title: Neurochemical and behavioral studies on the 5-HT1A-dependent antipsychotic action of the mGlu4receptor agonist LSP4-2022.
abstract: LSP4-2022 is a novel, orthosteric agonist of mGlu4receptor that induces antipsychotic-like activity in animal studies. In the present study, the involvement of 5-HT1Areceptors 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-HT1Aantagonist WAY100635 (0.1 mg/kg). The co-administration of sub-effective dose of the 5-HT1Aagonist (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-HT1Aantagonist, 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-HT1Ainteraction 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'.
authors.affiliation: Institute of Pharmacology, Polish Academy of Sciences, 31-343 Kraków, Poland.
authors.forename: Monika
authors.initials: M
authors.lastname: Woźniak
authors.affiliation: Institute of Pharmacology, Polish Academy of Sciences, 31-343 Kraków, Poland.
authors.forename: Krystyna
authors.initials: K
authors.lastname: Gołembiowska
authors.affiliation: Institute of Pharmacology, Polish Academy of Sciences, 31-343 Kraków, Poland.
authors.forename: Karolina
authors.initials: K
authors.lastname: Noworyta-Sokołowska
authors.affiliation: Laboratory of Pharmacological and Toxicological Chemistry and Biochemistry, UMR8601-CNRS, Paris Descartes University, Sorbonne Paris Cite,45, rue des Saints-Peres, 75270 Paris Cedex 06, France.
authors.forename: Francine
authors.initials: F
authors.lastname: Acher
authors.affiliation: Institute of Pharmacology, Polish Academy of Sciences, 31-343 Kraków, Poland.
authors.forename: Paulina
authors.initials: P
authors.lastname: Cieślik
authors.affiliation: Institute of Pharmacology, Polish Academy of Sciences, 31-343 Kraków, Poland.
authors.forename: Magdalena
authors.initials: M
authors.lastname: Kusek
authors.affiliation: Institute of Pharmacology, Polish Academy of Sciences, 31-343 Kraków, Poland.
authors.forename: Krzysztof
authors.initials: K
authors.lastname: Tokarski
authors.affiliation: Institute of Pharmacology, Polish Academy of Sciences, 31-343 Kraków, Poland.
authors.forename: Andrzej
authors.initials: A
authors.lastname: Pilc
authors.affiliation: Institute of Pharmacology, Polish Academy of Sciences, 31-343 Kraków, Poland. Electronic address: wierons@if-pan.krakow.pl.
authors.forename: Joanna M
authors.initials: JM
authors.lastname: Wierońska
mesh_terms: D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology*; D016291:Dizocilpine Maleate / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology; D007398:Interpersonal Relations; D008124:Locomotion / Q000187:drug effects / Q000502:physiology*; D008297:Male; D051379:Mice; D010721:Phosphinic Acids / Q000494:pharmacology*; D010879:Piperazines / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D044282:Receptor, Serotonin, 5-HT1A / Q000502:physiology*; D018094:Receptors, Metabotropic Glutamate / Q000819:agonists* / Q000502:physiology*; D012702:Serotonin Antagonists / Q000494:pharmacology
chemical_list: D014150:Antipsychotic Agents; D018690:Excitatory Amino Acid Agonists; C572429:LSP4-2022; D010721:Phosphinic Acids; D010879:Piperazines; D011725:Pyridines; D018094:Receptors, Metabotropic Glutamate; D012702:Serotonin Antagonists; D044282:Receptor, Serotonin, 5-HT1A; D016291:Dizocilpine Maleate; C090413:N-(2-(4-(2-methoxyphenyl)-1-piperazinyl)ethyl)-N-(2-pyridinyl)cyclohexanecarboxamide; C108823:metabotropic glutamate receptor 4
keywords: 5-HT(1A); Dopamine; GABA; Glutamate; Schizophrenia; Serotonin; mGlu