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

Autor: Yohn SE; Department of Pharmacology, Vanderbilt University, Nashville, TN, USA.; Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University, Nashville, TN, USA., Foster DJ; Department of Pharmacology, Vanderbilt University, Nashville, TN, USA.; Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University, Nashville, TN, USA.; Vanderbilt Kennedy Center, Vanderbilt University School of Medicine, Nashville, TN, USA., Covey DP; Department of Anatomy and Neurobiology, University of Maryland School of Medicine, Baltimore, MD, USA., Moehle MS; Department of Pharmacology, Vanderbilt University, Nashville, TN, USA.; Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University, Nashville, TN, USA., Galbraith J; Department of Pharmacology, Vanderbilt University, Nashville, TN, USA., Garcia-Barrantes PM; Department of Chemistry, Department of Biochemistry, Vanderbilt University, Nashville, TN, USA., Cho HP; Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University, Nashville, TN, USA., Bubser M; Department of Pharmacology, Vanderbilt University, Nashville, TN, USA.; Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University, Nashville, TN, USA., Blobaum AL; Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University, Nashville, TN, USA., Joffe ME; Department of Pharmacology, Vanderbilt University, Nashville, TN, USA.; Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University, Nashville, TN, USA., Cheer JF; Department of Anatomy and Neurobiology, University of Maryland School of Medicine, Baltimore, MD, USA.; Department of Psychiatry, University of Maryland School of Medicine, Baltimore, MD, USA., Jones CK; Department of Pharmacology, Vanderbilt University, Nashville, TN, USA.; Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University, Nashville, TN, USA.; Vanderbilt Kennedy Center, Vanderbilt University School of Medicine, Nashville, TN, USA., Lindsley CW; Department of Pharmacology, Vanderbilt University, Nashville, TN, USA.; Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University, Nashville, TN, USA.; Department of Chemistry, Department of Biochemistry, Vanderbilt University, Nashville, TN, USA., Conn PJ; Department of Pharmacology, Vanderbilt University, Nashville, TN, USA. Jeff.Conn@Vanderbilt.edu.; Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University, Nashville, TN, USA. Jeff.Conn@Vanderbilt.edu.; Vanderbilt Kennedy Center, Vanderbilt University School of Medicine, Nashville, TN, USA. Jeff.Conn@Vanderbilt.edu.
Jazyk: angličtina
Zdroj: Molecular psychiatry [Mol Psychiatry] 2020 Nov; Vol. 25 (11), pp. 2786-2799. Date of Electronic Publication: 2018 Aug 16.
DOI: 10.1038/s41380-018-0206-2
Abstrakt: 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.
Databáze: MEDLINE
Externí odkaz: