Binge drinking upregulates accumbens mGluR5-Homer2-PI3K signaling

Functional implications for alcoholism

Debra K. Cozzoli, Scott P. Goulding, Wu Zhang Ping, Bo Xiao, Jia Hua Hu, Alexis W. Ary, Ilona Obara, Alison Rahn, Hoda Abou-Ziab, Burgundy Tyrrel, Christina Marini, Naomi Yoneyama, Pamela Metten, Christopher Snelling, Marlin H. Dehoff, John Jr Crabbe, Deborah (Deb) Finn, Matthias Klugmann, Paul F. Worley, Karen K. Szumlinski

Research output: Contribution to journalArticle

113 Citations (Scopus)

Abstract

The glutamate receptor-associated protein Homer2 regulates alcohol-induced neuroplasticity within the nucleus accumbens (NAC), but the precise intracellular signaling cascades involved are not known. This study examined the role for NAC metabotropic glutamate receptor (mGluR)-Homer2- phosphatidylinositol 3-kinase (PI3K) signaling in regulating excessive alcohol consumption within the context of the scheduled high alcohol consumption (SHAC) model of binge alcohol drinking. Repeated bouts of binge drinking (∼1.5 g/kg per 30 min) elevated NAC Homer2a/b expression and increased PI3K activity in this region. Virus-mediated knockdown of NAC Homer2b expression attenuated alcohol intake, as did an intra-NAC infusion of the mGluR5 antagonist MPEP [2-methyl-6-(phenylethynyl)pyridine hydrochloride] (0.1-1 μg/side) and the PI3K antagonist wortmannin (50 ng/side), supporting necessary roles for mGluR5/Homer2/PI3K in binge alcohol drinking. Moreover, when compared with wild-type littermates, transgenic mice with an F1128R point mutation in mGluR5 that markedly reduces Homer binding exhibited a50%reduction in binge alcohol drinking, which was related to reduced NAC basal PI3K activity. Consistent with the hypothesis that mGluR5-Homer-PI3K signaling may be a mechanism governing excessive alcohol intake, the "anti-binge" effects of MPEP and wortmannin were not additive, nor were they observed in the mGluR5 F1128R transgenic mice. Finally, mice genetically selected for a high versus low SHAC phenotype differed in NAC mGluR, Homer2, and PI3K activity, consistent with the hypothesis that augmented NAC mGluR5-Homer2-PI3K signaling predisposes a high binge alcohol-drinking phenotype. Together, these data point to an important role for NAC mGluR5-Homer2-PI3K signaling in regulating binge-like alcohol consumption that has relevance for our understanding of the neurobiology of alcoholism and its pharmacotherapy.

Original languageEnglish (US)
Pages (from-to)8655-8668
Number of pages14
JournalJournal of Neuroscience
Volume29
Issue number27
DOIs
StatePublished - Jul 8 2009

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Phosphatidylinositol 3-Kinase
Binge Drinking
Nucleus Accumbens
Alcoholism
Alcohol Drinking
Up-Regulation
Metabotropic Glutamate Receptors
Alcohols
Transgenic Mice
Phenotype
Neuronal Plasticity
Neurobiology
Glutamate Receptors
Point Mutation
Viruses
Drug Therapy

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

Cozzoli, D. K., Goulding, S. P., Ping, W. Z., Xiao, B., Hu, J. H., Ary, A. W., ... Szumlinski, K. K. (2009). Binge drinking upregulates accumbens mGluR5-Homer2-PI3K signaling: Functional implications for alcoholism. Journal of Neuroscience, 29(27), 8655-8668. https://doi.org/10.1523/JNEUROSCI.5900-08.2009

Binge drinking upregulates accumbens mGluR5-Homer2-PI3K signaling : Functional implications for alcoholism. / Cozzoli, Debra K.; Goulding, Scott P.; Ping, Wu Zhang; Xiao, Bo; Hu, Jia Hua; Ary, Alexis W.; Obara, Ilona; Rahn, Alison; Abou-Ziab, Hoda; Tyrrel, Burgundy; Marini, Christina; Yoneyama, Naomi; Metten, Pamela; Snelling, Christopher; Dehoff, Marlin H.; Crabbe, John Jr; Finn, Deborah (Deb); Klugmann, Matthias; Worley, Paul F.; Szumlinski, Karen K.

In: Journal of Neuroscience, Vol. 29, No. 27, 08.07.2009, p. 8655-8668.

Research output: Contribution to journalArticle

Cozzoli, DK, Goulding, SP, Ping, WZ, Xiao, B, Hu, JH, Ary, AW, Obara, I, Rahn, A, Abou-Ziab, H, Tyrrel, B, Marini, C, Yoneyama, N, Metten, P, Snelling, C, Dehoff, MH, Crabbe, JJ, Finn, DD, Klugmann, M, Worley, PF & Szumlinski, KK 2009, 'Binge drinking upregulates accumbens mGluR5-Homer2-PI3K signaling: Functional implications for alcoholism', Journal of Neuroscience, vol. 29, no. 27, pp. 8655-8668. https://doi.org/10.1523/JNEUROSCI.5900-08.2009
Cozzoli, Debra K. ; Goulding, Scott P. ; Ping, Wu Zhang ; Xiao, Bo ; Hu, Jia Hua ; Ary, Alexis W. ; Obara, Ilona ; Rahn, Alison ; Abou-Ziab, Hoda ; Tyrrel, Burgundy ; Marini, Christina ; Yoneyama, Naomi ; Metten, Pamela ; Snelling, Christopher ; Dehoff, Marlin H. ; Crabbe, John Jr ; Finn, Deborah (Deb) ; Klugmann, Matthias ; Worley, Paul F. ; Szumlinski, Karen K. / Binge drinking upregulates accumbens mGluR5-Homer2-PI3K signaling : Functional implications for alcoholism. In: Journal of Neuroscience. 2009 ; Vol. 29, No. 27. pp. 8655-8668.
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AU - Ping, Wu Zhang

AU - Xiao, Bo

AU - Hu, Jia Hua

AU - Ary, Alexis W.

AU - Obara, Ilona

AU - Rahn, Alison

AU - Abou-Ziab, Hoda

AU - Tyrrel, Burgundy

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AU - Yoneyama, Naomi

AU - Metten, Pamela

AU - Snelling, Christopher

AU - Dehoff, Marlin H.

AU - Crabbe, John Jr

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