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

Abstract

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.

Schizophrenia, Dopamine and the Striatum: From Biology to Symptoms

“…Preclinical studies have shown that M4 positive allosteric modulators (PAMs) act on striatal MSNs to specifically inhibit dorsal striatum dopamine release via endocannabinoid signalling 114, 115. Other preclinical studies have shown that activation of group 1 metabotropic glutamate receptors may also selectively reduce dorsal striatum dopamine transmission via interaction with M4 receptors, but that unlike M4 activation, mGlu1 PAMs appear to have the advantage of not reducing motivational responding [115]. Encouragingly, a PAM of the M1/M4 receptor has shown efficacy in treating schizophrenia, although tolerability issues have prevented further clinical trials [116].…”

Neuropharmacological Insight from Allosteric Modulation of mGlu Receptors

“…Consistent with these mouse and human genetic studies, exciting new studies reveal that mGlu 1 PAMs have antipsychotic-like effects in preclinical models of NMDAR-hypofunction [32]. Extensive ex vivo and in vivo fast-scan cyclic voltammetry studies suggest that mGlu 1 PAMs exert their antipsychotic-like effects by reducing striatal dopamine release [32].…”

Targeting mGlu Receptors for Optimization of Antipsychotic Activity and Disease-Modifying Effect in Schizophrenia

“…An elegant manuscript describes a novel form of receptor-receptor interaction involving M4 muscarinic acetylcholine receptors and mGlu1 receptors ( 70 ). This interaction might pave the way to novel therapeutic strategies in schizophrenia.…”

“…Interestingly, this mechanism requires the co-activation of mGlu1 receptors, which are coupled to G q/11 , and, therefore, have the fisique du role to enhance the production of endocannabinoids. M4 receptors, which are coupled to G i/o , are also able to inhibit D1 receptor signaling, but this function is independent of mGlu1 receptors ( 70 ) ( Figure 1 ). Inhibition of dopamine release mediated by mGlu1 receptors explains the antipsychotic-like activity of selective mGlu1 PAMs in rodents ( 70 ) and holds promise for the treatment of positive symptoms of schizophrenia.…”

“…M4 receptors, which are coupled to G i/o , are also able to inhibit D1 receptor signaling, but this function is independent of mGlu1 receptors ( 70 ) ( Figure 1 ). Inhibition of dopamine release mediated by mGlu1 receptors explains the antipsychotic-like activity of selective mGlu1 PAMs in rodents ( 70 ) and holds promise for the treatment of positive symptoms of schizophrenia. Mutations of GRM1 (the gene encoding for the mGlu1 receptor) that reduce mGlu1 receptor signaling have been associated with schizophrenia ( 71 ), and mice lacking mGlu1 receptors display a psychotic-like phenotype ( 72 ).…”