This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH source,and thus could be represented in other CRISP entries. The institution listed isfor the Center, which is not necessarily the institution for the investigator.Experiments in rodents have indicated that dopamine is released from dendrites of cells in the substantia nigra pars compacta (SNc). Nigral dopamine release appears to modulate the activity of neurons in the substantia nigra pars reticulata (SNr). Activation of dopamine D1-like receptors (D1LRs) appears to reduce SNr activity via enhanced GABAergic inhibition. Activation of dopamine D2-like receptors (D2LRs) may enhance SNr activity via reduction of dopamine release and secondary reduced activation of D1LRs. It is thought that nigral dopamine loss appears to contribute to rodent parkinsonism by increasing SNr activity.Our experiments explored whether this scheme of dopamine actions applies to primates. Anatomic experiments characterized the subcellular and subsynaptic localization of dopamine receptors in the primate SN with immunogold electron microscopy. They are complemented by functional experiments in which the activity of SNr neurons is 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 are being measured with microdialysis. The experiments characterized the consequences of dopamine depletion in this system in animals that have been rendered hemiparkinsonian by intracarotid injections of the dopaminergic neurotoxin MPTP. We also tested the hypothesis that nigral infusions of D1LR agonist have antiparkinsonian behavioral effects.These studies provided insights into the anatomic basis and functional effects of nigral dopamine release in monkeys in the normal state and in parkinsonism. They helped 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) may act through local release of dopamine.
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