Function of dopamine in the primate substantia nigra

描述（由申请人提供）：啮齿动物和猫的实验表明，多巴胺从黑质致密部（SNc）细胞的树突释放，并可能通过作用于GABA能纹状体-黑质投射末端的d1样受体（D1LRs）增强黑质（SN）中GABA的释放，并通过作用于多巴胺d2样自受体（D2LRs）抑制其自身释放。神经多巴胺释放在功能上的重要作用之一是调节黑质网状部神经元的活动。D1LR激活似乎通过增强gaba能抑制来降低SNr活性。神经元D2LRs的激活可能通过减少多巴胺释放和D1LRs的继发性减少激活来增强信噪比活性。局部多巴胺能调节信噪比活性可能具有显著的行为效应。因此，神经性多巴胺缺失似乎通过增加信噪比活性来促进啮齿动物帕金森病。拟议的实验将探索多巴胺的这种行为是否适用于灵长类动物。解剖实验（目的1）将利用高分辨率免疫金电子显微镜表征灵长类动物SN中多巴胺受体的亚细胞和亚突触定位。他们将通过功能实验（目标2）进行补充，在记录的细胞附近局部微输注D1LRs或D2LRs的激动剂和拮抗剂之前、期间和之后，记录SNr神经元的活性，并通过微透析测量药物诱导的黑质GABA和多巴胺水平的变化。目标3和4下的实验将描述该系统中多巴胺耗竭的后果，与目标1和2下的实验相似，实验对象是通过颈动脉内注射多巴胺能神经毒素MPTP而导致偏帕金森病的动物。此外，我们将检验神经输注D1LR激动剂发挥抗帕金森行为作用的假设。这些研究将为了解正常状态和帕金森病猴子黑质多巴胺释放的解剖学基础和功能影响提供深入的见解。它们将帮助我们确定神经性多巴胺丢失是否与帕金森病有关，抗帕金森多巴胺能药物是否在SN中起部分作用，以及针对SN的恢复性治疗（例如腹侧中脑组织移植）是否可能通过局部释放多巴胺起作用。

DESCRIPTION (provided by applicant): Experiments in rodents and cats have indicated that dopamine is released from dendrites of cells in the substantia nigra pars compacta (SNc), and that it may enhance GABA release in the substantia nigra (SN) via an action on D1-like receptors (D1LRs) on terminals of the GABAergic striato-nigral projection, and inhibit its own release via an action on dopamine D2-like autoreceptors (D2LRs). One of the functionally important effects of nigral dopamine release is that it may modulate the activity of neurons in the substantia nigra pars reticulata (SNr). D1LR activation appears to reduce SNr activity via enhanced GABAergic inhibition. Activation of nigral D2LRs may enhance SNr activity via reduction of dopamine release and secondary reduced activation of D1LRs. Local dopaminergic modulation of SNr activity may have significant behavioral effects. Thus, nigral dopamine loss appears to contribute to rodent parkinsonism by increasing SNr activity. The proposed experiments will explore whether this scheme of dopamine actions applies to primates. Anatomic experiments (aim 1) will characterize the subcellular and subsynaptic localization of dopamine receptors in the primate SN with high-resolution immunogold electron microscopy. They will be complemented by functional experiments (aim 2) in which the activity of SNr neurons will be recorded before, during and after local microinfusions of agonists and antagonists for D1LRs or D2LRs in the vicinity of the recorded cells, and in which drug-induced changes in nigral GABA and dopamine levels will be measured with microdialysis. The experiments under aims 3 and 4 will characterize the consequences of dopamine depletion in this system with experiments similar to those under aims 1 and 2 in animals that have been rendered hemiparkinsonian by intracarotid injections of the dopaminergic neurotoxin MPTP. In addition, we will test the hypothesis that nigral infusions of D1LR agonist exert antiparkinsonian behavioral effects. These studies will provide insights into the anatomic basis and functional effects of nigral dopamine release in monkeys in the normal state and in parkinsonism. They will help us to determine whether nigral dopamine loss is involved in parkinsonism, whether antiparkinsonian dopaminergic drugs act in part in SN, and whether restorative therapies aimed at the SN (e.g., transplantation of ventral mesencephalic tissue) may act through local release of dopamine.