Brain 5 alpha-dihydroprogesterone and allopregnanolone synthesis in a mouse model of protracted social isolation

Allopregnanolone (ALLO), is a brain endogenous neurosteroid that binds with high affinity to gamma -aminobutyric acid type A (GABA(A)) receptors and p ositively modulates the action of GABA at these receptors. Unlike ALLO, 5 a lpha -dihydroprogesterone (5 alpha -DHP) binds with high affinity to intrac ellular progesterone receptors that regulate DNA transcription. To investig ate the physiological roles of ALLO and 5 alpha -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 alpha -reductase Type I and II) that c onverts progesterone into 5 alpha -DHP, the ALLO and 5 alpha -DHP content o f 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 alpha -DHP decline multiplied by the ALLO and 5 alpha -DHP concentrations at any given steady-state estimate th e rate of synthesis required to maintain that steady state. After 6 weeks o f social isolation, ALLO and 5 alpha -DHP biosynthesis rates were decreased to 30% of the values calculated in group-housed mice. Moreover, in sociall y isolated mice, the expression of 5 alpha -reductase Type I mRNA and prote in was approximately 50% lower than in group-housed mice whereas 3 alpha -h ydroxysteroid oxidoreductase mRNA expression was equal in the two groups. P rotracted social isolation in mice may provide a model to investigate wheth er 5 alpha -DHP by a genomic action, and ALLO by a nongenomic mechanism dow n-regulate the action of drugs acting as agonists, partial agonists, or pos itive allosteric modulators of the benzodiazepine recognition sites express ed by GABA(A) receptors.