Effects of M-amphetamine on Neural Circuit Development

描述（由申请方提供）：滥用安非他明及其衍生物， 包括甲基苯丙胺（METH）在内的毒品是一个巨大的社会医学问题。的 这些化合物的生物化学和行为效应有据可查， 但它们对发育中的神经元的影响 电路和随后从这些影响中恢复，没有得到很好的研究。 因为神经回路的模式是功能的主要决定因素， 这就造成了一个关键的空白，在理解的神经生物学基础， 胎儿暴露于药物导致的产后行为缺陷。数据 METH诱导的神经回路变化对于指导 METH的细胞和分子作用的研究，目的是 设计治疗方法来改善其功能效应。在成年动物中， 安非他明对多巴胺能（DA能）轴突具有神经毒性， 破坏fme神经元能（5 HTergic）轴突的终末乔木， 从中缝背核（DR），而串珠状5 HTergic轴突起源于 中缝嵴保持完整DA能神经元的胞体和轴突干， 5 HTergic神经元不变性。这允许缓慢的部分再生， 受损的5 HTergic轴突对大脑发育的类似研究有 缺乏因此，我们将研究METH对发展的影响， 5 HTergic和DA能电路。我们的实验包括另一个创新的 功能：由胺能轴突终末分泌的5 HT或DA与受体结合， 位于非胺能轴突终末和树突上的转运体。因为 神经递质，包括5-HT和DA，可以调节轴突的发育 和树突，MET诱导的5 HT或DA系统的损伤可能导致 目标内其他轴突或树突发育异常 这些系统。这可能会造成永久性的神经异常， 电路因此，我们研究METH对发育的影响， 5 HTergic或5 HTergic靶点中的范式、非胺能轴突和树突 DA能轴突。我们还将研究METH的细胞机制， 对神经回路的先前特征产生影响。 甲基苯丙胺的滥用者包括孕妇。因此，评估潜力至关重要。 对胎儿的神经损伤，并制定治疗策略。我们 实验以两种创新的方式推进这一目标：我们研究了 METH 1）在发育中的大脑和2）在非胺能神经元，其发展 很可能是由胺能神经元调节的，这些神经元是 METH.我们的实验也将推进1）胺能轴突如何 正常调节神经回路的发展和2）细胞 METH神经毒性的机制和METH对发育的作用 神经回路

DESCRIPTION (provided by applicant): Abuse of amphetamine and its derivatives, including methamphetamine (METH), is a great socio-medical problem. The biochemical and behavioral effects of these compounds are well-documented for the mature and developing brains but their effects on developing neuronal circuitry and the subsequent recovery from those effects, are not well-studied. Because the pattern of neural circuitry is a major determinant of function, this creates a crucial hiatus in understanding the neurobiological basis of the postnatal behavioral deficits that result from fetal drug exposure. Data on METH-induced changes in neural circuitry are also important for guiding investigations of the cellular and molecular actions of METH, that are aimed at devising therapies to ameliorate its functional effects. In adult animals, the amphetamines are neurotoxic to dopaminergic (DAergic) axons and selectively destroy the terminal arbors of fme serotonergic (5HTergic) axons originating from the dorsal raphe (DR), whereas beaded 5HTergic axons originating from the median raphe remain intact. The somata and axon trunks of the DAergic and 5HTergic neurons do not degenerate. This permits a slow partial regeneration of the damaged 5HTergic axons. Comparable studies in developing brains are lacking. Therefore, we will study the effects of METH on the development of 5HTergic and DAergic circuitry. Our experiments include another innovative feature: 5HT or DA secreted by aminergic axon terminals binds to receptors and transporters located on nonaminergic axon terminals and dendrites. Because neurotransmitters, including 5HT and DA, can modulate the development of axons and dendrites, METH-induced lesions of the 5HT or DA systems may cause abnormalities in the development of other axons or dendrites within the targets of those systems. This could produce permanent abnormalities in neural circuitry. Thus, we study the effects of METH on the development of paradigmatic, non-aminergic axons and dendrites in the targets of 5HTergic or DAergic axons. We will also study the cellular mechanisms by which METH produces its effects on the preceding features of neural circuitry. Abusers of METH include pregnant women. Thus, it is crucial to assess potential neurological damage to their fetuses and to develop therapeutic strategies. Our experiments advance this goal in 2 innovative ways: We study the actions of METH 1) in developing brains and 2) in non-aminergic neurons whose development is likely to be modulated by aminergic neurons that are a direct target of METH. Our experiments will also advance knowledge of 1) how aminergic axons normally modulate the development of neural circuitry and 2) the cellular mechanisms of METH neurotoxicity and of the actions of METH on developing neural circuitry.