ventral tegmental area.
Neuropsychopharmacology 2011; 36(5):993-1002N

Abstract

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.

Authors+Show Affiliations

Waggoner Center for Alcohol and Addiction Research, University of Texas at Austin, Austin, TX, USA.No affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

21248720

Citation

Perra, Simona, et al. "In Vivo Ethanol Experience Increases D(2) Autoinhibition in the Ventral Tegmental Area." Neuropsychopharmacology : Official Publication of the American College of Neuropsychopharmacology, vol. 36, no. 5, 2011, pp. 993-1002.
Perra S, Clements MA, Bernier BE, et al. In vivo ethanol experience increases D(2) autoinhibition in the ventral tegmental area. Neuropsychopharmacology. 2011;36(5):993-1002.
Perra, S., Clements, M. A., Bernier, B. E., & Morikawa, H. (2011). In vivo ethanol experience increases D(2) autoinhibition in the ventral tegmental area. Neuropsychopharmacology : Official Publication of the American College of Neuropsychopharmacology, 36(5), pp. 993-1002. doi:10.1038/npp.2010.237.
Perra S, et al. In Vivo Ethanol Experience Increases D(2) Autoinhibition in the Ventral Tegmental Area. Neuropsychopharmacology. 2011;36(5):993-1002. PubMed PMID: 21248720.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - In vivo ethanol experience increases D(2) autoinhibition in the ventral tegmental area. AU - Perra,Simona, AU - Clements,Michael A, AU - Bernier,Brian E, AU - Morikawa,Hitoshi, Y1 - 2011/01/19/ PY - 2011/1/21/entrez PY - 2011/1/21/pubmed PY - 2011/7/14/medline SP - 993 EP - 1002 JF - Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology JO - Neuropsychopharmacology VL - 36 IS - 5 N2 - 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. SN - 1740-634X UR - https://www.unboundmedicine.com/medline/citation/21248720/In_vivo_ethanol_experience_increases_D_2__autoinhibition_in_the_ventral_tegmental_area_ L2 - http://dx.doi.org/10.1038/npp.2010.237 DB - PRIME DP - Unbound Medicine ER -