title: Fluoxetine elevates allopregnanolone in female rat brain but inhibits a steroid microsomal dehydrogenase rather than activating an aldo-keto reductase.
abstract: OBJECTIVE
  Fluoxetine, a selective serotonin reuptake inhibitor, elevates brain concentrations of the neuroactive progesterone metabolite allopregnanolone, an effect suggested to underlie its use in the treatment of premenstrual dysphoria. One report showed fluoxetine to activate the aldo-keto reductase (AKR) component of 3α-hydroxysteroid dehydrogenase (3α-HSD), which catalyses production of allopregnanolone from 5α-dihydroprogesterone. However, this action was not observed by others. The present study sought to clarify the site of action for fluoxetine in elevating brain allopregnanolone.
  
  
  METHODS
  Adult male rats and female rats in dioestrus were treated with fluoxetine and their brains assayed for allopregnanolone and its precursors, progesterone and 5α-dihydroprogesterone. Subcellular fractions of rat brain were also used to investigate the actions of fluoxetine on 3α-HSD activity in both the reductive direction, producing allopregnanolone from 5α-dihydroprogesterone, and the reverse oxidative direction. Fluoxetine was also tested on these recombinant enzyme activities expressed in HEK cells.
  
  
  RESULTS
  Short-term treatment with fluoxetine increased brain allopregnanolone concentrations in female, but not male, rats. Enzyme assays on native rat brain fractions and on activities expressed in HEK cells showed fluoxetine did not affect the AKR producing allopregnanolone from 5α-dihydroprogesterone but did inhibit the microsomal dehydrogenase oxidizing allopregnanolone to 5α-dihydroprogesterone.
  
  
  CONCLUSIONS
  Fluoxetine elevated allopregnanolone in female rat brain by inhibiting its oxidation to 5α-dihydroprogesterone by a microsomal dehydrogenase. This is a novel site of action for fluoxetine, with implications for the development of new agents and/or dosing regimens to raise brain allopregnanolone.
authors.affiliation: Department of Neuroscience, Physiology and Pharmacology, University College London (UCL), London, UK.
authors.forename: J P
authors.initials: JP
authors.lastname: Fry
authors.forename: K Y
authors.initials: KY
authors.lastname: Li
authors.forename: A J
authors.initials: AJ
authors.lastname: Devall
authors.forename: S
authors.initials: S
authors.lastname: Cockcroft
authors.forename: J W
authors.initials: JW
authors.lastname: Honour
authors.forename: T A
authors.initials: TA
authors.lastname: Lovick
mesh_terms: D045002:3-alpha-Hydroxysteroid Dehydrogenase (B-Specific) / Q000037:antagonists & inhibitors* / Q000378:metabolism; D043582:5-alpha-Dihydroprogesterone / Q000378:metabolism; D000449:Aldehyde Reductase / Q000187:drug effects / Q000378:metabolism; D000074408:Aldo-Keto Reductases; D000818:Animals; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D005260:Female; D005473:Fluoxetine / Q000494:pharmacology*; D057809:HEK293 Cells; D006801:Humans; D008297:Male; D011280:Pregnanolone / Q000096:biosynthesis / Q000378:metabolism*; D011374:Progesterone / Q000378:metabolism; D051381:Rats; D017367:Selective Serotonin Reuptake Inhibitors / Q000494:pharmacology*
chemical_list: D045002:3-alpha-Hydroxysteroid Dehydrogenase (B-Specific); D043582:5-alpha-Dihydroprogesterone; D000449:Aldehyde Reductase; D000074408:Aldo-Keto Reductases; D005473:Fluoxetine; D011280:Pregnanolone; D011374:Progesterone; D017367:Selective Serotonin Reuptake Inhibitors