期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2001
卷号：98
期号：5
页码：2849-2854
DOI：10.1073/pnas.051628598
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：Allopregnanolone (ALLO), is a brain endogenous neurosteroid that binds with high affinity to {gamma}-aminobutyric acid type A (GABAA) receptors and positively modulates the action of GABA at these receptors. Unlike ALLO, 5-dihydroprogesterone (5-DHP) binds with high affinity to intracellular progesterone receptors that regulate DNA transcription. To investigate the physiological roles of ALLO and 5-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 (17{beta})-17-(bis-1-methyl amino carbonyl) androstane-3,5-diene-3-carboxylic acid (SKF105,111), an inhibitor of the enzyme (5-reductase Type I and II) that converts progesterone into 5-DHP, the ALLO and 5-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 5-DHP decline multiplied by the ALLO and 5-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 5-DHP biosynthesis rates were decreased to 30% of the values calculated in group-housed mice. Moreover, in socially isolated mice, the expression of 5-reductase Type I mRNA and protein was approximately 50% lower than in group-housed mice whereas 3-hydroxysteroid oxidoreductase mRNA expression was equal in the two groups. Protracted social isolation in mice may provide a model to investigate whether 5-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 GABAA receptors.
