NEUROTOXICITY OF HALLUCINOGENIC SUBSTITUTED AMPHETAMINES

本项目的目标是描述 取代的安非他明（MDA和MDMA）对CNS单胺能神经元的作用。 假设将被测试，这些药物的毒性作用是由于 肝脏代谢物的形成。 再生的潜力 将确定受损的5-羟色胺轴突的发芽和恢复。 一 将开发一种方法来测试代谢物的毒性， 肝微粒体孵育。 1)为了描述神经毒性效应， 免疫细胞化学将用于观察退化和备用 单胺轴突;神经递质水平的变化将通过 高效液相色谱法 将研究不同剂量以确定剂量-反应曲线 并识别受损的特定神经元区室。 区域 将研究前脑、脑干和脊髓的影响， 确定对5-羟色胺轴突的毒性作用的特异性， 确定可能被保留的中缝细胞群和轴突类型。 的细胞 受损与备用的5-羟色胺轴突的起源将通过以下方式来确定： 轴突运输方法。 将使用从大鼠中获得的结果 来指导灵长类动物神经毒性的类似研究。 2)必须 为了解决系统性MDA的神经毒性作用是否是由于 代谢产物或可能继发于体温过高或心血管变化。 为了证明母体化合物没有直接的神经毒性， 脑内剂量的药物将通过慢性 植入套管和微型泵。 3)研究发芽的可能性 并恢复受损的轴突，进行免疫细胞化学和HPLC 轴突运输方法将用于确定 哪些细胞群产生再生轴突。 4)鉴定 将尝试通过脑内给药 微量注射来自肝微粒体孵育的提取物， 毒品 这些研究应描述其机制、条件和 由取代的安非他明引起的神经毒性的特异性， 被广泛用作滥用药物。 此外，如果安全条件和 剂量可以确定，这些药物可能是有用的心理治疗。 由于在大学和专业团体中普遍存在的滥用行为， 毒品对美国年轻人的健康构成重大和严重的危害; 它们的巨大神经毒性需要明确确定， 在教育上宣传。

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.