In socially isolated mice, the reversal of brain allopregnanolone down-regulation mediates the anti-aggressive action of fluoxetine
In socially isolated mice, the reversal of brain allopregnanolone down-regulation mediates the anti-aggressive action of fluoxetine
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DOI：
10.1073/pnas.0337642100
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发表时间：
2003-02-18
影响因子：
11.1
通讯作者：
Guidotti, A
中科院分区：
文献类型：
--
作者：
Pinna, G;Dong, E;Guidotti, A
社会隔离（50只雄鼠，持续bb0 ~ 4周）与对入侵者的攻击和脑内异孕酮（Allo）含量的下调有关。雌性小鼠的SI可能下调脑Allo含量或诱导攻击性。氟西汀（临床使用的百忧解）是S-和r -氟西汀（FLX）混合物，在哺乳动物中代谢成S-和r -去甲氟西汀（NFLX）。FLX和NFLX的S异构体在正常脑Allo下调和减少SI诱导的攻击性方面比其各自的R异构体更活跃。因此，FLX立体特异性地降低了脑Allo下调和SI诱导的侵袭性，而5-羟色胺（5-HT）摄取抑制缺乏立体特异性。S-FLX和S-NFLX减少SI诱导的侵袭性和Allo脑含量下调的剂量至少比阻断5-HT再摄取的剂量低一个数量级。抑制5-羟色胺摄取的丙咪嗪剂量既不能降低攻击性，也不能使大脑Allo下调正常化。我们得出结论，在解释S-FLX和S-NFLX引起的攻击性降低方面，Allo脑含量正常化比5-HT再摄取抑制更有说服力。
Social isolation (50 of male mice lasting >4 weeks is associated with aggression toward intruders and a down-regulation of brain allopregnanolone (Allo) content. SI of female mice falls to down-regulate brain Allo content or to induce aggressiveness. Fluoxetine (Prozac in clinical use) is an S- and R-fluoxetine (FLX) mixture, which in mammals is metabolized into S- and R-norfluoxetine (NFLX). The S isomers of FLX and NFLX are more active than their respective R isomers in normalizing brain Allo down-regulation and in reducing the aggressiveness induced by SI. Thus, FLX stereospecifically reduces brain Allo down-regulation and the aggressiveness induced by SI, whereas serotonin (5-HT) uptake inhibition lacks stereospecificity. The doses of S-FLX and S-NFLX that reduce aggressiveness and Allo brain content down-regulation induced by SI are at least one order of magnitude lower than the doses that block 5-HT reuptake. Doses of imipramine that inhibit 5-HT uptake neither reduce aggressiveness nor normalize brain Allo down-regulation. We conclude that Allo brain content normalization is a better candidate than 5-HT reuptake inhibition to explain the reduction of aggressiveness elicited by S-FLX and S-NFLX.