Effects of M-amphetamine on Neural Circuit Development

描述(申请人提供)：滥用苯丙胺及其衍生物，包括甲基苯丙胺(冰毒)，是一个严重的社会医学问题。这个 这些化合物的生化和行为影响是有据可查的 成熟发育的大脑及其对神经元发育的影响 电路以及随后从这些影响中恢复的过程还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， 这造成了在理解神经生物学基础上的关键中断 因接触胎儿药物而导致的出生后行为缺陷。数据在 冰毒诱导的神经回路改变对指导也很重要 研究冰毒的细胞和分子作用，目的是 设计治疗方法以改善其功能效果。在成年动物中， 苯丙胺对多巴胺能轴突具有神经毒性，并选择性地 破坏发自FME 5-羟色胺能(5HT)轴突的终枝 来自中缝背侧(DR)，而珠状5H能轴突起源于中缝背核(DR) 中缝中线保持完好。多巴胺能神经元的胞体和轴突干 5H能神经元不退化。这允许缓慢的部分再生 受损的5H能轴突。在大脑发育方面的类似研究有 缺乏。因此，我们将研究冰毒对人类发育的影响。 5H能和DAR能回路。我们的实验包括另一项创新 特征：由胺能轴突终末分泌的5-羟色胺或多巴胺与受体和 转运体位于非胺能轴突终末和树突上。因为 神经递质，包括5-羟色胺和多巴胺，可以调节轴突的发育 而树突、冰毒对5-羟色胺或多巴胺系统的损伤可能导致 靶点内其他轴突或树突发育异常 这些系统中。这可能会导致永久性的神经异常。 电路。因此，我们研究了冰毒对糖尿病发展的影响。 5HTERATOR靶点内的聚集性非胺能轴突和树突 DAR能轴突。我们还将研究冰毒的细胞机制 对神经回路的前述特征产生影响。 滥用冰毒的人包括孕妇。因此，评估潜力是至关重要的。 对胎儿的神经损害，并开发治疗策略。我们的 实验以两种创新的方式推进了这一目标：我们研究了 方法1)在发育中的大脑中；2)在非胺能神经元中，其发育 很可能是由胺能神经元调制的，而胺能神经元是 冰毒。我们的实验还将促进人们对1)胺能轴突如何 正常调节神经回路的发育和2)细胞 冰毒的神经毒性机制及其在发育中的作用 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.