NEUROTOXICITY OF HALLUCINOGENIC SUBSTITUTED AMPHETAMINES

这项计划的目标是描述神经毒性效应 取代苯丙胺(丙二醛和MDMA)对中枢单胺能神经元的影响。 这一假设将得到检验，即这些药物的毒性作用是由于 形成一种肝脏代谢物。再生的潜力 将确定受损的5-羟色胺轴突的萌发和恢复。一个 将开发一种方法来测试来自于 肝微粒体孵育。1)为了确定神经毒性的影响， 免疫细胞化学将被用来可视化退化和幸免 单胺类轴突；神经递质水平的变化将由 高效液相色谱柱。将研究不同剂量以确定剂量-反应曲线。 并确定受损的特定神经元室。地区性 将研究前脑、脑干和脊髓的影响，以 确定5-羟色胺轴突毒性效应的特异性 确定可能幸免的中缝细胞组和轴突类型。的细胞 受损5-羟色胺轴突与备用5-羟色胺轴突的来源将通过 轴突运输方式。从老鼠身上获得的结果将被用于 以指导灵长类动物神经毒性的类似研究。2)它是必不可少的 为了确定全身性丙二醛的神经毒性效应是否归因于 代谢产物或可能继发于体温过高或心血管改变。 为了证明母体化合物没有直接的神经毒性，持续 脑内剂量的药物将由一名慢性 植入插管和微泵。3)研究发芽的潜力 并进行受损轴突的修复、免疫细胞化学和高效液相色谱分析 在长期存活后，将使用轴突运输方法来确定 哪些细胞组能产生再生轴突。4)识别 有毒的代谢物将在脑内尝试 小鼠肝微粒体孵化提取物的显微注射 毒品。这些研究应该表征机制、条件和 取代苯丙胺所致神经毒性的特异性 成为被广泛使用的滥用药物。此外，如果安全条件和 剂量是可以确定的，这些药物可能在心理治疗中有用。 由于在大学和专业团体中普遍存在虐待行为，这些 毒品对美国年轻人的健康构成了重大而严重的危害； 它们巨大的神经毒性需要确定下来，并 在教育方面进行宣传。

The goals of this project are to characterize the neurotoxic effects of substituted amphetamines (MDA and MDMA) upon CNS monoaminergic neurons. The hypothesis will be tested that the toxic effects of these drugs are due to the formation of a hepatic metabolite. The potential for regenerative sprouting and recovery of damaged serotonin axons will be determined. A method will be developed to test the toxicity of metabolites derived from hepatic microsomal incubations. 1) To characterize the neurotoxic effects, immunocytochemistry will be used to visualize degenerating and spared monoamine axons; changes in neurotransmitter levels will be determined by HPLC. Different doses will be studied to determine the dose-response curve and to identify the specific neuronal compartment damaged. Regional effects will be studied in forebrain, brainstem and spinal cord to determine the specificity of the toxic effect on serotonin axons and to identify raphe cell groups and axon types that may be spared. The cells of origin of damaged versus spared serotonin axons will be identified by axonal transport methods. The results obtained from the rat will be used to guide similar studies of neurotoxicity in primates. 2) It is essential to resolve whether the neurotoxic effects of systemic MDA are due to a metabolite or may be secondary to hyperthermia or cardiovascular changes. To show that the parent compound is not directly neurotoxic, sustained intracerebral doses of the drugs will be administered by a chronic implanted cannula and minipump. 3) To study the potential for sprouting and recovery of damaged axons, immunocytochemistry and HPLC will be done following long survivals; axon transport methods will be used to determine which cell groups give rise to regenerating axons. 4) Identification of the toxic class of metabolites will be attempted by intracerebral microinjection of extracts from hepatic microsomal incubations of the drugs. These studies should characterize the mechanism, conditions, and specificity of neurotoxicity caused by substituted amphetamines that have become widely used as drugs of abuse. Moreover, if safe conditions and doses can be identified, these drugs may be useful in psychotherapy. Because of widespread abuse among college and professional groups, these drugs constitute a major and serious health hazard to young Americans; their dramatic neurotoxicity needs to be established definitively and publicized educationally.