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Role of mGlu2 in the 5-HT2A receptor-dependent antipsychotic activity of clozapine in mice

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Abstract

Background

Serotonin 5-HT2A and metabotropic glutamate 2 (mGlu2) are neurotransmitter G protein-coupled receptors (GPCRs) involved in the signaling mechanisms underlying psychosis and schizophrenia treatment. Previous findings in mGlu2 knockout (KO) mice suggested that mGlu2 is necessary for head-twitch behavior, a rodent phenotype characteristic of hallucinogenic 5-HT2A receptor agonists. However, the role of mGlu2 in the behavioral effects induced by antipsychotic drugs remains poorly understood. Here, we tested antipsychotic-like behavioral phenotypes induced by the atypical antipsychotic clozapine in mGlu2-KO mice and wild-type control littermates.

Methods

Locomotor activity was tested in mGlu2-KO mice and control littermates injected (i.p.) with clozapine (1.5 mg/kg) or vehicle followed by MK801 (0.5 mg/kg), PCP (7.5 mg/kg), amphetamine (6 mg/kg), scopolamine (2 mg/kg), or vehicle. Using a virally (HSV) mediated transgene expression approach, the role of frontal cortex mGlu2 in the modulation of MK801-induced locomotor activity by clozapine treatment was also evaluated.

Results

The effect of clozapine on hyperlocomotor activity induced by the dissociative drugs MK801 and phencyclidine (PCP) was decreased in mGlu2-KO mice as compared to controls. Clozapine treatment, however, reduced hyperlocomotor activity induced by the stimulant drug amphetamine and the deliriant drug scopolamine in both wild-type and mGlu2-KO mice. Virally mediated over-expression of mGlu2 in the frontal cortex of mGlu2-KO mice rescued the ability of clozapine to reduce MK801-induced hyperlocomotion.

Conclusion

These findings further support the existence of a functionally relevant crosstalk between 5-HT2A and mGlu2 receptors in different preclinical models of antipsychotic activity.

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Funding

This study was supported by NIH grants R01-MH084894 (J.G.M.), R01-MH111940 (J.G.M.), and P50-AA022537 (M.F.M.).

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Author notes

  1. Kelsey S. Hideshima and Ashkhan Hojati contributed equally to this work.

Authors and Affiliations

  1. Department of Physiology and Biophysics, Virginia Commonwealth University School of Medicine, Richmond, VA, 23298, USA

    Kelsey S. Hideshima, Ashkhan Hojati, Justin M. Saunders, Doan M. On, Mario de la Fuente Revenga, Jong M. Shin, Ana Sánchez-González, Cassandra M. Dunn & Javier González-Maeso

  2. Department of Pharmacology and Toxicology, Virginia Commonwealth University School of Medicine, Richmond, VA, 23298, USA

    Alexander B. Pais, Anthony C. Pais, Michael F. Miles & Jennifer T. Wolstenholme

  3. VCU Alcohol Research Center, Virginia Commonwealth University School of Medicine, Richmond, VA, 23298, USA

    Alexander B. Pais, Anthony C. Pais, Michael F. Miles & Jennifer T. Wolstenholme

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  1. Kelsey S. Hideshima
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Correspondence to Javier González-Maeso.

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Experiments were conducted in accord with NIH guidelines and were approved by the Virginia Commonwealth University Animal Care and Use Committee.

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Hideshima, K.S., Hojati, A., Saunders, J.M. et al. Role of mGlu2 in the 5-HT2A receptor-dependent antipsychotic activity of clozapine in mice. Psychopharmacology 235, 3149–3165 (2018). https://doi.org/10.1007/s00213-018-5015-4

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