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

Abstract

BackgroundGroup 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.ResultsmGlu2/3−/−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.ConclusionsGroup 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.

Proof of mechanism and target engagement of glutamatergic drugs for the treatment of schizophrenia: RCTs of pomaglumetad and TS-134 on ketamine-induced psychotic symptoms and pharmacoBOLD in healthy volunteers

“…Thus, our findings appear clinically relevant. Furthermore, the whole brain analysis showed drug effects primarily within the predefined dACC ROI, along with significant clusters within dopaminergic areas (ventral striatum and caudate), consistent with preclinical studies suggesting broad interactions between mGluR2/3 and dopaminergic neurotransmission [ 70 – 72 ]. We caution that the whole brain analysis was not corrected for multiple comparisons and requires prospective replication.…”

Deletion of Metabotropic Glutamate Receptors 2 and 3 (mGlu2 & mGlu3) in Mice Disrupts Sleep and Wheel-Running Activity, and Increases the Sensitivity of the Circadian System to Light

“…Long-term voluntary wheel-running is known to be rewarding for rodents, and produces plastic changes in mesolimbic reward neurocircuity [ 88 ]. Significantly, striatal dopamine is reduced in Grm2/3 -/- mice, particularly in the nucleus accumbens [ 89 ], a brain region involved in reward and motivation [ 90 , 91 ].…”

Metabotropic glutamate receptor 3 (mGlu3; mGluR3; GRM3) in schizophrenia: Antibody characterisation and a semi-quantitative western blot study

“…This work fostered development of mGlu2/3 agonists as potential anti-schizophrenia treatments, with a high-profile positive clinical trial for one such drug, pomaglumetad methionil (Patil et al, 2007). Though this finding was not replicated, interest in group II mGluRs in schizophrenia and as antipsychotic drug targets has persisted (Lyon et al, 2011b, Fell et al, 2012, Vinson and Conn, 2012, Lane et al, 2013, Ellaithy et al, 2015, De Filippis et al, 2015, Pritchett et al, 2015, Walker and Conn, 2015), and a recent secondary analysis of the clinical trials suggests that pomaglumetad methionil may have antipsychotic efficacy early in the disease and in patients previously exposed to D2 dopamine antagonists (Kinon et al, 2015). …”