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Vol. 96, Issue 23, 13512-13517, November 9, 1999 (3
* Department of Obstetrics, Edited by Erminio Costa, University of Illinois, Chicago, IL, and
approved September 14, 1999 (received for review May 13, 1999)
The neurosteroid 3
Copyright © 1999 by The National Academy of Sciences 0027-8424/99/9613512-6$2.00/0
Neurobiology
Selective serotonin reuptake inhibitors directly alter activity
of neurosteroidogenic enzymes
hydroxysteroid
dehydrogenase / fluoxetine / allopregnanolone /
dihydroprogesterone)
and
,§
Department of Neurology, and Center for
Reproductive Sciences and The Metabolic Research Unit, University of
California, Box 0556, San Francisco, CA 94143-0556
-hydroxysteroid-5-pregnan-20-one
(allopregnanolone) acts as a positive allosteric modulator of
-aminobutyric acid at -aminobutyric acid type A receptors and
hence is a powerful anxiolytic, anticonvulsant, and anesthetic agent.
Allopregnanolone is synthesized from progesterone by reduction to
5-dihydroprogesterone, mediated by 5-reductase, and by reduction
to allopregnanolone, mediated by 3-hydroxysteroid dehydrogenase
(3-HSD). Previous reports suggested that some selective serotonin
reuptake inhibitors (SSRIs) could alter concentrations of
allopregnanolone in human cerebral spinal fluid and in rat brain
sections. We determined whether SSRIs directly altered the activities
of either 5-reductase or 3-HSD, using an in vitro
system containing purified recombinant proteins. Although rats appear
to express a single 3-HSD isoform, the human brain contains several
isoforms of this enzyme, including a new isoform we cloned from human
fetal brains. Our results indicate that the SSRIs fluoxetine,
sertraline, and paroxetine decrease the Km of
the conversion of 5-dihydroprogesterone to allopregnanolone by human
3-HSD type III 10- to 30-fold. Only sertraline inhibited the reverse
oxidative reaction. SSRIs also affected conversions of androgens to
3- and 3, 17
-reduced or -oxidized androgens mediated by
3-HSD type IIBrain. Another antidepressant, imipramine, was without any effect on allopregnanolone or androstanediol
production. The region-specific expression of 3-HSD type
IIBrain and 3-HSD type III mRNAs suggest that SSRIs will
affect neurosteroid production in a region-specific manner. Our results
may thus help explain the rapid alleviation of the anxiety and
dysphoria associated with late luteal phase dysphoria disorder and
major unipolar depression by these SSRIs.
§
To whom reprint requests should be addressed. E-mail:
mellon{at}cgl.ucsf.edu.
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