Brain 5alpha-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 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.
The Psychiatric Institute, Department of Psychiatry, University of Illinois, College of Medicine, 1601 West Taylor Street, Chicago, IL 60612, USA.
E
E
Dong
K
K
Matsumoto
V
V
Uzunova
I
I
Sugaya
H
H
Takahata
H
H
Nomura
H
H
Watanabe
E
E
Costa
A
A
Guidotti
D000818:Animals; D001483:Base Sequence; D001921:Brain / Q000201:enzymology / Q000378:metabolism*; D004247:DNA; D013196:Dihydrotestosterone / Q000378:metabolism*; D008297:Male; D051379:Mice; D023421:Models, Animal; D008969:Molecular Sequence Data; D011280:Pregnanolone / Q000096:biosynthesis* / Q000737:chemistry / Q000378:metabolism; D012934:Social Isolation
D013196:Dihydrotestosterone; D004247:DNA; D011280:Pregnanolone