Selective serotonin reuptake inhibitors directly alter activity of neurosteroidogenic enzymes

摘要: The neurosteroid 3α-hydroxysteroid-5α-pregnan-20-one (allopregnanolone) acts as a positive allosteric modulator of γ-aminobutyric acid at type A receptors and hence is powerful anxiolytic, anticonvulsant, anesthetic agent. Allopregnanolone synthesized from progesterone by reduction to 5α-dihydroprogesterone, mediated 5α-reductase, allopregnanolone, 3α-hydroxysteroid dehydrogenase (3α-HSD). Previous reports suggested that some selective serotonin reuptake inhibitors (SSRIs) could alter concentrations allopregnanolone in human cerebral spinal fluid rat brain sections. We determined whether SSRIs directly altered the activities either 5α-reductase or 3α-HSD, using an vitro system containing purified recombinant proteins. Although rats appear express single 3α-HSD isoform, contains several isoforms this enzyme, including new isoform we cloned fetal brains. Our results indicate fluoxetine, sertraline, paroxetine decrease Km conversion 5α-dihydroprogesterone III 10- 30-fold. Only sertraline inhibited reverse oxidative reaction. also affected conversions androgens 3α- 3α, 17β-reduced -oxidized IIBrain. Another antidepressant, imipramine, was without any effect on androstanediol production. region-specific expression IIBrain mRNAs suggest will affect production manner. may thus help explain rapid alleviation anxiety dysphoria associated with late luteal phase disorder major unipolar depression these SSRIs.