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The Journal of Neuroscience, March 1, 2000, 20(5):1982-1989
Neuroactive Steroid 3 -Hydroxy-5-Pregnan-20-One Modulates
Electrophysiological and Behavioral Actions of Ethanol
Margaret J.
VanDoren1, 2, 3,
Douglas B.
Matthews1, 2,
Gregory C.
Janis1, 2,
A.
Chistina
Grobin1, 2,
Leslie L.
Devaud2, and
A. Leslie
Morrow1, 2, 3
1 Departments of Psychiatry and Pharmacology,
2 Bowles Center for Alcohol Studies, and
3 Curriculum in Neurobiology, University of North Carolina
at Chapel Hill, Chapel Hill, North Carolina 27599-7178
Neuroactive steroids are synthesized de novo in
brain, yet their physiological significance remains elusive. We provide
biochemical, electrophysiological, and behavioral evidence that several
specific actions of alcohol (ethanol) are mediated by the neurosteroid 3 -hydroxy-5-pregnan-20-one (3,5-THP; allopregnanolone).
Systemic alcohol administration elevates 3,5-THP levels in the
cerebral cortex to pharmacologically relevant concentrations. The
elevation of 3,5-THP is dose- and time-dependent. Furthermore,
there is a significant correlation between 3,5-THP levels in
cerebral cortex and the hypnotic effect of ethanol. Blockade of
de novo biosynthesis of 5-reduced steroids using the
5-reductase inhibitor finasteride prevents several effects of
ethanol. Pretreatment with finasteride causes no changes in baseline
bicuculline-induced seizure threshold but reverses the anticonvulsant
effect of ethanol. Finasteride pretreatment also reverses ethanol
inhibition of spontaneous neural activity in medial septal/diagonal
band of Broca neurons while having no direct effect on spontaneous
firing rates. Thus, elevation of 3,5-THP levels by acute ethanol
administration represents a novel mechanism of ethanol action as well
as an important modulatory role for neurosteroids in the CNS.
Key words:
neuroactive steroids; ethanol; allopregnanolone; 3-hydroxy-5-pregnan-20-one; finasteride; nongenomic steroid
actions
Copyright © 2000 Society for Neuroscience 0270-6474/00/2051982-08$05.00/0
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