title: Dopamine regulates distinctively the activity patterns of striatal output neurons in advanced parkinsonian primates.
abstract: Nigrostriatal dopamine denervation plays a major role in basal ganglia circuitry disarray and motor abnormalities of Parkinson's disease (PD). Studies in rodent and primate models have revealed that striatal projection neurons, namely, medium spiny neurons (MSNs), increase the firing frequency. However, their activity pattern changes and the effects of dopaminergic stimulation in such conditions are unknown. Using single-cell recordings in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated primates with advanced parkinsonism, we studied MSN activity patterns in the transition to different motor states following levodopa administration. In the "off" state (baseline parkinsonian disability), a burst-firing pattern accompanied by prolonged silences (pauses) was found in 34% of MSNs, and 80% of these exhibited a levodopa response compatible with dopamine D1 receptor activation (direct pathway MSNs). This pattern was highly responsive to levodopa given that bursting/pausing almost disappeared in the "on" state (reversal of parkinsonism after levodopa injection), although this led to higher firing rates. Nonbursty MSNs fired irregularly with marked pausing that increased in the on state in the MSN subset with a levodopa response compatible with dopamine D2 receptor activation (indirect pathway MSNs), although the pause increase was not sustained in some units during the appearance of dyskinesias. Data indicate that the MSN firing pattern in the advanced parkinsonian monkey is altered by bursting and pausing changes and that dopamine differentially and inefficiently regulates these behaviorally correlated patterns in MSN subpopulations. These findings may contribute to understand the impact of striatal dysfunction in the basal ganglia network and its role in motor symptoms of PD.
authors.affiliation: Yerkes National Primate Research Center, Emory University School of Medicine, Atlanta, Georgia;
authors.forename: Arun
authors.initials: A
authors.lastname: Singh
authors.affiliation: Yerkes National Primate Research Center, Emory University School of Medicine, Atlanta, Georgia; Department of Neurobiology and Behavior, Stony Brook University, Stony Brook, New York;
authors.forename: Li
authors.initials: L
authors.lastname: Liang
authors.affiliation: Department of Integrative Physiology, National Institute for Physiological Sciences, Myodaiji, Okazaki, Japan;
authors.forename: Yoshiki
authors.initials: Y
authors.lastname: Kaneoke
authors.affiliation: Yerkes National Primate Research Center, Emory University School of Medicine, Atlanta, Georgia; Department of Neurology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Hubei, China; and.
authors.forename: Xuebing
authors.initials: X
authors.lastname: Cao
authors.affiliation: Yerkes National Primate Research Center, Emory University School of Medicine, Atlanta, Georgia; Department of Neurology, Emory University School of Medicine, Atlanta, Georgia spapa@emory.edu.
authors.forename: Stella M
authors.initials: SM
authors.lastname: Papa
mesh_terms: D000200:Action Potentials; D000818:Animals; D003342:Corpus Striatum / Q000166:cytology / Q000378:metabolism* / Q000503:physiopathology; D004298:Dopamine / Q000378:metabolism*; D015259:Dopamine Agents / Q000494:pharmacology*; D005260:Female; D007980:Levodopa / Q000494:pharmacology*; D020267:MPTP Poisoning / Q000378:metabolism* / Q000503:physiopathology; D008253:Macaca mulatta; D009474:Neurons / Q000187:drug effects / Q000378:metabolism* / Q000502:physiology; D017448:Receptors, Dopamine D2 / Q000378:metabolism
chemical_list: D015259:Dopamine Agents; D017448:Receptors, Dopamine D2; D007980:Levodopa; D004298:Dopamine
keywords: Parkinson's disease; basal ganglia; bursts; dyskinesias; electrophysiology; pauses; striatum