Early intervention with fluoxetine reverses abnormalities in the serotonergic system and behavior of rats exposed prenatally to dexamethasone
Early intervention with fluoxetine reverses abnormalities in the serotonergic system and behavior of rats exposed prenatally to dexamethasone
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DOI：
10.1016/j.neuropharm.2012.03.027
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发表时间：
2012-08-01
影响因子：
4.7
通讯作者：
Suzuki, Hidenori
中科院分区：
文献类型：
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作者：
Nagano, Masatoshi;Liu, Mingyan;Suzuki, Hidenori
许多精神疾病是在青春期后出现的。在各种易感因素中，产前压力被认为会导致焦虑症的症状。我们最近报道，产前地塞米松（DEX）暴露，模仿产前压力的某些方面，诱导雄性后代成年后的焦虑相关行为。在行为改变出现之前，下丘脑-垂体-肾上腺轴在出生后发育过程中出现异常。在本研究中，我们发现5-羟色胺（5-HT）信号传导异常，包括5-HT1A受体（5-HT1A- r） mRNA在内侧前额叶皮层（mPFC）的表达和海马（PW）中5-羟色胺含量的下降。这些结果支持使用血清素能药物的早期治疗干预来预防晚期出现的焦虑症状。为了验证这一假设，我们用氟西汀（FLX）（一种选择性5 -羟色胺再摄取抑制剂，通常用作抗焦虑药物）治疗了dex母亲所生的大鼠幼崽，从出生后2-21天（PD）开始通过母乳喂养。在PW11-13中检测的焦虑相关行为在产前暴露于dex并接受FLX治疗的后代中未被观察到。同样，FLX在PW3时增加了mPFC和腹侧海马中的5-HT浓度，并在PW4时使mPFC中的5-HT1A-R mRNA浓度正常化。mPFC和海马背侧脑源性神经营养因子（BDNF）蛋白的减少也在PW4时恢复。此外，5-HT1A-R完全激动剂(R)-(+)-8-羟基-2-（二正丙基氨基）四氢萘从PD2到21也可以防止产前暴露于dex的后代出现行为异常，这表明5-HT1A-Rs参与了新生儿FLX效应。总之，早期药物干预使血清素能传递正常化，有效地抑制了大鼠产前DEX暴露引起的症状的出现。(C) 2012 Elsevier Ltd.版权所有。
Many psychiatric disorders emerge after adolescence. Among a variety of predisposing factors, prenatal stress has been thought to cause the symptoms of anxiety disorders. We recently reported that prenatal dexamethasone (DEX) exposure, which mimics some aspects of prenatal stress, induced anxiety-related behaviors in male offspring when they reached adulthood. Before the emergence of behavioral changes, abnormalities occurred in the hypothalamic pituitary adrenal axis during postnatal development. In the present study, we found abnormalities in serotonin (5-HT) signaling, including decreased expression of 5-HT1A receptor (5-HT1A-R) mRNA in the medial prefrontal cortex (mPFC) and 5-HT content in the hippocampus at postnatal week (PW) 4. These results support using early therapeutic interventions with serotonergic drugs to prevent late-emerging anxiety symptoms. To test this hypothesis, we treated rat pups born to DEX-administered mothers with fluoxetine (FLX), a selective serotonin reuptake inhibitor commonly used as an anti-anxiety medication, via breast milk from postnatal day (PD) 2-21. Anxiety-related behaviors examined at PW11-13 were not observed in the prenatally DEX-exposed offspring that were treated with FLX. Likewise, FLX increased 5-HT concentrations in the mPFC and ventral hippocampus at PW3 and normalized 5-HT1A-R mRNA concentrations in the mPFC at PW4. The decrease in brain-derived neurotrophic factor (BDNF) protein in the mPFC and dorsal hippocampus was also restored at PW4. Furthermore, administration of the 5-HT1A-R full agonist (R)-(+)-8-hydroxy-2-(di-n-propylamino)tetralin from PD2 to 21 also prevented the emergence of behavioral abnormalities in the prenatally DEX-exposed offspring, implicating the involvement of 5-HT1A-Rs in the neonatal FLX effect. Collectively, an early pharmacological intervention to normalize serotonergic transmission effectively suppressed the emergence of symptoms induced by prenatal DEX exposure in rats. (C) 2012 Elsevier Ltd. All rights reserved.