Nucleus Accumbens mGluR5-Associated Signaling Regulates Binge Alcohol Drinking Under Drinking-in-the-Dark Procedures

Debra K. Cozzoli, Justin Courson, Amanda L. Caruana, Bailey W. Miller, Daniel I. Greentree, Andrew B. Thompson, Melissa G. Wroten, Ping Wu Zhang, Bo Xiao, Jia Hua Hu, Matthias Klugmann, Pamela Metten, Paul F. Worley, John C. Crabbe, Karen K. Szumlinski

Research output: Contribution to journalArticle

75 Scopus citations

Abstract

Background: Alcohol increases the expression of Group 1 metabotropic glutamate receptors (mGluRs) and their associated scaffolding protein Homer2 and stimulates phosphatidylinositol 3-kinase (PI3K) within the nucleus accumbens (NAC). Moreover, functional studies suggest that NAC Group 1 mGluR/Homer2/PI3K signaling may be a potential target for pharmacotherapeutic intervention in alcoholism. Methods: Immunoblotting was conducted to examine the effects of alcohol consumption under drinking-in-the-dark (DID) procedures on Group 1 mGluR-associated proteins in C57BL/6J (B6) mice. Follow-up behavioral studies examined the importance of Group 1 mGluR/Homer2/PI3K signaling within the NAC shell for limited-access alcohol drinking. Finally, immunoblotting examined whether the NAC expression of Group 1 mGluR-associated proteins is a genetic correlate of high alcohol drinking using a selectively bred high DID (HDID-1) mouse line. Results: Limited-access alcohol drinking under DID procedures up-regulated NAC shell Homer2 levels, concomitant with increases in mGluR5 and NR2B. Intra-NAC shell blockade of mGluR5, Homer2, or PI3K signaling, as well as transgenic disruption of the Homer binding site on mGluR5, decreased alcohol consumption in B6 mice. Moreover, transgenic disruption of the Homer binding site on mGluR5 and Homer2 deletion both prevented the attenuating effect of mGluR5 and PI3K blockade upon intake. Finally, the basal NAC shell protein expression of mGluR1 and Homer2 was increased in offspring of HDID-1 animals. Conclusions: Taken together, these data further implicate Group 1 mGluR signaling through Homer2 within the NAC in excessive alcohol consumption.

Original languageEnglish (US)
Pages (from-to)1623-1633
Number of pages11
JournalAlcoholism: Clinical and Experimental Research
Volume36
Issue number9
DOIs
StatePublished - Sep 2012

Keywords

  • HDID-1
  • Homer
  • MGluR1 receptors
  • MGluR5 receptors
  • PI3 kinase

ASJC Scopus subject areas

  • Medicine (miscellaneous)
  • Toxicology
  • Psychiatry and Mental health

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  • Cite this

    Cozzoli, D. K., Courson, J., Caruana, A. L., Miller, B. W., Greentree, D. I., Thompson, A. B., Wroten, M. G., Zhang, P. W., Xiao, B., Hu, J. H., Klugmann, M., Metten, P., Worley, P. F., Crabbe, J. C., & Szumlinski, K. K. (2012). Nucleus Accumbens mGluR5-Associated Signaling Regulates Binge Alcohol Drinking Under Drinking-in-the-Dark Procedures. Alcoholism: Clinical and Experimental Research, 36(9), 1623-1633. https://doi.org/10.1111/j.1530-0277.2012.01776.x