O'Dell Laura E, Alomary Ahmed A, Vallée Monique, Koob George F, Fitzgerald Robert L, Purdy Robert H
Department of Neuropharmacology, CVN-7, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA.
Eur J Pharmacol. 2004 Jan 26;484(2-3):241-7. doi: 10.1016/j.ejphar.2003.11.031.
Peripheral administration of alcohol has been demonstrated to cause significant increases in neurosteroid levels in the brain and periphery. These findings have led to several theories suggesting a role for neurosteroids in the actions of alcohol. However, the anatomical sources of these steroids (e.g., brain or periphery) are as yet unknown. This study utilized gas chromatography/mass spectrometry (GC/MS) to assess the levels of several neuroactive steroids in plasma and brain frontal cortex 30-360 min following acute administration of alcohol (2 g/kg, i.p.). Concentrations of pregnenolone, allopregnanolone (3alpha-hydroxy-5alpha-pregnan-20-one), and allotetrahydrodeoxycorticosterone (3alpha,21-dihydroxy-5alpha-pregnan-20-one) were all measured. In order to determine the contribution of peripheral endocrine organs to neurosteroid responses, neuroactive steroid levels were measured in both intact and adrenalectomized/gonadectomized male Wistar rats 30 min after acute administration of alcohol. Intact animals exhibited a maximal increase of pregnenolone in plasma and frontal cortex 30 min after acute administration of alcohol. In addition, allopregnanolone levels increased, with a maximal effect observed at 60 min in plasma. However, in the adrenalectomized/gonadectomized groups treated with alcohol, no significant increases of pregnenolone, allopregnanolone, or allotetrahydrodeoxycorticosterone were found after 30 min. Thus, the alcohol-induced response was associated first with a relatively rapid increase in the first and rate-limiting step in the conversion of cholesterol to steroids, leading to increases in pregnenolone levels. This response was followed by the further secretion of the anxiolytic neuroactive steroids allopregnanolone and allotetrahydrodeoxycorticosterone, both of which appeared to be of adrenal and gonadal origin.
经外周给予酒精已被证明会导致大脑和外周神经甾体水平显著升高。这些发现引发了几种理论，认为神经甾体在酒精作用中发挥作用。然而，这些甾体的解剖学来源（例如，大脑还是外周）尚不清楚。本研究利用气相色谱/质谱联用技术（GC/MS）评估急性给予酒精（2 g/kg，腹腔注射）后30 - 360分钟血浆和脑额叶皮质中几种神经活性甾体的水平。测量了孕烯醇酮、别孕烯醇酮（3α-羟基-5α-孕烷-20-酮）和别四氢脱氧皮质酮（3α,21-二羟基-5α-孕烷-20-酮）的浓度。为了确定外周内分泌器官对神经甾体反应的贡献，在急性给予酒精30分钟后，测量了完整的以及肾上腺切除/性腺切除的雄性Wistar大鼠的神经活性甾体水平。完整动物在急性给予酒精后30分钟，血浆和额叶皮质中的孕烯醇酮出现最大程度的增加。此外，别孕烯醇酮水平升高，在血浆中60分钟时观察到最大效应。然而，在接受酒精治疗的肾上腺切除/性腺切除组中，30分钟后未发现孕烯醇酮、别孕烯醇酮或别四氢脱氧皮质酮有显著增加。因此，酒精诱导的反应首先与胆固醇转化为甾体的第一步也是限速步骤中相对快速的增加有关，导致孕烯醇酮水平升高。随后是抗焦虑神经活性甾体别孕烯醇酮和别四氢脱氧皮质酮的进一步分泌，这两种甾体似乎都来源于肾上腺和性腺。
