Neonatal antidepressant exposure has lasting effects on behavior and serotonin circuitry
Neonatal antidepressant exposure has lasting effects on behavior and serotonin circuitry
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DOI：
10.1038/sj.npp.1300823
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发表时间：
2006-01-01
影响因子：
7.6
通讯作者：
Paul, IA
中科院分区：
文献类型：
--
作者：
Maciag, D;Simpson, KL;Paul, IA
在妊娠晚期服用选择性5-羟色胺再摄取抑制剂（SSRIs）的母亲所生的婴儿中，有很大一部分显示出抗抑郁药戒断的明显迹象，表明这些药物可以在生物学上显著的水平渗透子宫内的胎儿大脑。先前在啮齿类动物中的研究表明，早期暴露于某些抗抑郁药可导致成人行为和单胺能活性指数的持续异常。在这里，我们表明慢性新生儿（出生后8-21天）暴露于西酞普兰（5 mg/kg，每日两次，s.c.），一种有效的和高选择性的SSRI，导致中缝背核中的限速5-羟色胺合成酶（色氨酸羟化酶）和皮质中的5-羟色胺转运蛋白表达的显著降低，并持续到成年期。此外，新生儿暴露于西酞普兰在成年大鼠中产生选择性的行为变化，包括增加自发活动和减少性行为，类似于先前报道的抗抑郁药（非选择性单胺转运抑制剂）。这些数据表明，以前报道的抗抑郁药的神经行为影响是其对5-羟色胺转运体的影响的结果。此外，这些数据表明，在早期暴露于SSRIs可以破坏5-羟色胺系统的正常成熟，并改变降钙素依赖的神经元过程。目前尚不清楚SSRIs的这种作用是否在人类中存在;然而，这些数据表明，在子宫内，暴露于SSRIs可能会产生不可预见的长期神经行为后果。
A significant fraction of infants born to mothers taking selective serotonin reuptake inhibitors (SSRIs) during late pregnancy display clear signs of antidepressant withdrawal indicating that these drugs can penetrate fetal brain in utero at biologically significant levels. Previous studies in rodents have demonstrated that early exposure to some antidepressants can result in persistent abnormalities in adult behavior and indices of monoaminergic activity. Here, we show that chronic neonatal (postnatal days 8-21) exposure to citalopram (5 mg/kg, twice daily, s.c.), a potent and highly selective SSRI, results in profound reductions in both the rate-limiting serotonin synthetic enzyme (tryptophan hydroxylase) in dorsal raphe and in serotonin transporter expression in cortex that persist into adulthood. Furthermore, neonatal exposure to citalopram produces selective changes in behavior in adult rats including increased locomotor activity and decreased sexual behavior similar to that previously reported for antidepressants that are nonselective monoamine transport inhibitors. These data indicate that the previously reported neurobehavioral effects of antidepressants are a consequence of their effects on the serotonin transporter. Moreover, these data argue that exposure to SSRIs at an early age can disrupt the normal maturation of the serotonin system and alter serotonin-dependent neuronal processes. It is not known whether this effect of SSRIs is paralleled in humans; however, these data suggest that in utero, exposure to SSRIs may have unforeseen long-term neurobehavioral consequences.