Fluoxetine-elicited changes in brain neurosteroid content measured by negative ion mass fragmentography.
Fluoxetine-elicited changes in brain neurosteroid content measured by negative ion mass fragmentography.
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DOI：
10.1073/pnas.93.22.12599
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发表时间：
1996-10
影响因子：
11.1
通讯作者：
D. Uzunov;T. Cooper;E. Costa;A. Guidotti
中科院分区：
文献类型：
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作者：
D. Uzunov;T. Cooper;E. Costa;A. Guidotti
假手术或肾上腺切除/去势（ADX/CX）雄性大鼠腹腔注射氟西汀剂量依赖性（2.9-58 μ mol/kg i.p）增加脑内神经类固醇3 α -羟基-5 α -妊娠-20- 1（异孕酮，3 α, 5 α - th PROG）的含量。58 μ mol/kg氟西汀诱导脑3- α， 5 - α - th PROG含量增加持续2小时以上，其幅度与假手术大鼠（约3-10 pmol/g）和ADX/CX大鼠（2-9 pmol/g）相当，并与5 - α -孕酮-3,20-二酮（5 -二氢孕酮，5 - α - dh PROG）含量降低（从2.8至1.1 pmol/g）相关。大鼠服用氟西汀后，孕烯醇酮、孕酮和脱氢表雄酮含量没有变化。氟西汀引起的3 α、5 α - th PROG积累程度在不同脑区有所不同，在嗅球中增加最多。重要的是，氟西汀没有改变血浆中3 α， 5 α - th PROG的水平，在ADX/CX大鼠中，这一水平至少比在大脑中低两个数量级。另外两种5 -羟色胺再摄取抑制剂，帕罗西汀和丙咪嗪，在抑制脑5 -羟色胺摄取的剂量与氟西汀相同，要么明显低于氟西汀（帕罗西汀），要么不能增加（丙咪嗪）3 α， 5 α - th PROG脑含量。在氟西汀预孵育的ADX/CX大鼠脑切片中添加10微米的5 α - dh PROG（10微米，15分钟），可引起3 α， 5 α - th PROG的积累大于用载药预孵育的切片。氟西汀刺激脑3 α， 5 α - th PROG生物合成可能在该药的抗焦虑和抗烦躁作用中起作用。
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.