PRENATAL POLYDRUG EXPOSURE & CARDIOVASCULAR DEVELOPMENT

妊娠期间胎儿长期暴露于多种药物使用已达到 一些城市中心的流行病比例。最常见的药物之一 可卡因和酒精的母亲使用， 与胎儿生长迟缓、神经行为后遗症和 先天性结构缺陷在细胞水平上， 子宫内药物暴露已显示诱导突触前和 单胺能受体通路的突触后变化 中枢神经系统关于其影响，我们所知甚少。 慢性产前药物暴露对外周自主神经功能的影响， 特别是心血管系统的。然而，安装 新生儿心脏功能异常的证据与 妊娠期暴露于可卡因，单独或与 其他非法药物，已在临床上报告。 我们将使用慢性大鼠模型来检验以下假设： 可卡因单独使用或与酒精结合使用（1）改变了 突触后心肌B肾上腺素能受体信号通路和 通过胆碱能神经递质和自主神经递质改变其调节 神经肽、神经肽Y和血管活性肠肽;（2） 增强突触前交感神经的发育和功能， (3)改变出生后心肌收缩功能和自主神经功能 新生大鼠心脏的反应性。 我们的具体目标将是：（1）检查突触后心肌 bataAR通路及其通过毒蕈碱、NPY和VIP受体的调节 途径;并建立由于慢性产前药物的变化 暴露;（2）确定突触前肾上腺素能活动， 新生儿心脏，并记录药物暴露对去甲肾上腺素的影响 合成、有效性、周转和再吸收;（3）阐明 药物暴露对心律和收缩功能的影响;以及 心肌对外源性阳性药物的收缩反应 和负性肌力药。此外，我们将制定一项长期的 孕鼠血管收缩模型，以阐明原发性胎儿 可卡因对母亲的副作用。 从拟议的研究中获得的知识将提供更好的 了解药物损伤的机制和可能的功能 产前接触可卡因导致的心脏改变 和/或酒精。

Chronic fetal exposure to polydrug use during pregnancy has reached epidemic proportions in some urban centers. One of the most common drug combinations is the maternal use of cocaine and alcohol, which has been linked to fetal growth retardation, neurobehavioral sequelae and congenital structural defects. At the cellular level, repeated intrauterine drug exposure has been shown to induce presynaptic and postsynaptic changes in the monoaminergic receptor pathways in the central nervous system. Much less is known regarding the effect of chronic prenatal drug exposure on peripheral autonomic function, specifically that of the cardiovascular system. However, mounting evidence of abnormal neonatal cardiac function associated with gestational exposure to cocaine, either alone or in combination with other illicit drugs, have been reported clinically. We will use a chronic rat model to test the hypotheses that maternal cocaine use alone or in combination with alcohol (1) changes the postsynaptic myocardial B adrenergic receptor signaling pathway and alters its modulation by cholinergic neurotransmitters and autonomic neuropeptides, neuropeptide Y and vasoactive intestinal peptide; (2) enhances the presynaptic sympathetic neural development and function and (3) modifies postnatal myocardial contractile function and autonomic responsiveness in the neonatal rat heart. Our specific aims will be (1) to examine the postsynaptic myocardial bataAR pathway and its modulation by the muscarinic, NPY and VIP receptor pathways; and to establish the changes due to chronic prenatal drug exposure; (2) to determine presynaptic adrenergic activity in the neonatal heart and document the effect of drug exposure on norepinephrine synthesis, availability, turnover and reuptake; (3) to elucidate the effect of drug exposure on cardiac rhythm and contractile function; and the myocardial contractile response to exogenously administered positive and negative inotropic agents. In addition, we will develop a chronic vasoconstrictor model in the pregnant rat to elucidate the primary fetal effects of cocaine from those secondary to its effects on the mother. Knowledge gained from the proposed research will provide a better understanding of the mechanism of drug injury and possible functional alterations in the heart resulting from prenatal exposure to cocaine and/or alcohol.