Fluoxetine-elicited changes in brain neurosteroid content measured by negative ion mass fragmentography.
Fluoxetine administered intraperitoneally to sham-operated or adrenalectomized/castrated (ADX/CX) male rats dose-dependently (2.9-58 mumol/kg i.p.) increased the brain content of the neurosteroid 3 alpha-hydroxy-5 alpha-pregnan-20-one (allopregnanolone, 3 alpha, 5 alpha-TH PROG). The increase of brain 3 alpha, 5 alpha-TH PROG content elicited by 58 mumol/kg fluoxetine lasted more than 2 hr and the range of its extent was comparable in sham-operated (approximately 3-10 pmol/g) and ADX/CX rats (2-9 pmol/g) and was associated with a decrease (from 2.8 to 1.1 pmol/g) in the 5 alpha-pregnan-3,20-dione (5 alpha-dihydroprogesterone, 5 alpha-DH PROG) content. The pregnenolone, progesterone, and dehydroepiandrosterone content failed to change in rats receiving fluoxetine. The extent of 3 alpha, 5 alpha-TH PROG accumulation elicited by fluoxetine treatment differed in various brain regions, with the highest increase occurring in the olfactory bulb. Importantly, fluoxetine failed to change the 3 alpha, 5 alpha-TH PROG levels in plasma, which in ADX/CX rats were at least two orders of magnitude lower than in the brain. Two other serotonin re-uptake inhibitors, paroxetine and imipramine, in doses equipotent to those of fluoxetine in inhibiting brain serotonin uptake, were either significantly less potent than fluoxetine (paroxetine) or failed to increase (imipramine) 3 alpha, 5 alpha-TH PROG brain content. The addition of 10 microM of 5 alpha-DH PROG to brain slices of ADX/CX rats preincubated with fluoxetine (10 microM, 15 min) elicited an accumulation of 3 alpha, 5 alpha-TH PROG greater than in slices preincubated with vehicle. A fluoxetine stimulation of brain 3 alpha, 5 alpha-TH PROG biosynthesis might be operative in the anxiolytic and antidysphoric actions of this drug.
Uzunov
D P
DP
Department of Psychiatry, University of Illinois at Chicago 60612, USA.
Cooper
T B
TB
Costa
E
E
Guidotti
A
A
D004092:20-alpha-Dihydroprogesterone / Q000378:metabolism; D000315:Adrenalectomy; D000818:Animals; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D002369:Castration; D005473:Fluoxetine / Q000494:pharmacology*; D018757:GABA Modulators / Q000378:metabolism*; D008401:Gas Chromatography-Mass Spectrometry; D007099:Imipramine / Q000494:pharmacology; D008297:Male; D017374:Paroxetine / Q000494:pharmacology; D011280:Pregnanolone / Q000378:metabolism*; D011374:Progesterone / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D005680:gamma-Aminobutyric Acid / Q000378:metabolism
D018757:GABA Modulators; D005473:Fluoxetine; D004092:20-alpha-Dihydroprogesterone; D017374:Paroxetine; D011374:Progesterone; D005680:gamma-Aminobutyric Acid; D011280:Pregnanolone; D007099:Imipramine