Role of mGlu2 in the 5-HT2A receptor-dependent antipsychotic activity of clozapine in mice.
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, Alexander B Pais, Anthony C Pais, Michael F Miles, Jennifer T Wolstenholme, Javier González-Maeso
Psychopharmacology November 2018 DOI: 10.1007/s00213-018-5015-4 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Preclinical behavioral study in genetically modified mice Peer reviewed |
|---|---|
| Population | mGlu2 knockout mice and wild-type control littermates |
| Interventions | Clozapine MK801 PCP amphetamine scopolamine |
| Dose | clozapine 1.5 mg/kg; MK801 0.5 mg/kg; PCP 7.5 mg/kg; amphetamine 6 mg/kg; scopolamine 2 mg/kg |
| Measures | locomotor activity |
| Topics | LSD Serotonin |
| Keywords | Antipsychotics Clozapine Gpcr complexes Hallucinogens Schizophrenia Mglu2 receptor |
| Key points | Clozapine's reduction of MK801- and PCP-induced hyperlocomotion was attenuated in mGlu2 knockout mice relative to controls, whereas its reduction of amphetamine- and scopolamine-induced hyperlocomotion was preserved in both genotypes. Viral overexpression of mGlu2 in the frontal cortex of knockout mice restored clozapine's ability to reduce MK801-induced hyperlocomotion, which the authors argue supports a functional crosstalk between 5-HT2A and mGlu2 receptors. |
Abstract
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. 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. 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. These findings further support the existence of a functionally relevant crosstalk between 5-HT2A and mGlu2 receptors in different preclinical models of antipsychotic activity.
Comparable studies
Other preclinical and animal studies on serotonin, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| Psilocybin induces rapid and persistent growth of dendritic spines in frontal cortex in vivo Mice | 2021 | Observational cohort | |
| Neurotoxicity of the psychedelic amphetamine, methylenedioxymethamphetamine. Rats (implied by typical neurochemical study context) | 1987 | Experimental study | |
| Psychedelics promote neuroplasticity through the activation of intracellular 5-HT2A receptors In vitro and in vivo (rodent) models | 2023 | Experimental study | |
| 3,4-Methylenedioxymethamphetamine and 3,4-methylenedioxyamphetamine destroy serotonin terminals in rat brain: quantification of neurodegeneration by measurement of [3H]paroxetine-labeled serotonin uptake sites. Rat brain | 1987 | Animal experiment | |
| Comparison of the monoamine transporters from human and mouse in their sensitivities to psychostimulant drugs Human and mouse dopamine, norepinephrine, and serotonin transporters expressed in cells | 2006 | In vitro laboratory study |
Citations in the library
Cited by 3
- Psychedelic Targeting of Metabotropic Glutamate Receptor 2 and Its Implications for the Treatment of Alcoholism Cells March 22, 2023
- Prolonged epigenetic and synaptic plasticity alterations following single exposure to a psychedelic in mice bioRxiv (Cold Spring Harbor Laboratory) February 25, 2021
- Prolonged epigenomic and synaptic plasticity alterations following single exposure to a psychedelic in mice Cell Reports October 1, 2021
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