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Journal of Neuroscience, Vol 15, 4641-4650, Copyright © 1995 by Society for Neuroscience
Gas chromatographic-mass fragmentographic quantitation of 3 alpha- hydroxy-5 alpha-pregnan-20-one (allopregnanolone) and its precursors in blood and brain of adrenalectomized and castrated rats
DL Cheney, D Uzunov, E Costa and A Guidotti
Nathan S. Kline Institute for Psychiatric Research, Center for Neuropharmacology, Orangeburg, New York 10962, USA.
Coupling high performance liquid chromatography with gas chromatography-
mass fragmentography has made it possible to simultaneously measure
subpicomolar concentrations of allopregnanolone and its precursors,
pregnenolone, progesterone and 5 alpha-dihydroprogesterone (5 alpha- DHP)
in various brain areas. Allopregnanolone was measured in the brain of
adrenalectomized/castrated (ADX/CX) rats in nanomolar concentrations long
after peripheral sources of allopregnanolone were removed. A partial
decrease (approximately 30%) in the content of allopregnanolone was found
in the brains of ADX/CX rats compared to sham-operated rats. Moreover, the
content of allopregnanolone in brains of sham-operated as well as ADX/CX
rats was nonuniformly distributed (olfactory bulb > striatum > cortex
> hippocampus) and was one to two orders of magnitude higher than in
plasma or liver. Infusion of pregnenolone sulfate in ADX/CX rats elicited a
fourfold increase in 5 alpha-DHP and progesterone content and a seven- to
eightfold increase in the content of allopregnanolone in brain but not in
liver or plasma. Furthermore, the content of allopregnanolone in brain
increased to the same extent in both sham-operated and ADX/CX rats
following pregnenolone sulfate infusion. The 5 alpha-reductase inhibitor,
(17 beta)17[[bis(1- methylethyl)amino]carbonyl]
androstane-3,5-diene-3-carboxylic acid (SKF 105111), reduced the brain
content of allopregnanolone and blocked the increased formation of
allopregnanolone in brain following pregnenolone sulfate infusion. The
results clearly demonstrate that the synthesis of allopregnanolone from 5
alpha-DHP and progesterone occurs in the brain and that a significant
amount of allopregnanolone is synthesized locally in brain from its
precursors. These experiments suggest that the brain, like adrenals and
gonads, is a steroidogenic organ which produces allopregnanolone as one of
its own most important physiologically relevant steroids.
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