Flesinoxan treatment reduces 5-HT1A receptor mRNA in the dentate gyrus independently of high plasma corticosterone levels

• Published in: European journal of pharmacology Vol. 353; no. 2-3; pp. 207 - 214
• Main Authors: SIBUG, R. M, COMPAAN, J. C, MEIJER, O. C, VAN DER GUGTEN, J, OLIVIER, B, RON DE KLOET, E
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier 24.07.1998
• Subjects: Animals; Biological and medical sciences; Corticosterone - blood; Dentate Gyrus - drug effects; Dentate Gyrus - metabolism; In Situ Hybridization; Male; Medical sciences; Neuropharmacology; Pharmacology. Drug treatments; Piperazines - pharmacology; Psycholeptics: tranquillizer, neuroleptic; Psychology. Psychoanalysis. Psychiatry; Psychopharmacology; Rats; Rats, Wistar; Receptors, Serotonin - genetics; Receptors, Serotonin, 5-HT1; RNA, Messenger - genetics; RNA, Messenger - metabolism; Serotonin Receptor Agonists - pharmacology; Agonist; Rat; Corticosterone; Steroid hormone; Psychotropic; Rodentia; Central nervous system; Flesinoxan; Gene expression; Glucocorticoid; Vertebrata; Dentate gyrus; Mammalia; Messenger RNA; 5-HT1A Serotonine receptor; Tranquillizer; Animal; Adrenal hormone; Subcutaneous administration; Mechanism of action; Hippocampus; Brain (vertebrata); Rhinencephalon
• ISSN: 0014-2999; 1879-0712
• DOI: 10.1016/S0014-2999(98)00417-8

Flesinoxan acts as a full 5-HT1A receptor agonist and displays anxiolytic and anti-depressant properties. 5-HT1A receptor agonists, including flesinoxan, increase corticosterone (B) levels in the blood and reduces 5-HT1A receptor mRNA expression in the hippocampus. In this study, we examined whether the 5-HT1A receptor downregulation induced by flesinoxan involves corticosterone control of 5-HT1A receptor gene transcription. In experiment I, intact male Wistar rats (180-200 g) were treated with flesinoxan (1.0, 3.0 and 10 mg/kg bw, sc) or vehicle and decapitated 3 h later. Flesinoxan administration resulted in a significant, dose-dependent downregulation of 5-HT1A receptor mRNA in the dentate gyrus and dorsal raphe nucleus. In experiment II, rats were sham-operated and implanted with a cholesterol pellet (100 mg) or were adrenalectomized and implanted with a corticosterone pellet (20 mg corticosterone + 80 mg cholesterol). Flesinoxan injection also caused a dose-dependent decrease of 5-HT1A mRNA in the dentate gyrus of adrenalectomized animals with corticosterone replacement. There was no effect in the dorsal raphe nucleus. In experiment III, adrenalectomized and adrenalectomized + corticosterone rats were sc injected with flesinoxan (10 mg/kg bw) or vehicle, and flesinoxan appeared to downregulate 5-HT1A receptor expression in the dentate gyrus independently of corticosterone as well. No significant effects were observed in the dorsal raphe nucleus. It is concluded that flesinoxan reduces 5-HT1A receptor expression in the dentate gyrus both through homologous downregulation and a corticosterone-mediated effect on the serotonergic (5-HT) system.