The circadian system is a target and modulator of prenatal cocaine effects.
The circadian system is a target and modulator of prenatal cocaine effects.
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DOI：
10.1371/journal.pone.0000587
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发表时间：
2007-07-11
期刊：
影响因子：
3.7
通讯作者：
Zhdanova IV
中科院分区：
文献类型：
--
作者：
Shang EH;Zhdanova IV
产前接触可卡因可能对胚胎大脑发育有害，但对人类的结果仍有争议，所涉及的机制尚未得到很好的理解，有效的治疗方法尚未设计出来。我们推测，可卡因的产前影响可能与生理节律失调有关，这是由于整合生物钟功能的改变。在这里，我们介绍了一种新的高通量遗传特征良好的昼夜脊椎动物模型，用于研究产前可卡因的影响机制，通过证明减少的活力和改变的神经元发育模式后，反复暴露于可卡因在斑马鱼胚胎。这种效应与可卡因诱导的影响生长（生长激素，zGH）和神经传递（多巴胺转运蛋白，zDAT）的基因表达的急性变化有关。使用定量实时RT-PCR（QPCR）对昼夜节律基因表达的分析表明，可卡因急性地和剂量依赖性地改变昼夜节律基因（zPer-3、zBmal-1）和编码褪黑激素受体（zMelR）的基因的表达，所述褪黑激素受体（zMelR）介导对整个生物体的昼夜节律信息。此外，产前可卡因的效果取决于治疗时间，在白天更强大，与胚胎是否在光暗周期或持续光照下培养无关。后者表明参与遗传昼夜因素。主要的昼夜节律激素褪黑激素通过特定的褪黑激素受体起作用，抵消可卡因对神经元发育和基因表达的影响。这些研究结果表明，在一个昼夜脊椎动物，产前可卡因可以急性失调的昼夜节律基因的表达和那些影响褪黑激素信号，生长和神经传递，而重复的可卡因暴露可以改变神经元的发育。这些影响的可卡因和褪黑激素的衰减每天的变化表明，在产前可卡因暴露的昼夜因素的潜在预防或治疗作用。
Prenatal exposure to cocaine can be deleterious to embryonic brain development, but the results in humans remain controversial, the mechanisms involved are not well understood and effective therapies are yet to be designed. We hypothesize that some of the prenatal effects of cocaine might be related to dysregulation of physiological rhythms due to alterations in the integrating circadian clock function. Here we introduce a new high-throughput genetically well-characterized diurnal vertebrate model for studying the mechanisms of prenatal cocaine effects by demonstrating reduced viability and alterations in the pattern of neuronal development following repeated cocaine exposure in zebrafish embryos. This effect is associated with acute cocaine-induced changes in the expression of genes affecting growth (growth hormone, zGH) and neurotransmission (dopamine transporter, zDAT). Analysis of circadian gene expression, using quantitative real-time RT-PCR (QPCR), demonstrates that cocaine acutely and dose-dependently changes the expression of the circadian genes (zPer-3, zBmal-1) and genes encoding melatonin receptors (zMelR) that mediate the circadian message to the entire organism. Moreover, the effects of prenatal cocaine depend on the time of treatment, being more robust during the day, independent of whether the embryos are raised under the light-dark cycle or in constant light. The latter suggests involvement of the inherited circadian factors. The principal circadian hormone, melatonin, counteracts the effects of cocaine on neuronal development and gene expression, acting via specific melatonin receptors. These findings demonstrate that, in a diurnal vertebrate, prenatal cocaine can acutely dysregulate the expression of circadian genes and those affecting melatonin signaling, growth and neurotransmission, while repeated cocaine exposure can alter neuronal development. Daily variation in these effects of cocaine and their attenuation by melatonin suggest a potential prophylactic or therapeutic role for circadian factors in prenatal cocaine exposure.
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