Selective serotonin reuptake inhibitors directly alter activity of neurosteroidogenic enzymes

The neurosteroid 3 alpha-hydroxysteroid-5 alpha-pregnan-20-one (allo-pregnanolone) acts as a positive allosteric modulator of gamma-aminobutyric acid at gamma-aminobutyric acid type A receptors and hence is a powerful anxiolytic. anticonvulsant, and anesthetic agent. Allopregnanolone is synthesized from progesterone by reduction to 5 alpha-dihydroprogesterone, mediated by 5 alpha-reductase, and by reduction to allopregnanolone, mediated by 3 alpha-hydroxysteroid dehydrogenase (3 alpha-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 alpha-reductase or 3 alpha-HSD, using an in vitro system containing purified recombinant proteins. Although rats appear to express a single 3 alpha-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 K-m of the conversion of 5 alpha-dihydroprogesterone to allopregnanolone by human 3 alpha-HSD type III 10- to 30-fold. Only sertraline inhibited the reverse oxidative reaction. SSRIs also affected conversions of androgens to 3 alpha- and 3 alpha, 17 beta-reduced or -oxidized androgens mediated by 3 alpha-HSD type IIBrain. Another antidepressant, imipramine, was without any effect on allopregnanolone or androstanediol production. The region-specific expression of 3 alpha-HSD type IIBrain and 3 alpha-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.