SIGMA RECEPTORS AND DOPAMINE NEUROTRANSMISSION

结合实验表明Sigma结合位点的存在 有别于任何已知的脑神经递质受体或其他药物 结合部位。这些位点在结合方面是独一无二的，具有很高的亲和力 抗精神病药物和阿片类药物的非天然(+)对映体。 最近的发展表明，至少存在两种亚型的 Sigma受体，称为Sigma-1和Sigma-2。找到西格玛绑定 在许多脑区，特别是在脑干区域 运动，包括各种脑神经核团，红核， 小脑和富含多巴胺的黑质。对……的调查 Sigma受体在黑质-三叉神经多巴胺系统中的作用是 出于以下几个原因，多巴胺是及时和重要的：1)假设多巴胺 与精神分裂症和抗精神病药物的运动副作用有关 毒品。因此，了解Sigma受体在 调节多巴胺可能对抗精神病药物有影响 心理治疗。2)Sigma受体与抗精神病药物的关系 药物治疗从高度到中度具有额外的意义 典型抗精神病药物对Sigma受体的亲和力。这 暗示典型的抗精神病药物可能会影响多巴胺系统 虽然多巴胺能和Sigma能两种机制。3)新化合物； 其中一些具有亚纳摩尔亲和力，具有高度的选择性 对于Sigma受体，这些化合物明显去除了以前的 与使用弱和非选择性西格玛相关的障碍 配基。4)已开发出新的不可逆西格玛化合物 可以提供额外的药理学工具来阐明 Sigma受体在调节多巴胺功能中的生物学作用。5) 初步数据显示，某些西格玛化合物极易产生 强效的多巴胺对行为的影响。 基于这些考虑，我们建议调查行为， Sigma受体的神经化学和电生理效应 黑质纹状体多巴胺系统的激活。这些实验 同时关注功能和药理学问题。主 功能问题是确定西格玛配体的作用位点。 在黑质纹状体多巴胺系统内。药理研究 目的探讨Sigma受体在Sigma-2作用中的作用。 配基。这将通过确定相关性来实现 在这些体系中西格玛配体的效力和它们的结合之间 Sigma-1和Sigma-2受体。另一种方法是使用 不可逆西格玛配体，以研究它们作为 西格玛对抗者。在西格玛和西格玛之间建立清晰的联系 受体和黑质纹状体多巴胺功能可能对 抗精神病药物的认知和运动作用机制。

Binding experiments suggest the presence of sigma binding sites that are distinct from any known brain neurotransmitter receptor or other drug binding site. These sites are unique in binding with high affinity both antipsychotic drugs and the unnatural (+)-enantiomers of opiates. Recent developments indicate the presence of at least two subtypes of the sigma receptor, termed sigma-1 and sigma-2. Sigma binding is found in many brain areas, particularly in brainstem regions associated with movement, including various cranial nerve nuclei, the red nucleus, cerebellum and the dopamine-rich substantia nigra. An investigation of the role of sigma receptors in the nigros-triatal dopamine system is timely and important for several reasons: 1) Dopamine is hypothesized to be involved in schizophrenia and the motor side effects of antipsychotic drugs. Consequently, understanding the role of sigma receptors in modulating dopamine may have implications for antipsychotic drug therapy. 2) The relationship between sigma receptors and antipsychotic drug therapy takes on added significance from the high to moderate affinity of typical antipsychotic drugs for sigma receptors. This implies that typical antipsychotic drugs could affect dopamine systems though both dopaminergic and sigmaergic mechanisms. 3) New compounds, some with subnanomolar affinities, possess a high degree of selectivity for sigma receptors; these compounds apparently remove previous impediments associated with the use of weak and nonselective sigma ligands. 4) Novel irreversible sigma compounds have been developed that may provide additional pharmacological tools for elucidating the biological role of sigma receptors in modulating dopamine function. 5) Preliminary data indicate that certain sigma compounds produce extremely potent dopamine-mediated effects on behavior. Based on these considerations we propose to investigate the behavioral, neurochemical and electrophysiological consequences of sigma receptor activation in the nigrostriatal dopamine system. These experiments focus on both functional and pharmacological questions. The main functional question is to establish the sites of action of sigma ligands within the nigrostriatal dopamine system. The pharmacological studies aim to establish the role of sigma receptors in the actions of sigma- ligands. This will be accomplished by determining the correlation between the potency of sigma ligands in these systems and their binding to sigma-1 and sigma-2 receptors. The other approach will be to use irreversible sigma ligands to investigate their possible utilization as sigma antagonists. Establishing a clear connection between sigma receptors and nigrostriatal dopamine function may have implications for the mechanisms of the cognitive and motor actions antipsychotic drugs.