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 C. Crabbe, Deborah A. Finn, Matthias Klugmann, Paul F. Worley, Karen K. Szumlinski

Research output: Contribution to journalArticle

117 Scopus citations

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

ASJC Scopus subject areas

  • Neuroscience(all)

Fingerprint Dive into the research topics of 'Binge drinking upregulates accumbens mGluR5-Homer2-PI3K signaling: Functional implications for alcoholism'. Together they form a unique fingerprint.

  • Cite this

    Cozzoli, D. K., Goulding, S. P., Ping, W. Z., Xiao, B., Hu, J. H., Ary, A. W., Obara, I., Rahn, A., Abou-Ziab, H., Tyrrel, B., Marini, C., Yoneyama, N., Metten, P., Snelling, C., Dehoff, M. H., Crabbe, J. C., Finn, D. A., Klugmann, M., Worley, P. F., & 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