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Effect of genetic and pharmacological blockade of GABA receptors on the 5‐ HT 2C receptor function during stress
Author(s) -
Martin Cédric B. P.,
Gassmann Martin,
Chevarin Caroline,
Hamon Michel,
Rudolph Uwe,
Bettler Bernhard,
Lanfumey Laurence,
Mongeau Raymond
Publication year - 2014
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1111/jnc.12929
Subject(s) - gabaa receptor , bicuculline , receptor , gabaergic , gaba receptor antagonist , agonist , 5 ht receptor , endocrinology , chemistry , medicine , receptor antagonist , gabaa rho receptor , 5 ht2c receptor , pharmacology , 5 ht1 receptor , biology , serotonin , antagonist , biochemistry
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 GABA ergic interneurons. However, to date, the GABA receptor types that mediate the 5‐ HT 2C receptor‐induced feedback inhibition are still unknown. To address this question, we assessed the inhibition of 5‐ HT turnover by a 5‐ HT 2C 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‐ HT 2C receptor‐mediated inhibition of 5‐ HT turnover was reduced by the GABA ‐A receptor antagonist bicuculline. However, a significant effect of 5‐ HT 2C receptor activation persisted in mutant mice deficient in the α 3 subunit of GABA ‐A receptors. It can be inferred that non‐α 3 subunit‐containing GABA ‐A receptors, but not GABA ‐B receptors, mediate the 5‐ HT 2C ‐induced inhibition of stress‐induced increase in hippocampal 5‐ HT turnover in mice.Serotonin (5‐HT 2C ) receptors expressed by GABA interneurons (2) are known to drive an indirect, GABA‐mediated, inhibitory feedback control of 5‐HT neurons, especially under stressful conditions. Using mutant mice and selective ligands, we demonstrated that this feedback control involves not only GABA‐A receptors (1) but also GABA‐B1a receptors (4), that would inhibit the stimulatory influence of cortical glutamatergic afferences (3) on GABA interneurons. Adaptations of these 5‐HT‐GABA‐glu interactions may contribute to the anxiolytic effects of chronic antidepressant treatments.