mGluR7 Genetics and Alcohol: Intersection Yields Clues for Addiction

Abstract

Development of addiction to alcohol or other substances can be attributed in part to exposure-dependent modifications at synaptic efficacy leading to an organism which functions at an altered homeostatic setpoint. Genetic factors may also influence setpoints and the stability of the homeostatic system of an organism. Quantitative genetic analysis of voluntary alcohol drinking, and mapping of the involved genes in the quasi-congenic Recombinant QTL Introgression (RQI) strain system, identified Eac2 as a Quantitative Trait Locus (QTL) on mouse chromosome 6 which explained 18% of the variance with an effect size of 2.09 g/kg/day alcohol consumption, and Grm7 as a quantitative trait gene (QTG) underlying Eac2 (Vadasz et al., 2007a; Vadasz et al., 2007c). In earlier studies, the product of Grm7 mGluR7, a G protein-coupled receptor, has been implicated in stress systems (Mitsukawa et al., 2005), anxiety-like behaviors (Cryan et al., 2003), memory (Holscher et al., 2005), and psychiatric disorders (e.g., (Mick et al., 2008; Ohtsuki et al., 2008; Pergadia et al., 2008). Here, in experiments with mice, we show that (1) Grm7 knockout mice express increased alcohol consumption, (2) sub-congenic, and congenic mice carrying a Grm7 variant characterized by higher Grm7 mRNA drink less alcohol, and show a tendency for higher circadian dark phase motor activity in a wheel running paradigm, respectively, and (3) there are significant genetic differences in Grm7 mRNA abundance in the mouse brain between congenic and background mice identifying brain areas whose function is implicated in addiction related processes. We hypothesize that metabotropic glutamate receptors may function as regulators of homeostasis, and Grm7 (mGluR7) is involved in multiple processes (including stress, circadian activity, reward control, memory, etc.) which interact with substance use and the development of addiction. In conclusion, we suggest that mGluR7 is a significant new therapeutic target in addiction and related neurobehavioral disorders.

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

“…The same group has reported recently that: first, mGluR7-knockout mice express increased ethanol consumption and preference. Second, subcongenic and congenic mice that overexpress mGluR7 mRNA consume less alcohol in a two-bottle choice drinking test (Gyetvai et al, 2011). Our previous work on ethanol voluntary intake in rats suggested that AMN082 (10 mg/kg) reduced ethanol consumption and preference, without affecting ethanol blood levels.…”

“…More recently, we have reported that mGluR7 activation using AMN082 had no effect on ethanol-induced conditioned place preference (CPP) extinction (Bahi, 2012) but significantly reduced reinstatement after priming with a single dose of ethanol, an effect reversed by co-administration of MMPIP (Bahi, 2012). In the light of these findings, Gyetvai et al (2011) have shown that sub-congenic, and congenic mice carrying an mGluR7 variant characterized by higher mGluR7 mRNA drink less alcohol, in contrast to mGluR7 knockout mice, which express increased voluntary alcohol consumption.…”

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).…”

Genetical Genomics of Behavior: A Novel Chicken Genomic Model for Anxiety Behavior

“…Successful examples of behavioral QTG identification are almost exclusively limited to mouse and rat models (Yalcin et al 2004;Chiavegatto et al 2008;Kim et al 2009;Tomida et al 2009;Gyetvai et al 2011;Wang et al 2012;Heyne et al 2014), Drosophila (Anholt and Mackay 2004;Mackay 2004;Fitzpatrick et al 2005), and the honeybee (Robinson et al , 2008. The ramifications for the identification of such behavioral genes are many and varied.…”