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.

黑质和纹状体中的Sigma结合位点的存在 支持Sigma受体在调节中的作用 黑质纹状体多巴胺神经元。进一步支持这一论点 Sigma配体引起盘旋行为之后的发现 ICV之后的液内注射，超倒置和刻板印象 静脉内施用后，注射和抑制ni骨细胞发射。 拟议研究的总体目标是确定 Sigma受体配体调节多巴胺从 黑质纹状体多巴胺神经元，并确定 该法规可能会修改。具体而言，提议1） 确定五唑嗪的效力和对映选择性的等级顺序， N-酰胺级甲唑嗪和DTG诱导的释放增加 神经纹状体神经元的神经末端和树突的多巴胺； 2） 确定是否诱导的Sigma受体的下调调节是否 慢性氟哌啶醇治疗伴随着脱敏 Sigma配体诱导的纹状体和ni骨多巴胺释放； 3） 确定甲基苯丙胺的重复给药还是（+） - 五唑胺导致药物引起的反应敏化 纹状体多巴胺释放到随后的Sigma Iigand注入。 这些研究将是在清醒的，自由移动的老鼠中进行的 将评估多巴胺在纹状体和黑质中的释放 从体内定量细胞外多巴胺浓度 微透析。急性注射五唑胺，N-酰基-L-的作用 多巴胺细胞外浓度上的Normetazocine或DTG将会 在药物幼稚的大鼠中确定（特定的目标1），在接受治疗的大鼠中 长期与氟哌啶醇（特定的目标2）或在接受治疗的大鼠中 与甲基苯丙胺或五唑嗪一起长期（特定目标3）。结果 在拟议的研究中，将洞悉 黑质纹状体多巴胺神经元。鉴于这些神经元在 控制和姿势的控制以及抗精神病药的高亲和力 这些研究的结果也有Sigma受体的药物 对理解抗精神病药的运动副作用的影响 毒品。