SIGMA RECEPTOR REGULATION OF DOPAMINE NEURONS

黑质和纹状体中Sigma结合部位的存在 支持Sigma受体在调节 黑质纹状体多巴胺神经元。对这一论点的进一步支持是 Sigma配体引起的绕圈行为的研究 ICV后黑质注射、多动和刻板印象 静脉注射和抑制黑质细胞放电。 拟议研究的总体目标是确定以下范围 哪些Sigma受体配体调节多巴胺的释放 并确定黑质纹状体多巴胺神经元在什么条件下 这一规定可能会被修改。具体地说，建议1) 测定五唑西林的效价和对映体选择性的等级顺序， N-烯丙基-去甲氧基甲基佐辛和DTG诱导的大鼠肾上腺皮质激素释放增加 黑质纹状体神经元神经末梢和树突的多巴胺；2) 确定Sigma受体的下调是否由 慢性氟哌啶醇治疗伴随着脱敏的 Sigma配体诱导纹状体和黑质多巴胺的释放； 确定重复服用冰毒或(+)- 五唑西汀导致药物诱导的反应敏化 纹状体多巴胺释放到随后注射的Sigma配体。 这些研究将在清醒的、自由活动的大鼠身上进行，在这些大鼠中 将评估纹状体和黑质中多巴胺的释放。 从体内对细胞外多巴胺浓度的定量 微透析。急性注射五唑碱，N-烯丙基-2，4-二苯基-2，4-二甲基苯并 去甲三氢叶酸或DTG对细胞外多巴胺浓度的影响 在药物幼稚大鼠(特定目标1)中测定，在治疗大鼠中测定 长期使用氟哌啶醇(特定目标2)或治疗大鼠 长期使用甲基苯丙胺或五唑碱(具体目标3)。结果 将提供对神经调节的洞察力 黑质纹状体多巴胺神经元。鉴于这些神经元在脑内的作用 运动和姿势的控制与抗精神病药物的高亲和力 西格玛受体的药物，这些研究的结果也有 了解抗精神病药的运动副作用的意义 毒品。

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.