Neurochemical and behavioral studies on the 5-HT1A-dependent antipsychotic action of the mGlu4 receptor agonist LSP4-2022

Neuropharmacology. 2017 Mar 15;115:149-165. doi: 10.1016/j.neuropharm.2016.06.025. Epub 2016 Jul 25.


LSP4-2022 is a novel, orthosteric agonist of mGlu4 receptor that induces antipsychotic-like activity in animal studies. In the present study, the involvement of 5-HT1A receptors in LSP4-2022-induced antipsychotic actions and the neurochemical background of that interaction were investigated. In several behavioral tests the actions of effective doses of the compound (0.5-2 mg/kg) were antagonized via the administration of the 5-HT1A antagonist WAY100635 (0.1 mg/kg). The co-administration of sub-effective dose of the 5-HT1A agonist (R)-(S)-8-OH-DPAT (0.01 mg/kg) intensified the activity of ineffective doses of LSP4-2022, having no influence on the efficacy of the active doses. The co-administration of effective doses of both compounds did not intensify each other's action. In the microdialysis in vivo tests, MK-801 (0.6 mg/kg) induced an enhancement of the release of dopamine, serotonin, glutamate and GABA in the prefrontal cortex. Administration of LSP4-2022 (2 mg/kg) abolished this MK-801-induced effect on neurotransmitter release. Co-administration with WAY100635 (0.1 mg/kg), a 5-HT1A antagonist, completely (dopamine, serotonin) or partially (glutamate, GABA) counteracted this LSP4-2022-induced effect. Subsequently, the patch-clamp recordings of spontaneous EPSCs were performed. sEPSCs were evoked in slices from the mouse prefrontal cortex by DOI (10 μM). LSP4-2022 (2.5; 5 and 10 μm) reversed DOI-induced changes in both the frequency and amplitude of the sEPSCs, but the more robust effect on the frequency was observed. The administration of WAY100635 had no effect on the LSP4-2022-induced effects on sEPSCs, indicating that the mGlu4-5-HT1A interaction does not occur via single-neuron signaling but involves neuronal circuits that regulate neurotransmitter release. This article is part of the Special Issue entitled 'Metabotropic Glutamate Receptors, 5 years on'.

Keywords: 5-HT(1A); Dopamine; GABA; Glutamate; Schizophrenia; Serotonin; mGlu.

MeSH terms

  • Animals
  • Antipsychotic Agents / pharmacology*
  • Dizocilpine Maleate / pharmacology
  • Dose-Response Relationship, Drug
  • Excitatory Amino Acid Agonists / pharmacology
  • Interpersonal Relations
  • Locomotion / drug effects
  • Locomotion / physiology*
  • Male
  • Mice
  • Phosphinic Acids / pharmacology*
  • Piperazines / pharmacology
  • Pyridines / pharmacology
  • Rats
  • Rats, Wistar
  • Receptor, Serotonin, 5-HT1A / physiology*
  • Receptors, Metabotropic Glutamate / agonists*
  • Receptors, Metabotropic Glutamate / physiology*
  • Serotonin Antagonists / pharmacology


  • Antipsychotic Agents
  • Excitatory Amino Acid Agonists
  • LSP4-2022
  • Phosphinic Acids
  • Piperazines
  • Pyridines
  • Receptors, Metabotropic Glutamate
  • Serotonin Antagonists
  • Receptor, Serotonin, 5-HT1A
  • Dizocilpine Maleate
  • N-(2-(4-(2-methoxyphenyl)-1-piperazinyl)ethyl)-N-(2-pyridinyl)cyclohexanecarboxamide
  • metabotropic glutamate receptor 4