title: Effect of genetic and pharmacological blockade of GABA receptors on the 5-HT2C receptor function during stress.
abstract: Serotonin (5-HT)2C receptors play a role in psychoaffective disorders and often contribute to the antidepressant and anxiolytic effects of psychotropic drugs. During stress, activation of these receptors exerts a negative feedback on 5-HT release, probably by increasing the activity of GABAergic interneurons. However, to date, the GABA receptor types that mediate the 5-HT2C receptor-induced feedback inhibition are still unknown. To address this question, we assessed the inhibition of 5-HT turnover by a 5-HT2C receptor agonist (RO 60-0175) at the hippocampal level and under conditions of stress, after pharmacological or genetic inactivation of either GABA-A or GABA-B receptors in mice. Neither the GABA-B receptor antagonist phaclofen nor the specific genetic ablation of either GABA-B1a or GABA-B1b subunits altered the inhibitory effect of RO 60-0175, although 5-HT turnover was markedly decreased in GABA-B1a knock-out mice in both basal and stress conditions. In contrast, the 5-HT2C receptor-mediated inhibition of 5-HT turnover was reduced by the GABA-A receptor antagonist bicuculline. However, a significant effect of 5-HT2C receptor activation persisted in mutant mice deficient in the α3 subunit of GABA-A receptors. It can be inferred that non-α3 subunit-containing GABA-A receptors, but not GABA-B receptors, mediate the 5-HT2C -induced inhibition of stress-induced increase in hippocampal 5-HT turnover in mice.
authors.affiliation: Paris Descartes, University of Paris, Paris, France; UPMC, University of Paris, Paris, France; Inserm UMR S894, Centre de Psychiatrie et Neurosciences, Paris, France.
authors.forename: Cédric B P
authors.initials: CB
authors.lastname: Martin
authors.forename: Martin
authors.initials: M
authors.lastname: Gassmann
authors.forename: Caroline
authors.initials: C
authors.lastname: Chevarin
authors.forename: Michel
authors.initials: M
authors.lastname: Hamon
authors.forename: Uwe
authors.initials: U
authors.lastname: Rudolph
authors.forename: Bernhard
authors.initials: B
authors.lastname: Bettler
authors.forename: Laurence
authors.initials: L
authors.lastname: Lanfumey
authors.forename: Raymond
authors.initials: R
authors.lastname: Mongeau
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D005021:Ethylamines / Q000494:pharmacology; D018682:GABA Agents / Q000494:pharmacology*; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D006897:Hydroxyindoleacetic Acid / Q000378:metabolism; D007211:Indoles / Q000494:pharmacology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D044405:Receptor, Serotonin, 5-HT2C / Q000378:metabolism*; D018079:Receptors, GABA / Q000172:deficiency / Q000235:genetics*; D012701:Serotonin / Q000378:metabolism; D013315:Stress, Psychological / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology
chemical_list: D005021:Ethylamines; D018682:GABA Agents; D007211:Indoles; D044405:Receptor, Serotonin, 5-HT2C; D018079:Receptors, GABA; C103848:Ro 60-0175; D012701:Serotonin; D006897:Hydroxyindoleacetic Acid
keywords: GABA-A α3 subunit; GABA-B; bicuculline; knockout; phaclofen
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