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 [micro]mol/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 [micro]mol/kg fluoxetine lasted more than 2 hr and the range of its extent was comparable in sham-operated ([approximately equal to]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 [[micro]Molar] of 5[Alpha]-DH PROG to brain slices of ADX/CX rats preincubated with fluoxetine (10 [[micro]Molar], 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.