Prevalence and influence of cys407* Grm2 mutation in Hannover-derived Wistar rats: mGlu2 receptor loss links to alcohol intake, risk taking and emotional behaviour

Abstract

Modulation of metabotropic glutamate 2 (mGlu2) receptor function has huge potential for treating psychiatric and neurological diseases. Development of drugs acting on mGlu2 receptors depends on the development and use of translatable animal models of disease. We report here a stop codon mutation at cysteine 407 in Grm2 (cys407*) that is common in some Wistar rats. Therefore, researchers in this field need to be aware of strains with this mutation. Our genotypic survey found widespread prevalence of the mutation in commercial Wistar strains, particularly those known as Han Wistar. Such Han Wistar rats are ideal for research into the separate roles of mGlu2 and mGlu3 receptors in CNS function. Previous investigations, unknowingly using such mGlu2 receptor-lacking rats, provide insights into the role of mGlu2 receptors in behaviour. The Grm2 mutant rats, which dominate some selectively bred lines, display characteristics of altered emotionality, impulsivity and risk-related behaviours and increased voluntary alcohol intake compared with their mGlu2 receptor-competent counterparts. In addition, the data further emphasize the potential therapeutic role of mGlu2 receptors in psychiatric and neurological disease, and indicate novel methods of studying the role of mGlu2 and mGlu3 receptors. This article is part of the Special Issue entitled 'Metabotropic Glutamate Receptors, 5 years on'.

Differential effects of antipsychotic and propsychotic drugs on prepulse inhibition and locomotor activity in Roman high- (RHA) and low-avoidance (RLA) rats

“…Moreover, the results obtained with DOI and clozapine + MK-801 on PPI are consistent with the finding that the RHA-I strain has an alteration of the 5-HT2A/mGluR2 complex (i.e., a deficit of mGlu2 receptors and a relative increase of 5-HT2A receptors; Klein et al 2014; Wood et al 2016), similar to that observed in schizophrenic patients (Gonzalez-Maeso et al 2008). Thus, RHA-I rats may represent a model of dopamine- and 5-HT2A/mGluR2-related schizophrenia-relevant features.…”

“…Accordingly, the expression of psychotic states by 5-HT receptor agonists and antipsychotic effects by atypical antipsychotic drugs (i.e., 5-HT receptor antagonists) requires the presence of both 5-HT2A and mGluR2 receptors (Fribourg et al 2011; Gonzalez-Maeso et al 2008; Klein et al 2014). Remarkably, as reported by Klein et al (2014), RHA-I rats showed no detectable protein levels of mGlu2 receptor protein in the frontal cortex, hippocampus, and the striatum, a deficit that is apparently due to a mutation in the grm2 gene (Wood et al 2016). Thus, in line with the above evidence, it seems plausible that the reduced PPI-impairing effects of DOI in RHA-I rats (relative to RLA-Is) may be due to their low cerebral density of mGluR2 receptors.…”

“…RHA rats exhibit deficits in latent inhibition (Fernandez-Teruel et al 2006; Esnal et al 2016), augmented mesocortical dopaminergic response to stress (Giorgi et al 2003), and enhanced locomotor as well as mesolimbic dopaminergic sensitization upon the repeated administration of dopaminergic psychostimulants (Corda et al 2005; Giorgi et al 2007; Guitart-Masip et al 2008a, b), a more robust functional tone of nigrostriatal and mesolimbic dopamine neurons (Tournier et al 2013) and neurochemical and neuromorphological evidence of decreased hippocampal function (Garcia-Falgueras et al 2012; Meyza et al 2009; Salles et al 2001). With regard to other schizophrenia-linked neurotransmitter systems, like serotonin and glutamate, Klein et al (2014) have shown that RHA-I rats exhibit a dramatically reduced density of mGluR2 receptors in the prefrontal cortex and hippocampus and increased binding density of 5HT2A receptors in the prefrontal cortex (Klein et al 2014; Wood et al 2016), similarly to what has been observed post mortem in the brains of schizophrenic patients. Gonzalez-Maeso et al (2007, 2008) proposed that 5-HT2A and mGlu2 receptors engage in a functional interaction that plays a crucial role in pre-attentive processes (sensorimotor gating) and in psychotic states.…”

Presynaptic G Protein-Coupled Receptors: Gatekeepers of Addiction?

“…Intercrossing studies suggest that this allele is directly linked to increased alcohol consumption and preference in P rats (Zhou et al, 2013). Further investigation of lines of rats selectively bred for alcohol-related behaviors has also revealed an association between Grm2 * 407 and alcohol consumption (Wood et al, 2016). Importantly, this mutation is also present in many commercially available rat lines; therefore, extreme care must be taken when choosing strains and sources of rats for studying drug seeking and taking, particularly in regards to evaluating the effects of mGlu 2 on drug-related behaviors.…”

“…Importantly, this mutation is also present in many commercially available rat lines; therefore, extreme care must be taken when choosing strains and sources of rats for studying drug seeking and taking, particularly in regards to evaluating the effects of mGlu 2 on drug-related behaviors. Conversely, rats lacking mGlu 2 can serve as valuable controls for the specificity of mGlu 2 -targeted drug effects (Augier et al, 2016; Wood et al, 2016). …”