Reversal of caffeine-induced anxiety by neurosteroid 3-alpha-hydroxy-5-alpha-pregnane-20-one in rats
Reversal of caffeine-induced anxiety by neurosteroid 3-alpha-hydroxy-5-alpha-pregnane-20-one in rats
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DOI：
10.1016/j.neuropharm.2004.11.016
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发表时间：
2005-04-01
影响因子：
4.7
通讯作者：
Chopde, CT
中科院分区：
文献类型：
--
作者：
Jain, NS;Hirani, K;Chopde, CT
咖啡因已被证明增加脑和血浆中神经类固醇3 α-羟基-5 α-胆甾烷-20-酮（3 α，5 α-THP）的含量，该神经类固醇3 α-羟基-5 α-胆甾烷-20-酮（3 α，5 α-THP）变构调节GABA（A）受体。本研究采用大鼠高架十字迷宫实验评价了神经甾体3a，5a-THP在咖啡因诱导的焦虑样效应中的作用。急性给予咖啡因（50或100 mg/kg，i. p.）产生焦虑样活性，其通过用神经类固醇3a，5a-THP或孕酮、GABAA激动剂蝇蕈醇或苯二氮卓受体激动剂地西泮预处理而逆转。相反，咖啡因在先前用GABAA受体拮抗剂、荷包牡丹碱或各种神经甾体生物合成酶抑制剂（即曲洛司坦、非那肽或吲哚美辛）治疗的动物中产生更高的焦虑。此外，DHEAS（一种负性调节GABAA受体的神经类固醇）预处理也增强了咖啡因诱导的焦虑。此外，肾上腺切除术增强了咖啡因的焦虑样反应，表明外周类固醇生成的贡献作用。因此，据推测，神经类固醇3 α，5 α-THP通过GABAA受体活性的正调节可能作为对抗咖啡因诱导的焦虑的反调节机制。(c)2005爱思唯尔有限公司保留所有权利。
Caffeine has been shown to increase brain and plasma content of neurosteroid 3 alpha-hydroxy-5 alpha-pregnan-20-one (3 alpha,5 alpha-THP) that allosterically modulates GABA(A) receptors. The present study evaluated the role of neurosteroid 3a,5a-THP in the caffeine-induced anxiogenic-like effect using the elevated plus-maze (EPM) test in rats. Acute administration of caffeine (50 or 100 mg/kg, i.p.) produced anxiogenic-like activity that was reversed by pretreatment with the neurosteroid 3a,5a-THP or progesterone, the GABAA agonist muscimol, or the benzodiazepine receptor agonist diazepam. On the contrary, caffeine produced higher anxiety in animals previously treated with the GABAA receptor antagonist, bicuculline or either of the various neurosteroid biosynthesis enzyme inhibitors viz. trilostane, finasteride or indomethacin. Furthermore, pretreatment with DHEAS, a neurosteroid that negatively modulates GABAA receptors also enhanced the caffeine-induced anxiety. Moreover, adrenalectomy potentiated the anxiogenic-like response of caffeine indicating the contributory role of peripheral steroidogenesis. Thus, it is speculated that neurosteroid 3 alpha,5 alpha-THP through positive modulation of GABAA receptor activity may serve as a counter-regulatory mechanism against caffeine-induced anxiety. (c) 2005 Elsevier Ltd. All rights reserved.