NEUROTOXIC EFFECTS OF DRUGS ON SEROTONERGIC NEURONS

这一建议的目的是扩大我们正在进行的研究， 描述精神药物对多巴胺能神经元的神经毒性 神经元这些研究将主要采用解剖学方法， 描述神经元对药物诱导损伤的反应， 受损的神经元隔室，并将解剖学和 毒性的生化参数。这些实验应该确定 改变情绪的药物作用的部位，阐明药物的作用机制， 毒性，并评估研究药物神经毒性作用的标准。一 中心问题是评估神经毒性药物的结构证据 影响，以便为神经元损伤提供明确的证据， 确定损坏程度。目标是：一。进一步表征 3，4-亚甲二氧基- 安非他明（MDA）和相关安非他明衍生物：A.识别 完整的中缝轴突近端段，并测试假设， 退化仅限于轴突终端使用顺行轴突 运输; B.确定中缝细胞体对损伤的反应， 高分辨率光学和电子显微镜; C.分析5-HT MDA处理后的神经再支配，并确定发芽的性质 5-HT轴突。R.表征神经毒性药物与5-HT的结合 摄取载体，并确定不同的摄取位点是否与 有两类5-羟色胺轴突，它们对这些神经元的敏感性不同， 毒品三.分析解剖与生化的相关性 相同动物的神经毒性参数。四.药物的影响 对肌间神经丛中5-HT神经元的影响将被研究，以确定 它们是否表现出与大脑类似的毒性作用。五.产前 将采用安非他明衍生物和脑啡肽的给药 研究它们对血清素神经元发育的影响， 对围产期前脑发育的继发性影响。的 拟议的研究应提供关于 药物诱导的神经毒性、再生潜力和药物 怀孕期间的影响。这些研究还应提供新的工具， 适用于人类和其他灵长类动物，用于评估 滥用药物。

The objective of this proposal, which extends our ongoing studies, is to characterize the neurotoxicity of psychotropic drugs upon serotonergic neurons. These studies will employ primarily anatomic methods to characterize the response of neurons to drug-induced injury, to identify the neuronal compartment that is damaged, and to correlate anatomic and biochemical parameters of toxicity. These experiments should identify the sites at which mood-altering drugs act, clarify the mechanisms of drug toxicity, and evaluate criteria to study the neurotoxic effects of drugs. A central issue is to evaluate structural evidence for neurotoxic drug effects in order to provide definitive evidence for neuronal injury and to determine the extent of damage. The aims are: I. Further characterize the structural damage to serotonergic neurons produced by 3,4-methylenedioxy- amphetamine (MDA) and related amphetamine derivatives: A. identify the intact proximal segment of raphe axons and test the hypothesis that degeneration is restricted to axon terminals using anterograde axonal transport; B. determine the response of raphe cell bodies to injury using high resolution light and electron microscopy; C. analyze 5-HT reinnervation after MDA treatment and determine the properties of sprouting 5-HT axons. R. Characterize the binding of neurotoxic drugs to the 5-HT uptake carrier, and determine whether different uptake sites are associated with two classes of 5-HT axons that are differentially vulnerable to these drugs. III. Analyze the correlation between anatomic and biochemical parameters of neurotoxicity in the same animals. IV. The effects of drugs on 5-HT neurons in the myenteric plexus will be studied to determine whether they show toxic effects similar to those in the brain. V. Prenatal administration of amphetamine derivatives and enkephalins will be employed to study their effects on serotonin neuron development and possible secondary effects on forebrain development in the perinatal period. The proposed studies should provide new information regarding the mechanisms of drug-induced neurotoxicity, the potential for regeneration, and drug effects during pregnancy. These studies should also provide new tools, applicable to man and other primates, for assessing the neurotoxicity of drugs of abuse.