SIGMA RECEPTORS AND DOPAMINE NEUROTRANSMISSION

结合实验表明存在σ结合位点， 不同于任何已知的大脑神经递质受体或其他药物 结合位点 这些位点是独特的，在结合与高亲和力， 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，至少有两种亚型的存在， σ受体，称为σ-1和σ-2。 发现σ结合 在许多大脑区域，特别是在脑干区域， 运动，包括各种脑神经核，红核， 小脑和富含多巴胺的黑质。 调查 σ受体在黑质-三重多巴胺系统中的作用是 及时和重要的几个原因：1）多巴胺被假设为 精神分裂症和抗精神病药物的运动副作用 毒品 因此，理解sigma受体在 调节多巴胺可能对抗精神病药物 疗法2)σ受体与抗精神病药物的关系 药物治疗从高到中具有额外的意义 典型抗精神病药物对σ受体的亲和力。 这 这意味着典型的抗精神病药物可能会影响多巴胺系统， 虽然都是多巴胺能和σ能机制。3)新化合物， 一些具有亚纳摩尔亲和力，具有高度选择性 对于σ受体;这些化合物显然去除了先前的 与使用弱和非选择性西格玛相关的障碍 配体。4)新型不可逆西格玛化合物已被开发出来， 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。第五章） 初步数据表明，某些σ化合物产生极高的 多巴胺对行为的影响 基于这些考虑，我们建议调查行为， σ受体的神经化学和电生理学后果 黑质纹状体多巴胺系统的激活。 这些实验 关注功能和药理学问题。 主要 功能性问题是确定σ配体的作用位点 黑质纹状体多巴胺系统中。 的药理学研究 目的是建立sigma受体在sigma- 配体。 这将通过确定相关性来实现 在这些系统中σ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 不可逆的σ配体，以研究它们作为 σ拮抗剂。 在sigma之间建立明确的联系 受体和黑质纹状体多巴胺功能可能与 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.