Fluoxetine-elicited changes in brain neurosteroid content measured by negative ion mass fragmentography

被引:282
作者
Uzunov, DP [1 ]
Cooper, TB [1 ]
Costa, E [1 ]
Guidotti, A [1 ]
机构
[1] NATHAN S KLINE INST PSYCHIAT RES,ANALYT PSYCHOPHARMACOL LAB,ORANGEBURG,NY 10962
关键词
D O I
10.1073/pnas.93.22.12599
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
Fluoxetine administered intraperitoneally to sham-operated or adrenalectomized/castrated (ADX/CX) male rats dose-dependently (2.9-58 mu 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 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-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 mu M of 5 alpha-DH PROG to brain slices of ADX/CX rats preincubated with fluoxetine (10 mu M, 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.
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页码:12599 / 12604
页数:6
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