Mutual activation of glutamatergic mGlu4 and muscarinic M4 receptors reverses schizophrenia-related changes in rodents

Psychopharmacology (Berl). 2018 Oct;235(10):2897-2913. doi: 10.1007/s00213-018-4980-y. Epub 2018 Jul 27.


Rationale: Metabotropic glutamate receptors and muscarinic M4 receptors have been proposed as novel targets for various brain disorders, including schizophrenia. Both receptors are coupled to Go/i proteins and are expressed in brain circuits that are important in schizophrenia. Therefore, their mutual activation may be an effective treatment and allow minimizing the doses of ligands required for optimal activity.

Objectives: In the present studies, subactive doses of mGlu4 and M4 activators (LSP4-2022 and VU152100, respectively) were administered to investigate the mutual interaction between mGlu4 and M4 receptors in animal models of schizophrenia.

Methods: The behavioral tests used were MK-801-induced hyperactivity, (±)-2.5-dimethoxy-4-iodoamphetamine hydrochloride (DOI)-induced head twitches, the modified forced swim test, and MK-801-induced disruptions of social interactions and novel object recognition. DOI-induced spontaneous excitatory postsynaptic currents (sEPSCs) in brain slices and positron emission tomography (PET) in were used to establish the ability of these compounds to modulate the glutamatergic and dopaminergic systems. Rotarod was used to assess putative adverse effects.

Results: The mutual administration of subactive doses of LSP4-2022 and VU152100 exerted similar antipsychotic-like efficacy in animals as observed for active doses of both compounds, indicating their additive actions. VU152100 inhibited the DOI-induced frequency (but not amplitude) of sEPSCs in the frontal cortex, confirming presynaptic regulation of glutamate release. Both compounds reversed amphetamine-induced decrease in D2 receptor levels in the striatum, as measured with [18F]fallypride. The compounds did not induce any motor impartments when measured in rotarod test.

Conclusions: Based on our results, the simultaneous activation of M4 and mGlu4 receptors is beneficial in reversing MK-801- and amphetamine-induced schizophrenia-related changes in animals.

Keywords: Animal model; Metabotropic glutamate receptor; Muscarinic receptor; Schizophrenia.

MeSH terms

  • Amphetamine / toxicity
  • Animals
  • Antipsychotic Agents / pharmacology
  • Antipsychotic Agents / therapeutic use*
  • Disease Models, Animal
  • Dizocilpine Maleate / toxicity
  • Dose-Response Relationship, Drug
  • Excitatory Amino Acid Agonists / pharmacology
  • Excitatory Amino Acid Agonists / therapeutic use
  • Male
  • Mice
  • Motor Activity / drug effects
  • Motor Activity / physiology
  • Phosphinic Acids / pharmacology
  • Phosphinic Acids / therapeutic use
  • Receptor, Muscarinic M4 / agonists
  • Receptor, Muscarinic M4 / metabolism*
  • Receptors, Metabotropic Glutamate / agonists
  • Receptors, Metabotropic Glutamate / metabolism*
  • Rodentia
  • Schizophrenia / chemically induced
  • Schizophrenia / drug therapy*
  • Schizophrenia / metabolism*


  • Antipsychotic Agents
  • Excitatory Amino Acid Agonists
  • LSP4-2022
  • Phosphinic Acids
  • Receptor, Muscarinic M4
  • Receptors, Metabotropic Glutamate
  • Dizocilpine Maleate
  • Amphetamine
  • metabotropic glutamate receptor 4