In vivo measures of nigrostriatal neuronal response to unilateral MPTP treatment.
A single unilateral intracarotid infusion of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) into non-human primates causes injury to the nigrostriatal pathway including nigral cell bodies, axons and striatal terminal fields. In this model, motor parkinsonism correlates well with the loss of nigral dopaminergic cell bodies but only correlates with in vitro measures of nigrostriatal terminal fields when nigral cell loss does not exceed 50%. The goals of this study are to determine the relationship of motor parkinsonism with the degree of injury to nigrostriatal axons, as reflected by in vitro fiber length density measures, and compare in vivo with in vitro measures of striatal terminal fields. We determined axon integrity by measuring fiber length density with tyrosine hydroxylase (TH) immunohistology and dopamine transporter (DAT) density with DAT immunohistology. We then calculated the terminal arbor size and compared these measures with previously published data of quantified in vivo positron emission tomography (PET) measures of presynaptic dopaminergic neurons, autoradiographic measures of DAT and vesicular monoamine transporter type 2 (VMAT2), striatal dopamine, nigral cell counts, and parkinsonian motor ratings in the same animals. Our data demonstrate that in vivo and in vitro measures of striatal terminal fields correlate with each other regardless of the method of measurement. PET-based in vivo striatal measures accurately reflect in vitro measures of DAT and VMAT2. Terminal arbor size and other terminal field measures correlate with nigral TH immunoreactive (TH-ir) cell counts only when nigral TH-ir cell loss does not exceed 50%. Fiber length density was the only striatal measure that linearly correlated with motor ratings (Spearman: r=-0.81, p<0.001, n=16).
Neurology, Washington University, St. Louis, MO 63110, USA.
LinLin
L
Tian
Neurology, Washington University, St. Louis, MO 63110, USA.
Morvarid
M
Karimi
Neurology, Washington University, St. Louis, MO 63110, USA.
Chris A
CA
Brown
Neurology, Washington University, St. Louis, MO 63110, USA.
Susan K
SK
Loftin
Neurology, Washington University, St. Louis, MO 63110, USA; Radiology, Washington University, St. Louis, MO 63110, USA; Neurobiology, Washington University, St. Louis, MO 63110, USA; Occupational Therapy, Washington University, St. Louis, MO 63110, USA; Physical Therapy, Washington University, St. Louis, MO 63110, USA. Electronic address: joel@npg.wustl.edu.
Joel S
JS
Perlmutter
D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine / Q000494:pharmacology; D000818:Animals; D002452:Cell Count; D002851:Chromatography, High Pressure Liquid; D003042:Cocaine / Q000031:analogs & derivatives / Q000493:pharmacokinetics; D003342:Corpus Striatum / Q000187:drug effects / Q000473:pathology*; D004195:Disease Models, Animal; D050483:Dopamine Plasma Membrane Transport Proteins / Q000378:metabolism; D018765:Dopamine Uptake Inhibitors / Q000493:pharmacokinetics; D007839:Functional Laterality / Q000187:drug effects*; D008251:Macaca; D008297:Male; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D020734:Parkinsonian Disorders / Q000139:chemically induced* / Q000000981:diagnostic imaging / Q000473:pathology*; D049268:Positron-Emission Tomography; D011485:Protein Binding / Q000187:drug effects; D013378:Substantia Nigra / Q000187:drug effects / Q000473:pathology*; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism; D050493:Vesicular Monoamine Transport Proteins / Q000378:metabolism
D050483:Dopamine Plasma Membrane Transport Proteins; D018765:Dopamine Uptake Inhibitors; D050493:Vesicular Monoamine Transport Proteins; C021279:(1R-(exo,exo))-3-(4-fluorophenyl)-8-methyl-8- azabicyclo(3.2.1)octane-2-carboxylic acid, methyl ester; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D014446:Tyrosine 3-Monooxygenase; D003042:Cocaine
MPTP; Nigrostriatal; PET; Striatal terminal field