Activation of the mGlu 1 metabotropic glutamate receptor has antipsychotic-like effects and is required for efficacy of M 4 muscarinic receptor allosteric modulators

Recent clinical and preclinical studies suggest that selective activators of the M muscarinic acetylcholine receptor have potential as a novel treatment for schizophrenia. M 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 -type G proteins whereas M transduction occurs through Gα -type G proteins. We now report that the ability of M to inhibit dopamine release and induce antipsychotic-like effects in animal models is dependent on co-activation of the Gα -coupled mGlu 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 (GRM1) are associated with schizophrenia, and points to GRM1/mGlu as a gene within the "druggable genome" that could be targeted for the treatment of schizophrenia. Herein, we report that potentiation of mGlu signaling following thalamo-striatal stimulation is sufficient to inhibit striatal dopamine release, and that a novel mGlu positive allosteric modulator (PAM) exerts robust antipsychotic-like effects through an endocannabinoid-dependent mechanism. However, unlike M , mGlu does not directly inhibit dopamine D receptor signaling and does not reduce motivational responding. Taken together, these findings highlight a novel mechanism of cross talk between mGlu and M and demonstrate that highly selective mGlu PAMs may provide a novel strategy for the treatment of positive symptoms associated with schizophrenia.