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.
