Sibug R M, Compaan J C, Meijer O C, Van der Gugten J, Olivier B, De Kloet E R
Leiden/Amsterdam Center for Drug Research, Division of Medical Pharmacology, Sylvius Laboratories, Leiden, The Netherlands.
Eur J Pharmacol. 1998 Jul 24;353(2-3):207-14. 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.
氟西诺生作为一种完全的5-羟色胺1A（5-HT1A）受体激动剂，具有抗焦虑和抗抑郁特性。包括氟西诺生在内的5-HT1A受体激动剂会提高血液中皮质酮（B）的水平，并降低海马体中5-HT1A受体的信使核糖核酸（mRNA）表达。在本研究中，我们检测了氟西诺生诱导的5-HT1A受体下调是否涉及皮质酮对5-HT1A受体基因转录的调控。在实验I中，对体重180 - 200克的雄性Wistar大鼠进行完整处理，用氟西诺生（1.0、3.0和10毫克/千克体重，皮下注射）或赋形剂处理，3小时后断头处死。给予氟西诺生导致齿状回和中缝背核中5-HT1A受体mRNA显著的、剂量依赖性下调。在实验II中，对大鼠进行假手术并植入胆固醇丸（100毫克），或进行肾上腺切除术并植入皮质酮丸（20毫克皮质酮 + 80毫克胆固醇）。注射氟西诺生也导致在接受皮质酮替代的肾上腺切除动物的齿状回中5-HT1A mRNA呈剂量依赖性降低。在中缝背核中没有影响。在实验III中，对肾上腺切除和肾上腺切除 + 皮质酮的大鼠皮下注射氟西诺生（10毫克/千克体重）或赋形剂，氟西诺生似乎也能独立于皮质酮下调齿状回中5-HT1A受体的表达。在中缝背核中未观察到显著影响。结论是，氟西诺生通过同源下调以及对血清素能（5-HT）系统的皮质酮介导作用，降低齿状回中5-HT1A受体的表达。
