Rupprecht R, di Michele F, Hermann B, Ströhle A, Lancel M, Romeo E, Holsboer F
Department of Psychiatry, Ludwig Maximilian University, Munich, Germany.
Brain Res Brain Res Rev. 2001 Nov;37(1-3):59-67. doi: 10.1016/s0165-0173(01)00123-0.
Besides their binding to cognate intracellular receptors gonadal steroids may also act as functional antagonists at the 5-HT3 receptor. A structure-activity relationship for the actions of a variety of steroids at the 5-HT3 receptor was elaborated that differed considerably from that known for GABA(A) receptors. Steroids appear to interact allosterically with ligand-gated ion channels at the receptor membrane interface. The functional antagonism of gonadal steroids at the 5-HT3 receptor may play a role for the development and course of nausea during pregnancy and of psychiatric disorders. Moreover, we could demonstrate that 3alpha-reduced neuroactive steroids concurrently modulate the GABA(A) receptor and regulate gene expression via the progesterone receptor after intracellular oxidation. Animal studies showed that progesterone is converted rapidly into GABAergic neuroactive steroids in vivo. Progesterone reduces locomotor activity in a dose dependent fashion in male Wister rats. Moreover, progesterone and 3alpha,5alpha-tetrahydroprogesterone produce a benzodiazepine-like sleep EEG profile in rats and humans. In addition, there is a dysequilibrium of such 3alpha-reduced neuroactive steroids during major depression which is corrected by successful treatment with antidepressants. Neuroactive steroids may further be involved in the treatment of depression and anxiety with antidepressants in patients during ethanol withdrawal. First studies in patients with panic disorder suggest that neuroactive steroids may also play a pivotal role in human anxiety. The genomic and non-genomic effects of steroids in the brain contribute to the pathophysiology of psychiatric disorders and the mechanisms of action of antidepressants. Neuroactive steroids affect a broad spectrum of behavioral functions through their unique molecular properties and may constitute a yet unexploited class of drugs.
除了与同源细胞内受体结合外，性腺类固醇还可能作为5-HT3受体的功能性拮抗剂发挥作用。阐述了多种类固醇在5-HT3受体上作用的构效关系，这与已知的GABA(A)受体的构效关系有很大不同。类固醇似乎在受体膜界面与配体门控离子通道发生变构相互作用。性腺类固醇在5-HT3受体上的功能性拮抗作用可能在孕期恶心的发生和发展以及精神疾病中起作用。此外，我们能够证明，3α-还原神经活性类固醇在细胞内氧化后，可同时调节GABA(A)受体并通过孕酮受体调节基因表达。动物研究表明，孕酮在体内可迅速转化为具有GABA能的神经活性类固醇。孕酮以剂量依赖的方式降低雄性Wister大鼠的运动活性。此外，孕酮和3α,5α-四氢孕酮在大鼠和人类中产生类似苯二氮䓬的睡眠脑电图特征。此外，在重度抑郁症期间，这种3α-还原神经活性类固醇存在失衡，而抗抑郁药的成功治疗可纠正这种失衡。神经活性类固醇可能还参与了乙醇戒断期间患者使用抗抑郁药治疗抑郁症和焦虑症。对惊恐障碍患者的初步研究表明，神经活性类固醇在人类焦虑中可能也起关键作用。类固醇在大脑中的基因组和非基因组效应有助于精神疾病的病理生理学以及抗抑郁药的作用机制。神经活性类固醇通过其独特的分子特性影响广泛的行为功能，可能构成一类尚未开发的药物。
