Dong E, Matsumoto K, Uzunova V, Sugaya I, Takahata H, Nomura H, Watanabe H, Costa E, Guidotti A
The Psychiatric Institute, Department of Psychiatry, University of Illinois, College of Medicine, 1601 West Taylor Street, Chicago, IL 60612, USA.
Proc Natl Acad Sci U S A. 2001 Feb 27;98(5):2849-54. doi: 10.1073/pnas.051628598.
Allopregnanolone (ALLO), is a brain endogenous neurosteroid that binds with high affinity to gamma-aminobutyric acid type A (GABA(A)) receptors and positively modulates the action of GABA at these receptors. Unlike ALLO, 5alpha-dihydroprogesterone (5alpha-DHP) binds with high affinity to intracellular progesterone receptors that regulate DNA transcription. To investigate the physiological roles of ALLO and 5alpha-DHP synthesized in brain, we have adopted a mouse model involving protracted social isolation. In the frontal cortex of mice, socially isolated for 6 weeks, both neurosteroids were decreased by approximately 50%. After administration of (17beta)-17-(bis-1-methyl amino carbonyl) androstane-3,5-diene-3-carboxylic acid (SKF105,111), an inhibitor of the enzyme (5alpha-reductase Type I and II) that converts progesterone into 5alpha-DHP, the ALLO and 5alpha-DHP content of frontal cortex of both group-housed and socially isolated mice decreased exponentially to 10%-20% of control values in about 30 min. The fractional rate constants (k h(-1)) of ALLO and 5alpha-DHP decline multiplied by the ALLO and 5alpha-DHP concentrations at any given steady-state estimate the rate of synthesis required to maintain that steady state. After 6 weeks of social isolation, ALLO and 5alpha-DHP biosynthesis rates were decreased to 30% of the values calculated in group-housed mice. Moreover, in socially isolated mice, the expression of 5alpha-reductase Type I mRNA and protein was approximately 50% lower than in group-housed mice whereas 3alpha-hydroxysteroid oxidoreductase mRNA expression was equal in the two groups. Protracted social isolation in mice may provide a model to investigate whether 5alpha-DHP by a genomic action, and ALLO by a nongenomic mechanism down-regulate the action of drugs acting as agonists, partial agonists, or positive allosteric modulators of the benzodiazepine recognition sites expressed by GABA(A) receptors.
别孕烯醇酮（ALLO）是一种脑内源性神经甾体，它以高亲和力与γ-氨基丁酸A型（GABA(A)）受体结合，并在这些受体上正向调节GABA的作用。与ALLO不同，5α-二氢孕酮（5α-DHP）以高亲和力与调节DNA转录的细胞内孕酮受体结合。为了研究脑内合成的ALLO和5α-DHP的生理作用，我们采用了一个涉及长期社会隔离的小鼠模型。在社会隔离6周的小鼠额叶皮质中，两种神经甾体均下降了约50%。给予（17β）-17-（双-1-甲基氨基羰基）雄甾烷-3,5-二烯-3-羧酸（SKF105,111），一种将孕酮转化为5α-DHP的Ⅰ型和Ⅱ型5α-还原酶的抑制剂后，群居和社会隔离小鼠额叶皮质中的ALLO和5α-DHP含量在约30分钟内呈指数下降至对照值的10%-20%。ALLO和5α-DHP下降的分数速率常数（kh(-1)）乘以任何给定稳态下的ALLO和5α-DHP浓度，可估算维持该稳态所需的合成速率。经过6周的社会隔离后，ALLO和5α-DHP的生物合成速率降至群居小鼠计算值的30%。此外，在社会隔离的小鼠中，Ⅰ型5α-还原酶的mRNA和蛋白表达比群居小鼠低约50%，而两组中3α-羟基类固醇氧化还原酶的mRNA表达相等。小鼠的长期社会隔离可能提供一个模型，用于研究5α-DHP是否通过基因组作用，以及ALLO是否通过非基因组机制下调作为GABA(A)受体表达的苯二氮䓬识别位点的激动剂、部分激动剂或正变构调节剂的药物的作用。
