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

Molecular Psychiatry volume 25, pages 2786–2799 (2020)Cite this article

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Abstract

Recent clinical and preclinical studies suggest that selective activators of the M4 muscarinic acetylcholine receptor have potential as a novel treatment for schizophrenia. M4 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 Gαq/11-type G proteins whereas M4 transduction occurs through Gαi/o-type G proteins. We now report that the ability of M4 to inhibit dopamine release and induce antipsychotic-like effects in animal models is dependent on co-activation of the Gαq/11-coupled mGlu1 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 mGlu1 (GRM1) are associated with schizophrenia, and points to GRM1/mGlu1 as a gene within the “druggable genome” that could be targeted for the treatment of schizophrenia. Herein, we report that potentiation of mGlu1 signaling following thalamo-striatal stimulation is sufficient to inhibit striatal dopamine release, and that a novel mGlu1 positive allosteric modulator (PAM) exerts robust antipsychotic-like effects through an endocannabinoid-dependent mechanism. However, unlike M4, mGlu1 does not directly inhibit dopamine D1 receptor signaling and does not reduce motivational responding. Taken together, these findings highlight a novel mechanism of cross talk between mGlu1 and M4 and demonstrate that highly selective mGlu1 PAMs may provide a novel strategy for the treatment of positive symptoms associated with schizophrenia.

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Acknowledgements

We would like to thank Douglas Shaw and Ginger Milne for their invaluable assistance. This work was supported by funding from an NIH Institutional Training Grant (T32 MH065215-14) and Ruth L. Kirschstein National Research Service Award (F32MH113266) to SEY, a NARSAD Young Investigator Award to DJF, grants to PJC from National Institute of Mental Health (MH062646) and the National Institute of Neurological Disease and Stroke (NS031373), National Institute on Drug Abuse grants to JFC (DA022340 and DA042595) and a NARSA to DPC (DA041827). Research conducted by the Vanderbilt Neurochemistry Core is supported by the EKS NICHD of the NIH (U54HD083211). Data generated by the Neurochemistry Core is solely the responsibility of the authors and does not necessarily represent the official views of the NIH.

Author contributions:

SEY and PJC conceived the studies and wrote the manuscript. SEY, DJF, DPC, MSM, CKJ, JFC, and MB designed experiments. SEY, DPC, MSM, JG, ALB, HPC, and MB conducted experiments and analyzed the data. CWL and PMBG provided pharmacological tools utilized in this study.

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Authors and Affiliations

  1. Department of Pharmacology, Vanderbilt University, Nashville, TN, USA

    Samantha E. Yohn, Daniel J. Foster, Mark S. Moehle, Jordan Galbraith, Michael Bubser, Max E. Joffe, Carrie K. Jones, Craig W. Lindsley & P. Jeffrey Conn

  2. Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University, Nashville, TN, USA

    Samantha E. Yohn, Daniel J. Foster, Mark S. Moehle, Hyekyung P. Cho, Michael Bubser, Anna L. Blobaum, Max E. Joffe, Carrie K. Jones, Craig W. Lindsley & P. Jeffrey Conn

  3. Vanderbilt Kennedy Center, Vanderbilt University School of Medicine, Nashville, TN, USA

    Daniel J. Foster, Carrie K. Jones & P. Jeffrey Conn

  4. Department of Anatomy and Neurobiology, University of Maryland School of Medicine, Baltimore, MD, USA

    Dan P. Covey & Joseph F. Cheer

  5. Department of Chemistry, Department of Biochemistry, Vanderbilt University, Nashville, TN, USA

    Pedro M. Garcia-Barrantes & Craig W. Lindsley

  6. Department of Psychiatry, University of Maryland School of Medicine, Baltimore, MD, USA

    Joseph F. Cheer

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  1. Samantha E. Yohn
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Correspondence to P. Jeffrey Conn.

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Competing interests

CWL and PJC are inventors on patents that protect different classes of metabotropic glutamate allosteric modulators. CWL has been funded by the NIH, Johnson and Johnson, Bristol-Myers Squibb, AstraZeneca, Michael J. Fox Foundation, as well as Seaside Therapeutics. He has consulted for AbbVie and received compensation. PJC has been funded by NIH, AstraZeneca, Bristol-Myers Squibb, Michael J. Fox Foundation, Dystonia Medical Research Foundation, CHDI Foundation, and Thome Memorial Foundation. Over the past three years he has served on the Scientific Advisory Boards for Michael J. Fox Foundation, Stanley Center for Psychiatric Research Broad Institute, Karuna Pharmaceuticals, Lieber Institute for Brain Development, Clinical Mechanism and Proof of Concept Consortium, and Neurobiology Foundation for Schizophrenia and Bipolar Disorder. SEY, DJF, DPC, MSM, JG, PMGB, HPC, MB, ALB, MEJ, JFC, and CKJ declare no potential conflicts of interest.

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Yohn, S.E., Foster, D.J., Covey, D.P. et al. Activation of the mGlu1 metabotropic glutamate receptor has antipsychotic-like effects and is required for efficacy of M4 muscarinic receptor allosteric modulators. Mol Psychiatry 25, 2786–2799 (2020). https://doi.org/10.1038/s41380-018-0206-2

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