1. Paris Descartes, University of Paris, , Paris, France;2. UPMC, University of Paris, , Paris, France;3. Inserm UMR S894, Centre de Psychiatrie et Neurosciences, , Paris, France;4. Department of Biomedicine, Institute of Physiology, University of Basel, , Basel, Switzerland;5. Laboratory of Genetic Neuropharmacology, McLean Hospital, , Belmont, Massachusetts, USA;6. Department of Psychiatry, Harvard Medical School, , Boston, Massachusetts, USA;7. EA4475, Pharmacologie de la circulation cérébrale, Université Paris Descartes, , Paris, France
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.
