Loss of metabotropic glutamate receptor 2 escalates alcohol consumption

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 110; no. 42; pp. 16963 - 16968
• Main Authors: Zhou, Zhifeng, Karlsson, Camilla, Liang, Tiebing, Xiong, Wei, Kimura, Mitsuru, Tapocik, Jenica D., Yuan, Qiaoping, Barbier, Estelle, Feng, Austin, Flanigan, Meghan, Augier, Eric, Enoch, Mary-Anne, Hodgkinson, Colin A., Shen, Pei-Hong, Lovinger, David M., Edenberg, Howard J., Heilig, Markus, Goldman, David
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 15.10.2013; NATIONAL ACADEMY OF SCIENCES; National Acad Sciences
• Subjects: Alcohol drinking; Alcohol Drinking - drug therapy; Alcohol Drinking - genetics; Alcohol Drinking - metabolism; Alcohol Drinking - pathology; Alcoholic beverages; Alcohols; Alleles; Animal models; Animals; Biological Sciences; Codon, Terminator; Crosses, Genetic; Excitatory Amino Acid Antagonists - pharmacology; Gene expression; Gene Expression Regulation - drug effects; Gene Expression Regulation - genetics; Genes; Genetic diversity; genetic heterogeneity; Genetic loci; Genomics; glutamic acid; Glutamic Acid - metabolism; Heterogeneity; Hippocampus; homozygosity; Mice; Mice, Knockout; Rats; Rats, Wistar; Receptors; Receptors, Metabotropic Glutamate - antagonists & inhibitors; Receptors, Metabotropic Glutamate - biosynthesis; Receptors, Metabotropic Glutamate - genetics; Rodents; sequence analysis; Sequencing; Stop codon; Synapses - genetics; Synapses - metabolism; Synaptic Transmission - drug effects; Synaptic Transmission - genetics; selectively bred lines; gene identification
• ISSN: 0027-8424; 1091-6490; 1091-6490
• DOI: 10.1073/pnas.1309839110

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.