INTERACTIONS BETWEEN SIGMA AND NMDA RECEPTORS

Sigma 和 NMDA 受体之间的相互作用

• 批准号: 2240465
• 负责人: J. Michael Walker
• 金额: $ 8.79万
• 依托单位: BROWN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1993
• 资助国家: 美国
• 起止时间: 1993-06-01 至 1998-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2240465
• 关键词: NMDA receptors; PCP receptor; dopamine; dopamine antagonists; electrophysiology; excitatory aminoacid; glycine; hippocampus; inhibitor /antagonist; laboratory rat; long term potentiation; molecular site; neuropharmacology; polyamines; receptor binding; reticular formation; substantia nigra; zinc

Recent work has demonstrated that very low doses (1 mug/kg, i.v.) can approximately double the excitatory effect of NMDA iontophoretically applied to hippocampal (CA3) pyramidal neurons. Furthermore, the NMDA antagonist CPP was found to inhibit the increased glucose utilization produced by the sigma ligand DTG (1 mg/kg, i.p.), and CPP blocks the ability of DTG to cause increased dopamine release. Based on these findings it appears that sigma ligands (at least in some cases) positively modulate NMDA responses. Three sets of experiments are proposed to further examine this possibility in order to 1) Further characterize the interactions between sigma and NMDA in the hippocampus; 2) use the radioligand binding techniques to examine whether such interactions can be observed at the level of membrane-receptor interactions; and 3) to determine the generality of these interactions - i.e., to examine whether sigma/NMDA interactions are found in neural systems outside the hippocampus, with special emphasis on the nigrostriatal dopamine system. These experiments are relevant to mental health. Some experiments suggest that sigma ligands may serve as antipsychotic drugs, or as pharmacotherapeutic agents for antipsychotic drug-induced movement disorders. In addition, the investigations in the hippocampus may have relevance to learning and memory and thus have implications for certain mental illnesses such as Alzheimer's disease or other diseases that affect mental health.

最近的研究表明，非常低的剂量（1 杯/公斤，静脉注射）可以 NMDA 离子电渗疗法的兴奋作用大约是两倍 应用于海马（CA3）锥体神经元。 此外，国家药品管理局 发现拮抗剂 CPP 可以抑制葡萄糖利用的增加 由 sigma 配体 DTG（1 mg/kg，腹腔注射）产生，CPP 阻断 DTG 导致多巴胺释放增加的能力。 基于这些 研究发现似乎西格玛配体（至少在某些情况下） 积极调节 NMDA 反应。 三组实验分别是 建议进一步研究这种可能性，以便 1) 进一步 表征海马中 sigma 和 NMDA 之间的相互作用； 2) 使用放射性配体结合技术来检查是否存在这样的情况 可以在膜受体水平观察到相互作用 互动； 3) 确定这些相互作用的普遍性 - 即，检查 sigma/NMDA 相互作用是否存在于神经元中 海马体以外的系统，特别强调 黑质纹状体多巴胺系统。 这些实验与心理健康相关。 一些实验 表明 sigma 配体可以作为抗精神病药物，或作为 用于抗精神病药物引起的运动的药物治疗剂 失调。 此外，对海马体的研究可能有 与学习和记忆相关，因此对某些方面有影响 精神疾病，例如阿尔茨海默病或其他疾病 影响心理健康。