FLUOXETINE-ELICITED CHANGES IN BRAIN NEUROSTEROID CONTENT MEASURED BYNEGATIVE-ION MASS FRAGMENTOGRAPHY

Fluoxetine administered intraperitoneally to sham-operated or adrenale ctomized/castrated (ADX/CX) male rats dose-dependently (2.9-58 mu mol/ kg i,p.) increased the brain content of the neurosteroid 3 alpha-hydro xy-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 mu mol/kg fluoxetine lasted more than 2 hr and the range of its extent was comparable in sham-operated (approximate 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-dihydroprogester one, 5 alpha-DH PROG) content, The pregnenolone, progesterone, and deh ydroepiandrosterone content failed to change in rats receiving fluoxet ine. The extent of 3 alpha,5 alpha-TH PROG accumulation elicited by fl uoxetine treatment differed in various brain regions, with the highest increase occurring in the olfactory bulb, Importantly, fluoxetine fai led to change the 3 alpha,5 alpha-TH PROG levels in plasma, which in A DX/CX rats were at least two orders of magnitude lower than in the bra in. Two other serotonin re-uptake inhibitors, paroxetine and imipramin e, in doses equipotent to those of fluoxetine in inhibiting brain sero tonin uptake, were either significantly less potent than fluoxetine (p aroxetine) or failed to increase (imipramine) 3 alpha,5 alpha-TH PROG brain content, The addition of 10 mu M of 5 alpha-DH PROG to brain sli ces of ADX/CX rats preincubated with fluoxetine (10 mu M, 15 min) elic ited 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.