NEUROLEPTICS, SIGMA SITES AND NEUROTOXICITY

神经调节剂、西格玛位点和神经毒性

• 批准号: 3430111
• 负责人: JOSE M MUSACCHIO
• 金额: $ 8.18万
• 依托单位: NEW YORK UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1992
• 资助国家: 美国
• 起止时间: 1992-05-01 至 1994-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3430111
• 关键词: antipsychotic agents; autoradiography; brain metabolism; drug administration rate /duration; drug metabolism; guinea pigs; haloperidol; histopathology; laboratory mouse; laboratory rat; morphinans; neurotoxins; opioid receptor; species difference; tardive dyskinesia

The purpose of this project is to determine the nature of the down- regulation of haloperidol-sensitive dextromethorphan/sigma binding sites. These studies have important implications for the understanding of neuroleptic-induced tardive side effects. Long term treatment with neuroleptics is known to produce marked side effects, some of which are irreversible. This study will focus on the effects of haloperidol, other neuroleptics and their metabolites. Chronic administration of haloperidol produces a down-regulation of dextromethorphan/sigma binding sites in mice, rats and guinea pigs. This has been confirmed in our laboratory. Besides, preliminary experiments have demonstrated that some metabolites of haloperidol produced a raid marked and long-lasting inhibition of the dextromethorphan/sigma sites. The temporal characteristics of these changes are indicative of a neurotoxic phenomenon. The nature of the inhibition observed will be studied using radioreceptor assays followed by computer-assisted modeling. This will indicate the type of site that is down-regulated. Radioreceptor autoradiography will be used to locate the most sensitive areas in the brain, and histopathologic techniques to determine signs of neurotoxicity. This is an important component of the proposed research because it has been described that there are histopathologic changes in brain nuclei of patients that developed tardive dyskinesia after prolonged neuroleptic administration. Mice, rats and guinea pigs will be used to determine whether there is any species difference. This study has important implications for the understanding of the long-term extrapyramidal motor side effects of neuroleptics, such as tardive dyskinesia.

这个项目的目的是确定羽绒的性质- 氟哌啶醇敏感的右美沙芬/西格玛结合位点的调节。 这些研究对于理解 抗精神病药引起的迟发性副作用。长期治疗，使用 众所周知，抗精神病药物会产生明显的副作用，其中一些是 不可逆转。这项研究将集中在氟哌啶醇，其他 抗精神病药物及其代谢物。 长期服用氟哌啶醇可下调血管紧张素转换酶 小鼠、大鼠和豚鼠体内的右美沙芬/西格玛结合部位。这 已经在我们的实验室得到了证实。此外，初步实验 已经证明氟哌啶醇的一些代谢物会产生一种突袭 显著和持久地抑制右美沙芬/西格玛位点。 这些变化的时间特征表明 神经毒性现象。 观察到的抑制的性质将用放射受体进行研究。 检测后进行计算机辅助建模。这将指示类型 被下调的网站。将使用放射感受器放射自显影 定位大脑中最敏感的区域，并进行组织病理学检查 确定神经毒性迹象的技术。这是一个重要的 拟议研究的组成部分，因为已经描述过 患者脑内核团的组织病理学变化 长期服用抗精神病药后迟发性运动障碍。老鼠，大鼠 豚鼠将被用来确定是否有任何物种 不同。这项研究对于理解 抗精神病药物的长期锥体外系运动副作用，如 迟发性运动障碍。