Activation of the mGlu1 metabotropic glutamate receptor has antipsychotic-like effects and is required for efficacy of M4 muscarinic receptor allosteric modulators

Recent clinical and preclinical studies suggest that selective activators of the M 4 muscarinic acetylcholine receptor have potential as a novel treatment for schizophrenia. M 4 activation inhibits striatal dopamine release by mobilizing endocannabinoids, providing a mechanism for local effects on dopamine signaling in the striatum but not in extrastriatal areas. G protein-coupled receptors (GPCRs) typically induce endocannabinoid release through activation of Gα q/11 -type G proteins whereas M 4 transduction occurs through Gα i/o -type G proteins. We now report that the ability of M 4 to inhibit dopamine release and induce antipsychotic-like effects in animal models is dependent on co-activation of the Gα q/11 -coupled mGlu 1 subtype of metabotropic glutamate (mGlu) receptor. This is especially interesting in light of recent findings that multiple loss of function single nucleotide polymorphisms (SNPs) in the human gene encoding mGlu 1 ( GRM1 ) are associated with schizophrenia, and points to GRM1 /mGlu 1 as a gene within the “druggable genome” that could be targeted for the treatment of schizophrenia. Herein, we report that potentiation of mGlu 1 signaling following thalamo-striatal stimulation is sufficient to inhibit striatal dopamine release, and that a novel mGlu 1 positive allosteric modulator (PAM) exerts robust antipsychotic-like effects through an endocannabinoid-dependent mechanism. However, unlike M 4 , mGlu 1 does not directly inhibit dopamine D 1 receptor signaling and does not reduce motivational responding. Taken together, these findings highlight a novel mechanism of cross talk between mGlu 1 and M 4 and demonstrate that highly selective mGlu 1 PAMs may provide a novel strategy for the treatment of positive symptoms associated with schizophrenia.