The causal role of the mGluR2 stop codon in altered alcohol preference was supported by multiple layers of evidence (Zhou et al., 2013). Genetic linkage analysis in the F2 rats derived from intercrossed inbred P and NP rats showed that homozygous stop codon carriers had significantly increased alcohol consumption and preference. Pharmacological blockade of mGluR2 receptor by mGluR2/mGluR3 antagonist LY341495 also significantly escalated alcohol self-administration in Wistar rats trained in an operant self-reinforcement paradigm. To further validate whether the loss of mGluR2 causally contributes to excessive alcohol intake, we examined alcohol-drinking behavior in Grm2 knockout mice. Tested by a two-bottle free choice scheme and an escalation procedure, Grm2-null mice showed significantly higher levels of alcohol consumption and preference than the wild-type control.
