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

Psychopharmacology (Berl). 2018 Nov;235(11):3149-3165. doi: 10.1007/s00213-018-5015-4. Epub 2018 Sep 12.

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.

Keywords: 5-HT2A receptor; Antipsychotics; Clozapine; GPCR complexes; Hallucinogens; LSD; Schizophrenia; Serotonin; mGlu2 receptor.

MeSH terms

  • Animals
  • Antipsychotic Agents / pharmacology
  • Antipsychotic Agents / therapeutic use*
  • Clozapine / pharmacology
  • Clozapine / therapeutic use*
  • Frontal Lobe / drug effects
  • Frontal Lobe / metabolism
  • Male
  • Mice
  • Mice, Knockout
  • Phencyclidine / toxicity
  • Psychomotor Agitation / drug therapy*
  • Psychomotor Agitation / metabolism*
  • Psychotic Disorders / drug therapy
  • Psychotic Disorders / metabolism
  • Receptor, Serotonin, 5-HT2A / physiology*
  • Receptors, Metabotropic Glutamate / deficiency
  • Receptors, Metabotropic Glutamate / physiology*
  • Schizophrenia / chemically induced
  • Schizophrenia / drug therapy
  • Schizophrenia / metabolism

Substances

  • Antipsychotic Agents
  • Receptor, Serotonin, 5-HT2A
  • Receptors, Metabotropic Glutamate
  • metabotropic glutamate receptor 2
  • Phencyclidine
  • Clozapine