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.

最近的工作表明，非常低剂量（1杯/千克，i.v.）可以 大约是NMDA离子phototodopodopodotodopodotody的兴奋作用的两倍 应用于海马（CA3）锥体神经元。 此外，NMDA 发现拮抗剂CPP抑制增加的葡萄糖利用率 由Sigma配体DTG（1 mg/kg，i.p.）产生的，CPP阻止了 DTG导致多巴胺释放的能力。 基于这些 发现Sigma配体（至少在某些情况下） 积极调节NMDA响应。 三组实验是 提议进一步检查这种可能性，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检查是否存在 可以在膜受体的水平上观察到相互作用 互动； 3）确定这些相互作用的一般性 - 即，检查是否在神经中发现Sigma/NMDA相互作用 海马以外的系统，特别强调 黑质多巴胺系统。 这些实验与心理健康有关。 一些实验 表明Sigma配体可以用作抗精神病药或 用于抗精神病药诱导运动的药物治疗剂 疾病。 此外，海马的调查可能具有 与学习和记忆有关，因此对某些 精神疾病，例如阿尔茨海默氏病或​​其他疾病 影响心理健康。