Loss of metabotropic glutamate receptor 2 escalates alcohol consumption

Zhifeng Zhou, Camilla Karlsson, Tiebing Liang, Wei Xiong, Mitsuru Kimura, Jenica D. Tapocik, Qiaoping Yuan, Estelle Barbier, Austin Feng, Meghan Flanigan, Eric Augier, Mary Anne Enoch, Colin A. Hodgkinson, Pei Hong Shen, David M. Lovinger, Howard J. Edenberg, Markus Heilig, David Goldman

Research output: Contribution to journalArticle

61 Scopus citations

Abstract

Identification of genes influencing complex traits is hampered by genetic heterogeneity, the modest effect size of many alleles, and the likely involvement of rare and uncommon alleles. Etiologic complexity can be simplified in model organisms. By genomic sequencing, linkage analysis, and functional validation, we identified that genetic variation of Grm2, which encodes metabotropic glutamate receptor 2 (mGluR2), alters alcohol preference in animal models. Selectively bred alcohol-preferring (P) rats are homozygous for a Grm2 stop codon (Grm2 *407) that leads to largely uncompensated loss of mGluR2. mGluR2 receptor expression was absent, synaptic glutamate transmission was impaired, and expression of genes involved in synaptic function was altered. Grm2 *407 was linked to increased alcohol consumption and preference in F2 rats generated by intercrossing inbred P and nonpreferring rats. Pharmacologic blockade of mGluR2 escalated alcohol self-administration in Wistar rats, the parental strain of P and nonpreferring rats. The causal role of mGluR2 in altered alcohol preference was further supported by elevated alcohol consumption in Grm2 -/- mice. Together, these data point to mGluR2 as an origin of alcohol preference and a potential therapeutic target.

Original languageEnglish (US)
Pages (from-to)16963-16968
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume110
Issue number42
DOIs
StatePublished - Oct 15 2013

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Keywords

  • Gene identification
  • Selectively bred lines

ASJC Scopus subject areas

  • General

Cite this

Zhou, Z., Karlsson, C., Liang, T., Xiong, W., Kimura, M., Tapocik, J. D., Yuan, Q., Barbier, E., Feng, A., Flanigan, M., Augier, E., Enoch, M. A., Hodgkinson, C. A., Shen, P. H., Lovinger, D. M., Edenberg, H. J., Heilig, M., & Goldman, D. (2013). Loss of metabotropic glutamate receptor 2 escalates alcohol consumption. Proceedings of the National Academy of Sciences of the United States of America, 110(42), 16963-16968. https://doi.org/10.1073/pnas.1309839110