ROLE OF DOPAMINE IN THE DEVELOPMENT OF DRUG-INDUCED NEUROTOXICITY

多巴胺在药物引起的神经毒性发展中的作用

• 批准号: 4694637
• 负责人: C J SCHMIDT
• 金额: --
• 依托单位: NATIONAL HEART, LUNG, AND BLOOD INSTITUTE
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/4694637
• 关键词: amphetamines; ascorbate; centrally acting drug; dihydroxyphenylalanine; dopamine; dosage; drug interactions; neuropharmacology; neurotoxins; oxidoreductase inhibitor; serotonin; tyrosine 3 monooxygenase

The possible involvement of dopamine in the neurotoxicity of a number of centrally acting drugs is being examined. The hypothesized role of dopamine in the selective toxicity of the parkinsonism-inducing compound 1-MPTP was investigated using mice pretreated with agents which alter endogenous dopamine synthesis in a defined manner. Treatment with the competitive inhibitor of tyrosine hydroxylase, alpha-methy-p-tyrosine, did not alter the dopaminergic neurotoxicity of l-MPTP nor did treatment with large doses of the dopamine precursor L-DOPA. In related experiments, the mechanism behind the requirement for dopamine synthesis in the sesrotonergic neurotoxicity of central stimulants such as methamphetamine was studied. Serotonergic neurons were shown to take up dopamine via their high affinity uptake system. This uptake was facilitated by ascorbic acid just as the neurotoxicity of methamphetamine requires normal levels of ascorbic acid in vivo. More recently we have also demonstrated that dopamine release induced by drug stimulation in vivo does enter serotonergic neurons where it displaces endogenous stores of serotonin.

多巴胺可能参与了一些神经毒性， 中枢作用药物正在接受检查。 假设的角色 多巴胺在帕金森综合征诱导化合物的选择性毒性中的作用 1-使用用改变MPTP的试剂预处理的小鼠研究MPTP。 内源性多巴胺的合成。 给药 酪氨酸羟化酶的竞争性抑制剂，α-甲基-p-酪氨酸， 不改变l-MPTP的多巴胺能神经毒性， 大剂量的多巴胺前体左旋多巴 在相关的实验中，需要多巴胺的机制 中枢兴奋剂，如 甲基苯丙胺进行了研究。 5-羟色胺能神经元被证明摄取了 多巴胺通过其高亲和力摄取系统。 这种吸收是 就像甲基苯丙胺的神经毒性一样 需要体内正常水平的抗坏血酸。 最近， 也证明了体内药物刺激诱导的多巴胺释放 确实进入肾上腺素能神经元， 血清素