Majewska M D
Addiction Research Center, National Institute on Drug Abuse, Baltimore, MD 21224.
Ciba Found Symp. 1990;153:83-97; discussion 97-106. doi: 10.1002/9780470513989.ch5.
Certain endogenous steroids are modulators of GABAA receptors. Tetrahydroprogesterone (THP, 5 alpha-pregnan-3 alpha-ol-20-one) and tetrahydrodeoxy-corticosterone (THDOC, 5 alpha-pregnane-3 alpha, 21-diol-20-one) behave as allosteric agonists of GABAA receptors whereas pregnenolone sulphate acts as an antagonist. THP and THDOC modulate ligand binding to GABAA receptors like barbiturates; they potentiate binding of the GABAA receptor agonist muscimol and the benzodiazepine flunitrazepam and they allosterically inhibit binding of the convulsant t-butylbicyclophosphorothionate. THP and THDOC also stimulate chloride uptake and currents in synaptoneurosomes and neurons. Pregnenolone sulphate acts principally as an allosteric GABAA receptor antagonist; it competitively inhibits binding of [35S] TBPS and blocks GABA agonist-activated Cl- uptake and currents in synaptoneurosomes and neurons. In behavioural experiments the GABA-agonistic steroid THDOC shows anxiolytic actions whereas the GABA-antagonistic steroid pregnenolone sulphate antagonizes barbiturate-induced hypnosis. Changes in physiological levels of GABAergic steroids may alter GABAA receptor function, influencing neuronal excitability and CNS arousal. For example, pregnancy and the puerperium are associated with alterations in GABAA receptor binding which might be attributable to steroid actions.
某些内源性类固醇是GABAA受体的调节剂。四氢孕酮（THP，5α-孕烷-3α-醇-20-酮）和四氢脱氧皮质酮（THDOC，5α-孕烷-3α，21-二醇-20-酮）作为GABAA受体的变构激动剂，而孕烯醇酮硫酸盐则作为拮抗剂。THP和THDOC像巴比妥类药物一样调节配体与GABAA受体的结合；它们增强GABAA受体激动剂蝇蕈醇和苯二氮卓类药物氟硝西泮的结合，并且变构抑制惊厥剂叔丁基双环磷硫代酸盐的结合。THP和THDOC还刺激突触体神经小体和神经元中的氯离子摄取和电流。孕烯醇酮硫酸盐主要作为GABAA受体的变构拮抗剂；它竞争性抑制[35S]TBPS的结合，并阻断GABA激动剂激活的突触体神经小体和神经元中的氯离子摄取和电流。在行为实验中，具有GABA激动作用的类固醇THDOC表现出抗焦虑作用，而具有GABA拮抗作用的类固醇孕烯醇酮硫酸盐则拮抗巴比妥类药物诱导的催眠作用。GABA能类固醇生理水平的变化可能会改变GABAA受体的功能，影响神经元兴奋性和中枢神经系统觉醒。例如，妊娠和产褥期与GABAA受体结合的改变有关，这可能归因于类固醇的作用。
