SIGMA RECEPTOR REGULATION OF DOPAMINE NEURONS

多巴胺神经元的 Sigma 受体调节

• 批准号: 2249009
• 负责人: GARY GUDELSKY
• 金额: $ 6.74万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1994
• 资助国家: 美国
• 起止时间: 1994-04-01 至 1996-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2249009
• 关键词: PCP receptor; corpus striatum; dopamine; drug receptors; haloperidol; laboratory rat; methamphetamine; microdialysis; neurotransmitters; pentazocine; statistics /biometry; stereotaxic techniques; substantia nigra

The existence of sigma binding sites in the substantia nigra and striatum is supportive of a role of sigma receptors in the regulation of nigrostriatal dopamine neurons. Further supportive of this contention are the findings that sigma ligands induce circling behavior following intranigral injections, hyperlocomotion and stereotypy following icv injections and inhibition of nigral cell firing after iv administration. The overall goal of the proposed studies is to establish the extent to which sigma receptor ligands regulate the release of dopamine from nigrostriatal dopamine neurons and determine the conditions under which this regulation might be modified. Specifically, it is proposed to 1) determine the rank order of potency and enantioselectivity of pentazocine, N-allyl-nortmetazocine and DTG-induced increases in the release of dopamine from nerve terminals and dendrites of nigrostriatal neurons; 2) determine whether the down regulation of sigma receptors induced by chronic haloperidol treatment is accompanied by a desensitization of the sigma ligand induced release of striatal and nigral dopamine; and 3) determine whether the repeated administration of methamphetamine or (+)- pentazocine results in a drug-induced sensitization of the response of striatal dopamine release to a subsequent injection of the sigma Iigand. These studies will be conducted in awake, freely moving rats in which the release of dopamine in the striatum and substantia nigra will be assessed from the quantitation of extracellular dopamine concentrations by in vivo microdialysis. The effects of an acute injection of pentazocine, N-allyl- normetazocine or DTG on the extracellular concentrations of dopamine will be determined in drug naive rats (specific aim 1), in rats treated chronically with haloperidol (specific aim 2) or in rats treated chronically with methamphetamine or pentazocine (specific aim 3). Results of the proposed studies will provide insight into the neuromodulation of nigrostriatal dopamine neurons. In view of the role of these neurons in the control of movement and posture and the high affinity of antipsychotic drugs for sigma receptors, results from these studies also have implication for understanding the motor side effects of antipsychotic drugs.

黑质和纹状体中存在sigma结合位点 支持σ受体在调节 黑质纹状体多巴胺神经元进一步支持这一论点的是 发现σ配体诱导盘旋行为， icv后黑质内注射、过度运动和刻板 注射和静脉内给药后抑制黑质细胞放电。 拟议研究的总体目标是确定 哪种σ受体配体调节多巴胺的释放 黑质纹状体多巴胺神经元，并确定条件下， 这一规定可以修改。具体而言，建议1） 确定喷他佐辛的效力和对映体选择性的等级顺序， N-烯丙基-去甲唑辛和DTG诱导的 黑质纹状体神经元的神经末梢和树突中的多巴胺; 2） 确定是否由以下因素诱导的σ受体下调： 慢性氟哌啶醇治疗伴随着 σ配体诱导纹状体和黑质多巴胺的释放;和3） 确定是否重复施用甲基苯丙胺或（+）- 喷他佐辛导致药物诱导的对 纹状体多巴胺释放到随后的σ配体注射。 这些研究将在清醒、自由活动的大鼠中进行，其中 将评估纹状体和黑质中多巴胺的释放 从细胞外多巴胺浓度的定量， 微透析急性注射喷他佐辛，N-烯丙基- 去甲甲唑辛或DTG对细胞外多巴胺浓度的影响将 在未给药大鼠（具体目的1）、给药大鼠 长期使用氟哌啶醇（具体目的2）或在大鼠中治疗 长期使用甲基苯丙胺或喷他佐辛（具体目标3）。结果 的拟议研究将提供深入了解的神经调制 黑质纹状体多巴胺神经元鉴于这些神经元在 运动和姿势的控制以及抗精神病药物的高亲和力 σ受体的药物，这些研究的结果也 理解抗精神病药物运动副作用的意义 毒品