The anxiolytic-like effects of the neurosteroid allopregnanolone: Interactions with GABA(A) receptors
The anxiolytic-like effects of the neurosteroid allopregnanolone: Interactions with GABA(A) receptors
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DOI：
10.1016/s0014-2999(97)00096-4
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发表时间：
1997-04-23
影响因子：
5
通讯作者：
Britton, KT
中科院分区：
文献类型：
--
作者：
Brot, MD;Akwa, Y;Britton, KT
神经类固醇3 α -羟基-5 α -孕酮-20- 1（异孕酮）被系统地给予大鼠，在盖勒-塞夫特冲突范式中进行测试，这是一种建立的焦虑动物模型。发现异孕酮在8mg /kg剂量时产生显著的抗焦虑样作用。当三种作用于γ -氨基丁酸/苯二氮卓受体-氯离子复合物（GABA，受体）上的配体与异孕酮酮结合时，异孕酮酮的抗冲突作用仅被苯二氮卓受体逆激动剂RO15-4513（乙基-8-叠氮-5,6-二氢-5-甲基-6-氧- 4h -咪唑[1,5- α]-[1,4]苯二氮卓-3-羧酸盐）有效逆转。由于这种反向激动剂已被报道能抑制GABA(A)激活的神经元膜氯离子通量，因此GABA(A)受体中氯离子通道的刺激很可能是异孕酮作用的重要组成部分。相比之下，苯二氮卓类受体拮抗剂氟马西尼（乙基-8-氟-5,6-二氢-5-甲基-6-氧- 4h -咪唑[1,5- α]-[1,4]苯二氮卓-3-羧酸盐）不能阻断异孕酮酮的抗焦虑作用，表明异孕酮酮不会直接结合在苯二氮卓类部位。异丙基双环磷酸结合在氨基丁酸（GABA）受体上的微旋毒素位点并阻断乙醇的行为，也能剂量依赖性地逆转这种神经类固醇的抗冲突作用。结果表明，异孕酮可能在苯二氮卓受体逆激动剂RO15-4513的特异性位点或在微旋毒素位点起作用，以产生其有效的抗焦虑样行为作用。(C) 1997爱思唯尔科学有限公司
The neurosteroid 3 alpha-hydroxy-5 alpha-pregnan-20-one (allopregnanolone) was administered systemically to rats which were tested in the Geller-Seifter conflict paradigm, an established animal model of anxiety. Allopregnanolone was found to produce significant anxiolytic-like effects at a dose of 8 mg/kg. When three ligands that function at different sites on the gamma-aminobutyric acid/benzodiazepine receptor-chloride ionophore complex (GABA, receptors) were examined in conjunction with allopregnanolone, the anti-conflict effects of allopregnanolone were effectively reversed only by the benzodiazepine receptor inverse agonist RO15-4513 (ethyl-8-azido-5,6-dihydro-5-methyl-6-oxo-4H-imidazo [1,5-alpha]-[1,4]benzodiazepine-3-carboxylate). Since this inverse agonist has been reported to inhibit the GABA(A)-activated chloride flux in neuronal membranes, it is likely that the stimulation of the chloride channel in GABA(A) receptors is an important component of the effects of allopregnanolone. In contrast, the benzodiazepine receptor antagonist flumazenil (ethyl-8-fluoro-5,6-dihydro-5-methyl-6-oxo-4H-imidazo [1,5-alpha]-[1,4]benzodiazepine-3-carboxylate) did not block the anxiolytic-like actions of allopregnanolone, indicating that allopregnanolone does not bind at the benzodiazepine site directly. Isopropylbicyclophosphate, which binds at the picrotoxinin site on the GABA, receptors and blocks the behavioral actions of ethanol, also dose-dependently reversed the anti-conflict effect of this neurosteroid. The results suggest that allopregnanolone may be working either at a site specific for the benzodiazepine receptor inverse agonist RO15-4513 or at the picrotoxinin site to produce its potent anxiolytic-like behavioral effects. (C) 1997 Elsevier Science B.V.