Glutamate receptor metabotropic 7 is cis-regulated in the mouse brain and modulates alcohol drinking

Abstract

Alcoholism is a heritable disease that afflicts about 8% of the adult population. Its development and symptoms, such as craving, loss of control, physical dependence, and tolerance, have been linked to changes in mesolimbic, mesocortical neurotransmitter systems utilizing biogenic amines, GABA, and glutamate. Identification of genes predisposing to alcoholism, or to alcohol-related behaviors in animal models, has been elusive because of variable interactions of multiple genes with relatively small individual effect size and sensitivity of the predisposing genotype to lifestyle and environmental factors. Here, using near-isogenic advanced animal models with reduced genetic background interactions, we integrate gene mapping and gene mRNA expression data in segregating and congenic mice and identify glutamate receptor metabotropic 7 (Grm7) as a cis-regulated gene for alcohol consumption. Traditionally, the mesoaccumbal dopamine reward hypothesis of addiction and the role of the ionotropic glutamate receptors have been emphasized. Our results lend support to an emerging direction of research on the role of metabotropic glutamate receptors in alcoholism and drug addiction. These data suggest for the first time that Grm7 is a risk factor for alcohol drinking and a new target in addiction therapy.

Viral-Mediated Knockdown of mGluR7 in the Nucleus Accumbens Mediates Excessive Alcohol Drinking and Increased Ethanol-Elicited Conditioned Place Preference in Rats

“…In fact, when C57BL/6J male mice were trained to self-administer ethanol or sucrose, it was reported that AMN082 produced a significant reduction in ethanol and sucrose reinforced responding and inhibited locomotor activity (Salling et al, 2008). Vadasz et al (2007) when using near-isogenic advanced animal models with reduced genetic background interactions, were able to identify mGluR7 as a cis-regulated gene for ethanol consumption. The same group has reported recently that: first, mGluR7-knockout mice express increased ethanol consumption and preference.…”

Disease-driven detection of differential inherited SNP modules from SNP network

“…After locating these SNPs in genes (the start and end positions of genes were obtained from the GENE database of NCBI as of February 2002), we obtained 222 candidate genes associated with alcoholism. Among these genes, many have been previously demonstrated to be associated with alcoholism, including GRM7 (Vadasz et al, 2007), NRXN1 (Shah et al, 2010;Wisniowiecka-Kowalnik et al, 2010), ERBB4 (Luo and Miller, 2000), GRIA1 (Hu et al, 2008), ITPR1 (Saito et al, 1996), NTS (Ehlers et al, 1999;Erwin et al, 2001), TTN (Hunter et al, 2003), LAMB1 (Mash et al, 2007) and VWF (Mash et al, 2007). NRXN1 is the only gene that could also be detected by haplotype analysis.…”

Glutamate Signaling in Alcohol Abuse and Dependence

“…However, unlike the effects of Group 1 mGluR inhibitors or Group 2 mGluR activators, AMN082 pretreatment blocks ethanol-induced locomotor stimulation (Bahi, 2011). There also exists genetic evidence to support a potential role for mGlu7 receptors in alcohol consumption; employing near-isogenic advanced murine models with reduced genetic background interactions, Vadasz et al (2007) identified the mGlu7 receptor as a cis-regulated gene for ethanol consumption and reported that, akin to the effects of pharmacological inhibition of receptor function , mGlu7-receptor-null mutant mice exhibit greater alcohol consumption and preference compared to WT controls (Gyetvai et al, 2011). Interestingly, subcongenic and congenic mice that overexpress mGluR7 mRNA exhibit the opposite phenotype than the KO and consume less alcohol (Gyetvai et al, 2011).…”