Binge Drinking Upregulates Accumbens mGluR5-Homer2-PI3K Signaling: Functional Implications for Alcoholism

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-phosphatidylinos...

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Published in:	The Journal of neuroscience Vol. 29; no. 27; pp. 8655 - 8668
Main Authors:	Cozzoli, Debra K, Goulding, Scott P, Zhang, Ping Wu, 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 C, Finn, Deborah A, Klugmann, Matthias, Worley, Paul F, Szumlinski, Karen K
Format:	Journal Article
Language:	English
Published:	United States Soc Neuroscience 08-07-2009 Society for Neuroscience
Subjects:	Alcoholism - enzymology Alcoholism - genetics Alcoholism - metabolism Animals Carrier Proteins - biosynthesis Carrier Proteins - genetics Carrier Proteins - physiology Ethanol - toxicity Homer Scaffolding Proteins Male Mice Mice, Inbred C57BL Mice, Transgenic Nucleus Accumbens - drug effects Nucleus Accumbens - enzymology Nucleus Accumbens - metabolism Phenotype Phosphatidylinositol 3-Kinases - biosynthesis Phosphatidylinositol 3-Kinases - genetics Phosphatidylinositol 3-Kinases - physiology Receptor, Metabotropic Glutamate 5 Receptors, Metabotropic Glutamate - biosynthesis Receptors, Metabotropic Glutamate - genetics Receptors, Metabotropic Glutamate - physiology Signal Transduction - drug effects Signal Transduction - physiology Up-Regulation - drug effects Up-Regulation - physiology
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Summary:	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 ( approximately 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 microg/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 a 50% 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.
ISSN:	0270-6474 1529-2401
DOI:	10.1523/JNEUROSCI.5900-08.2009