Khisti Rahul T, VanDoren Margaret J, O'Buckley Todd, Morrow A Leslie
Departments of Psychiatry and Pharmacology, Bowles Center for Alcohol Studies, University of North Carolina at Chapel Hill, School of Medicine, CB #7178, Chapel Hill, NC 27599-7178, USA.
Brain Res. 2003 Aug 8;980(2):255-65. doi: 10.1016/s0006-8993(03)02978-0.
Systemic ethanol administration elevates plasma and brain levels of GABAergic neuroactive steroids, including 3alpha-hydroxy-5alpha-pregnan-20-one (3alpha,5alpha-THP) that contribute to specific behavioral actions of ethanol. The present study determined the effect of adrenalectomy and 5alpha-reductase type-1/type-2 enzyme inhibition, known to reduce neuroactive steroids, on ethanol-induced increases in cerebral cortical levels of 3alpha,5alpha-THP and hypnotic effects in male rats. Systemic ethanol administration to male rats increases plasma levels of progesterone and corticosterone similar to acute stress, indicating release of these steroids from adrenal glands. Adrenalectomy markedly reduced the elevation of cerebral cortical 3alpha,5alpha-THP and plasma progesterone levels and reduced the duration of ethanol-induced loss of righting reflex. Prior systemic administration of 5alpha-dihydroprogesterone (10 or 15 mg/kg, i.p.), an immediate precursor of 3alpha,5alpha-THP, to adrenalectomized rats not only restored the ethanol-induced increases in cerebral cortical 3alpha,5alpha-THP levels but also reversed the effect of adrenalectomy on ethanol-induced loss of righting reflex. Prior administration of the 5alpha-reductase inhibitor finasteride (2 x 25, 2 x 75 or 2 x 150 mg/kg, s.c.) and the 5alpha-reductase type-1 inhibitor SKF-105,111 (50 mg/kg, i.p.) did not reduce ethanol-induced increases in the cerebral cortical levels of 3alpha,5alpha-THP at hypnotic doses of ethanol. Furthermore, these drugs did not alter the duration of loss of righting reflex. However, significant correlations between cerebral cortical 3alpha,5alpha-THP levels and the duration of loss of righting reflex were obtained regardless of finasteride administration. These results demonstrate the contributory role of neuroactive steroids in the ethanol-induced loss of righting reflex and the source of ethanol-induced elevation of GABAergic neuroactive steroids. Ethanol-induced increases in neurosteroids could be pertinent to the etiology of sleep-related disorders associated with alcoholism.
全身性给予乙醇会提高血浆和大脑中γ-氨基丁酸能神经活性甾体的水平，包括3α-羟基-5α-孕烷-20-酮（3α,5α-四氢孕酮），这些甾体参与乙醇的特定行为作用。本研究确定了已知会降低神经活性甾体的肾上腺切除术和1型/2型5α-还原酶抑制对乙醇诱导的雄性大鼠大脑皮质3α,5α-四氢孕酮水平升高及催眠作用的影响。对雄性大鼠全身性给予乙醇会使血浆孕酮和皮质酮水平升高，类似于急性应激，表明这些甾体从肾上腺释放。肾上腺切除术显著降低了大脑皮质3α,5α-四氢孕酮和血浆孕酮水平的升高，并缩短了乙醇诱导的翻正反射消失的持续时间。对肾上腺切除的大鼠预先全身性给予3α,5α-四氢孕酮的直接前体5α-二氢孕酮（10或15毫克/千克，腹腔注射），不仅恢复了乙醇诱导的大脑皮质3α,5α-四氢孕酮水平升高，还逆转了肾上腺切除术对乙醇诱导的翻正反射消失的影响。预先给予5α-还原酶抑制剂非那雄胺（2×25、2×75或2×150毫克/千克，皮下注射）和1型5α-还原酶抑制剂SKF-105,111（50毫克/千克，腹腔注射），在乙醇催眠剂量下并未降低乙醇诱导的大脑皮质3α,5α-四氢孕酮水平升高。此外，这些药物并未改变翻正反射消失的持续时间。然而，无论是否给予非那雄胺，大脑皮质3α,5α-四氢孕酮水平与翻正反射消失持续时间之间均存在显著相关性。这些结果证明了神经活性甾体在乙醇诱导的翻正反射消失中的作用以及乙醇诱导的γ-氨基丁酸能神经活性甾体升高的来源。乙醇诱导的神经甾体增加可能与酒精中毒相关的睡眠相关障碍的病因有关。
