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The Journal of Neuroscience, July 8, 2009, 29(27):8655-8668; doi:10.1523/JNEUROSCI.5900-08.2009
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Behavioral/Systems/Cognitive
Binge Drinking Upregulates Accumbens mGluR5–Homer2–PI3K Signaling: Functional Implications for Alcoholism
Debra K. Cozzoli,1 Scott P. Goulding,1 Ping Wu Zhang,2 Bo Xiao,2 Jia-Hua Hu,2 Alexis W. Ary,1 Ilona Obara,1,3 Alison Rahn,1 Hoda Abou-Ziab,1 Burgundy Tyrrel,1 Christina Marini,1 Naomi Yoneyama,4 Pamela Metten,4 Christopher Snelling,4 Marlin H. Dehoff,2 John C. Crabbe,4 Deborah A. Finn,4 Matthias Klugmann,5 Paul F. Worley,2 andKaren K. Szumlinski1 1Department of Psychology and the Neuroscience Research Institute, University of California at Santa Barbara, Santa Barbara, California 93106-9660, 2Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, 3Department of Pain Pharmacology, Institute of Pharmacology, Polish Academy of Sciences, 31-512 Krakow, Poland, 4Department of Behavioral Neuroscience, Oregon Health and Science University and Veterans Affairs Medical Research, Portland, Oregon 97239, and 5Department of Physiological Chemistry, University of Mainz, 55099 Mainz, Germany
Correspondence should be addressed to Dr. Karen K. Szumlinski, Department of Psychology, University of California at Santa Barbara, Santa Barbara, CA 93106-9660. Email: szumlinski{at}psych.ucsb.edu
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 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 mGluR5F1128R 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.
Received Dec. 11, 2008; revised May 20, 2009; accepted May 20, 2009.
Correspondence should be addressed to Dr. Karen K. Szumlinski, Department of Psychology, University of California at Santa Barbara, Santa Barbara, CA 93106-9660. Email: szumlinski{at}psych.ucsb.edu
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