Decreased striatal dopamine in group II metabotropic glutamate receptor (mGlu2/mGlu3) double knockout mice

Background: Group II metabotropic glutamate receptors (mGlu2 and mGlu3, encoded by Grm2 and Grm3) have been the focus of attention as treatment targets for a number of psychiatric conditions. Double knockout mice lacking mGlu2 and mGlu3 (mGlu2/3−/−) show a subtle behavioural phenotype, being hypoactive under basal conditions and in response to amphetamine, and with a spatial memory deficit that depends on the arousal properties of the task. The neurochemical correlates of this profile are unknown. Here, we measured tissue levels of dopamine, 5-HT, noradrenaline and their metabolites in the striatum and frontal cortex of mGlu2/3−/− double knockout mice, using high performance liquid chromatography. We also measured the same parameters in mGlu2−/− and mGlu3−/− single knockout mice. Results: mGlu2/3−/−mice had reduced dopamine levels in the striatum but not in frontal cortex, compared to wild-types. In a separate cohort we replicated this deficit and, using tissue punches, found it was more prominent in the nucleus accumbens than in dorsolateral striatum. Noradrenaline, 5-HT and their metabolites were not altered in the striatum of mGlu2/3−/− mice, although the noradrenaline metabolite MHPG was increased in the cortex. In mGlu2−/− and mGlu3−/− single knockout mice we found no difference in any monoamine or metabolite, in either brain region, compared to their wild-type littermates. Conclusions: Group II metabotropic glutamate receptors impact upon striatal dopamine. The effect may contribute to the behavioural phenotype of mGlu2/3−/− mice. The lack of dopaminergic alterations in mGlu2−/− and mGlu3−/− single knockout mice reveals a degree of redundancy between the two receptors. The findings support the possibility that interactions between mGlu2/3 and dopamine may be relevant to the pathophysiology and therapy of schizophrenia and other disorders