Modulation of γ-aminobutyric acid (GABA) receptors and the feeding response by neurosteroids in Hydra vulgaris
Modulation of γ-aminobutyric acid (GABA) receptors and the feeding response by neurosteroids in Hydra vulgaris
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DOI：
10.1016/s0306-4522(97)00515-0
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发表时间：
1998-08-01
期刊：
影响因子：
3.3
通讯作者：
Biggio, G
中科院分区：
文献类型：
--
作者：
Concas, A;Pierobon, P;Biggio, G
γ-氨基丁酸（GABA）受体存在于来自普通水螅（Hydra vulgaris）的膜制备物中，普通水螅是具有神经系统的最原始生物之一。这些受体对蝇蕈醇和苯二氮卓类药物敏感，似乎在调节摄食反应中起重要作用。神经类固醇的作用。全身麻醉剂和GABA拮抗剂对从水螅制备的膜中的GABA（A）受体和对摄食反应的作用现在已经被研究。神经甾体四氢孕酮和四氢脱氧皮质酮增加[（3）H]GABA与水螅膜的结合，具有纳摩尔效力（EC（50），分别为141 +/- 11和623 +/- 36 nM）和高效力（最大增加分别为79+/-6.5和62+/-4%），而四氢孕酮的3 β-羟基差向异构体无效。苯二氮卓受体配体地西泮（100 μ M）、氯硝西泮（100 μ M）和阿倍卡尼尔（30 μ M）分别使[（3）H]GABA与水螅膜的结合增强22%、20%和24%;特异性苯二氮卓拮抗剂氟马西尼（100 μ M）消除了这种作用。相反，外周苯二氮卓受体配体4 '氯地西泮不能影响[（3）H]GABA与水螅膜的结合。全身麻醉剂丙泊酚和阿法沙龙同样增加（分别为+38%和+30%）[（3）H]GABA结合。GABA（A）受体拮抗剂SR 95531可完全抑制[（3）H]GABA与水螅膜的结合，而荷包牡丹碱则无此作用。这些不同药物对GABA（A）受体的体外调节与它们对谷胱甘肽诱导的活体动物摄食反应的影响相关。四氢孕酮和四氢脱氧皮质酮（1至10 μ M）以剂量依赖性方式延长了10 μ M谷胱甘肽诱导的张口持续时间，最大效应分别为+33和+29%，在10 μ M神经甾体时明显。阿法沙龙（10 μ M）同样增加（+33%）谷胱甘肽的作用。SR 95531以剂量依赖方式抑制类固醇对摄食反应的影响;叔丁基环磷酸硫酯（1 μ M），一种特异性Cl（-）通道阻滞剂，与印防己毒素相似，但不与荷包牡丹碱相似，缩短了反应持续时间，也抵消了1 μ M的类固醇效应。这些结果表明，GABA（A）类固醇对受体的作用是动物界的古老特征，并且这些受体的药理学性质在进化过程中高度保守。(C)1998年IBRO。出版社：Elsevier Science Ltd
gamma-Aminobutyric acid (GABA) receptors are present in membrane preparations from Hydra vulgaris, one of the most primitive organisms with a nervous system. These receptors are sensitive to muscimol and benzodiazepines and appear to be important in the regulation of the feeding response. The effects of neurosteroids. general anaesthetics, and GABA antagonists on GABA(A) receptors in membranes prepared from Hydra and on the feeding response have now been investigated. The neurosteroids tetrahydroprogesterone and tetrahydrodeoxycorticosterone increased [(3)H]GABA binding to hydra membranes with nanomolar potency (EC(50), 141 +/- 11 and 623 +/- 36 nM, respectively) and high efficacy (maximal increase 79+/-6.5 and 62+/-4%, respectively), whereas the 3 beta-hydroxy epimer of tetrahydroprogesterone was ineffective. The benzodiazepine receptor ligands diazepam (100 mu M), clonazepam (100 mu M) and abecarnil (30 mu M) enhanced [(3)H]GABA binding to Hydra membranes by 22; 20 and 24%, respectively; effects abolished by the specific benzodiazepine antagonist flumazenil (100 mu M). On the contrary, the peripheral benzodiazepine receptor ligand 4'chlorodiazepam failed to affect [(3)H]GABA binding to Hydra membranes. The general anaesthetics propofol and alphaxalone similarly increased (+38% and +30%, respectively) [(3)H]GABA binding. Moreover, [(3)H]GABA binding to Hydra membranes was completely inhibited by the GABA(A) receptor antagonist SR 95531, whereas bicuculline was without effect. The modulation of GABA(A) receptors in vitro by these various drugs correlated with their effects on the glutathione-induced feeding response in the living animals. Tetrahydroprogesterone and tetrahydrodeoxycorticosterone (I to 10 mu M) prolonged, in a dose-dependent manner, the duration of mouth opening induced by 10 mu M glutathione, with maximal effects of +33 and +29%, respectively, apparent at 10 mu M neurosteroid. Alphaxalone (10 mu M) similarly increased (+33%) the effect of glutathione. The effects of steroids on the feeding response were inhibited by SR 95531 in a dose-dependent manner; t-butylbyclophosphorothyonate (1 mu M), a specific Cl(-) channel blocker, which pei se, like picrotoxin but not bicuculline, shortened the duration of the response, also counteracted the steroids effects at 1 mu M.These results suggest that the modulation of GABA(A) receptors by steroids is an ancient characteristic of the animal kingdom and that the pharmacological properties of these receptors have been highly conserved through evolution. (C) 1998 IBRO. Published by Elsevier Science Ltd.