title: Reduced noradrenergic innervation of ventral midbrain dopaminergic cell groups and the subthalamic nucleus in MPTP-treated parkinsonian monkeys.
abstract: There is anatomical and functional evidence that ventral midbrain dopaminergic (DA) cell groups and the subthalamic nucleus (STN) receive noradrenergic innervation in rodents, but much less is known about these interactions in primates. Degeneration of NE neurons in the locus coeruleus (LC) and related brainstem NE cell groups is a well-established pathological feature of Parkinson's disease (PD), but the development of such pathology in animal models of PD has been inconsistent across species and laboratories. We recently demonstrated 30-40% neuronal loss in the LC, A5 and A6 NE cell groups of rhesus monkeys rendered parkinsonian by chronic administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). In this study, we used dopamine-beta-hydroxylase (DβH) immunocytochemistry to assess the impact of this neuronal loss on the number of NE terminal-like varicosities in the substantia nigra pars compacta (SNC), ventral tegmental area (VTA), retrorubral field (RRF) and STN of MPTP-treated parkinsonian monkeys. Our findings reveal that the NE innervation of the ventral midbrain and STN of normal monkeys is heterogeneously distributed being far more extensive in the VTA, RRF and dorsal tier of the SNC than in the ventral SNC and STN. In parkinsonian monkeys, all regions underwent a significant (~50-70%) decrease in NE innervation. At the electron microscopic level, some DβH-positive terminals formed asymmetric axo-dendritic synapses in VTA and STN. These findings demonstrate that the VTA, RRF and SNCd are the main ventral midbrain targets of ascending NE inputs, and that these connections undergo a major break-down in chronically MPTP-treated parkinsonian monkeys. This severe degeneration of the ascending NE system may contribute to the pathophysiology of ventral midbrain and STN neurons in PD.
authors.affiliation: Yerkes National Primate Research Center, Emory University, 954, Gatewood Rd NE, Atlanta, GA 30322, USA; Udall Center of Excellence for Parkinson's Disease, Emory University, 954, Gatewood Rd NE, Atlanta, GA 30322, USA. Electronic address: gjeyara@emory.edu.
authors.forename: Gunasingh Jeyaraj
authors.initials: GJ
authors.lastname: Masilamoni
authors.affiliation: Yerkes National Primate Research Center, Emory University, 954, Gatewood Rd NE, Atlanta, GA 30322, USA; Department of Neurology, Emory University, 954, Gatewood Rd NE, Atlanta, GA 30322, USA. Electronic address: ogroove@emory.edu.
authors.forename: Olivia
authors.initials: O
authors.lastname: Groover
authors.affiliation: Yerkes National Primate Research Center, Emory University, 954, Gatewood Rd NE, Atlanta, GA 30322, USA; Department of Neurology, Emory University, 954, Gatewood Rd NE, Atlanta, GA 30322, USA; Udall Center of Excellence for Parkinson's Disease, Emory University, 954, Gatewood Rd NE, Atlanta, GA 30322, USA. Electronic address: ysmit01@emory.edu.
authors.forename: Yoland
authors.initials: Y
authors.lastname: Smith
mesh_terms: D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine / Q000494:pharmacology*; D000818:Animals; D003712:Dendrites / Q000187:drug effects / Q000378:metabolism; D004195:Disease Models, Animal; D059290:Dopaminergic Neurons / Q000187:drug effects* / Q000378:metabolism; D020267:MPTP Poisoning / Q000188:drug therapy* / Q000473:pathology; D008253:Macaca mulatta; D008297:Male; D008636:Mesencephalon / Q000187:drug effects* / Q000503:physiopathology; D013378:Substantia Nigra / Q000187:drug effects / Q000503:physiopathology; D020531:Subthalamic Nucleus / Q000187:drug effects* / Q000503:physiopathology; D017557:Ventral Tegmental Area / Q000187:drug effects / Q000503:physiopathology
chemical_list: D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine
keywords: Dopamine beta hydroxylase; Locus coeruleus; Noradrenaline; Norepinephrine; Parkinson's disease; Substantia nigra; Ultrastructure; Ventral tegmental area