Brain 5α-Dihydroprogesterone and Allopregnanolone Synthesis in a Mouse Model of Protracted Social Isolation

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 98; no. 5; pp. 2849 - 2854
• Main Authors: Dong, Erbo, Matsumoto, Kinzo, Uzunova, Veska, Sugaya, Ikuko, Takahata, Hiroki, Nomura, Hiroaki, Watanabe, Hiroshi, Costa, Erminio, Guidotti, Alessandro
• Format: Journal Article
• Language: English
• Published: National Academy of Sciences 27-02-2001; National Acad Sciences; The National Academy of Sciences
• Subjects: 5^a-dihydroprogesterone; 5a-Dihydroprogesterone; allopregnanolone; Biological Sciences; Biosynthesis; Cerebellum; Down regulation; Enzymes; Messenger RNA; Olfactory bulb; Pharmacology; Receptors; Social isolation; Steroids
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.051628598

Allopregnanolone (ALLO), is a brain endogenous neurosteroid that binds with high affinity to γ-aminobutyric acid type A (GABAA) receptors and positively modulates the action of GABA at these receptors. Unlike ALLO, 5α-dihydroprogesterone (5α-DHP) binds with high affinity to intracellular progesterone receptors that regulate DNA transcription. To investigate the physiological roles of ALLO and 5α-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 (17β)-17-(bis-1-methyl amino carbonyl) androstane-3,5-diene-3-carboxylic acid (SKF105,111), an inhibitor of the enzyme (5α-reductase Type I and II) that converts progesterone into 5α-DHP, the ALLO and 5α-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 5α-DHP decline multiplied by the ALLO and 5α-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 5α-DHP biosynthesis rates were decreased to 30% of the values calculated in group-housed mice. Moreover, in socially isolated mice, the expression of 5α-reductase Type I mRNA and protein was approximately 50% lower than in group-housed mice whereas 3α-hydroxysteroid oxidoreductase mRNA expression was equal in the two groups. Protracted social isolation in mice may provide a model to investigate whether 5α-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.