Function of dopamine in the primate substantia nigra

描述（申请人提供）：在啮齿动物和猫中的实验已经表明，多巴胺从黑质丘脑部（SNc）中的细胞树突释放，并且它可以通过作用于GABA能纹状体-黑质投射末端上的D1样受体（D1 LRs）来增强黑质（SN）中的GABA释放，并通过对多巴胺D2样自身受体（D2 LRs）的作用抑制其自身的释放。黑质多巴胺释放的重要功能之一是调节黑质网状部（SNr）神经元的活动。D1 LR激活似乎通过增强GABA能抑制降低SNr活性。黑质D2 LRs的激活可能通过减少多巴胺释放和D1 LRs的继发性激活减少来增强SNr活性。SNr活性的局部多巴胺能调节可能具有显著的行为效应。因此，黑质多巴胺的损失似乎有助于啮齿动物帕金森氏症的增加SNr活动。拟议中的实验将探索这种多巴胺作用机制是否适用于灵长类动物。解剖学实验（目的1）将采用高分辨率免疫金电子显微镜表征灵长类SN中多巴胺受体的亚细胞和突触下定位。它们将通过功能实验（目的2）进行补充，在功能实验中，将在记录细胞附近局部微量输注D1 LR或D2 LR激动剂和拮抗剂之前、期间和之后记录SNr神经元的活性，并且将用微透析测量药物诱导的黑质GABA和多巴胺水平变化。目标3和4下的实验将表征该系统中多巴胺耗竭的后果，实验与目标1和2下的实验相似，在通过颈动脉内注射多巴胺能神经毒素MPTP而导致偏侧帕金森病的动物中进行。此外，我们将测试的假设，黑质注入D1 LR激动剂发挥抗帕金森病行为的影响。这些研究将提供深入了解在正常状态和帕金森症的猴子黑质多巴胺释放的解剖基础和功能的影响。它们将帮助我们确定黑质多巴胺丢失是否与帕金森综合征有关，抗帕金森病多巴胺能药物是否部分作用于SN，以及针对SN的恢复性治疗（例如，腹侧中脑组织移植）可通过多巴胺的局部释放起作用。

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.