Involvement of GABAB Receptor Signaling in Antipsychotic-like Action of the Novel Orthosteric Agonist of the mGlu4 Receptor, LSP4-2022

Current Neuropharmacology
Monika WoźniakJ M Wierońska

Abstract

Considering that ligands of metabotropic glutamate and GABA receptors may exert beneficial effects on schizophrenia, we assessed the actions of the first mGlu>4-selective orthosteric agonist, LSP4-2022, in several tests reflecting positive, negative, and cognitive symptoms of schizophrenia. Moreover, we investigated the possible involvement of GABAB receptors in LSP4-2022-induced actions. Hyperactivity induced by MK-801 or amphetamine and DOI-induced head twitches in mice were used as the models of positive symptoms. The social interaction test, modified forced swim test (FST), and novel object recognition (NOR) test were used as the models of negative and cognitive symptoms of schizophrenia. LSP4-2022 inhibited hyperactivity (in a dose-dependent manner, 0.5-2 mg/kg) induced by MK-801 or amphetamine and DOI-induced head twitches. In mGlu4 receptor knockout mice, LSP4-2022 was not effective. However, it reversed MK-801-induced impairment in the social interaction test and the MK-801-induced increase of immobility in the modified FST. In the NOR test, LSP4-2022 was active at a dose of 2 mg/kg. GABAB receptor antagonist, CGP55845 (10 mg/kg), reversed LSP4-2022-induced effects in hyperactivity and head twitch tests. At the same tim...Continue Reading

Citations

Oct 9, 2018·Frontiers in Molecular Neuroscience·Paulina CieślikJoanna Wierońska
Mar 23, 2019·International Journal of Molecular Sciences·Iulia Zoicas, Johannes Kornhuber
Jan 9, 2019·Frontiers in Molecular Neuroscience·Bartłomiej PochwatGabriel Nowak
Nov 14, 2019·International Journal of Molecular Sciences·Iulia Zoicas, Johannes Kornhuber
Apr 28, 2017·Molecular Brain·James MaksymetzP Jeffrey Conn
Nov 26, 2020·International Journal of Molecular Sciences·Paulina Cieślik, Joanna M Wierońska
May 1, 2021·Journal of Clinical Medicine·Waldemar Kryszkowski, Tomasz Boczek
Jun 19, 2018·Pharmacology, Biochemistry, and Behavior·Monika WoźniakJoanna M Wieronska
Jun 17, 2020·Current Drug Targets·Hemen S Ved, Gaurav M Doshi
Feb 6, 2018·Journal of Medicinal Chemistry·Chelliah SelvamFrancine C Acher

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