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The Journal of Neuroscience, September 1, 2001, 21(17):6853-6861
Relationship between the Appearance of Symptoms and the Level of Nigrostriatal Degeneration in a Progressive 1-Methyl-4-Phenyl-1,2,3,6-Tetrahydropyridine-Lesioned Macaque Model of Parkinson's Disease
Erwan Bezard1, 2, Sandra Dovero2, Caroline Prunier3, Paula Ravenscroft1, Sylvie Chalon3, Denis Guilloteau3, Alan R. Crossman1, 4, Bernard Bioulac2, Jonathan M. Brotchie1, 4, and Christian E. Gross2 1 Manchester Movement Disorder Laboratory, Division of Neuroscience, School of Biological Sciences, University of Manchester, Manchester, M13 9PT, United Kingdom, 2 Basal Gang, Laboratoire de Neurophysiologie, Centre National de la Recherche Scientifique Unité Mixte de Recherche 5543, Université Victor Segalen, 33076 Bordeaux Cedex, France, 3 Institut National de la Santé et de la Recherche Médicale U316, Laboratoire de Biophysique Médicale et Pharmaceutique, 37200 Tours, France, and 4 Motac Neuroscience Ltd., Manchester M13 9XX, United Kingdom
The concept of a threshold of dopamine (DA) depletion for onset of Parkinson's disease symptoms, although widely accepted, has, to date, not been determined experimentally in nonhuman primates in which a more rigorous definition of the mechanisms responsible for the threshold effect might be obtained. The present study was thus designed to determine (1) the relationship between Parkinsonian symptom appearance and level of degeneration of the nigrostriatal pathway and (2) the concomitant presynaptic and postsynaptic striatal response to the denervation, in monkeys treated chronically with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine according to a regimen that produces a progressive Parkinsonian state. The kinetics of the nigrostriatal degeneration described allow the determination of the critical thresholds associated to symptom appearance, these were a loss of 43.2% of tyrosine hydroxylase-immunopositive neurons at the nigral level and losses of 80.3 and 81.6% DA transporter binding and DA content, respectively, at the striatal level. Our data argue against the concept that an increase in DA metabolism could act as an efficient adaptive mechanism early in the disease progress. Surprisingly, the D2-like DA receptor binding showed a biphasic regulation in relation to the level of striatal dopaminergic denervation, i.e., an initial decrease in the presymptomatic period was followed by an upregulation of postsynaptic receptors commencing when striatal dopaminergic homeostasis is broken. Further in vivo follow-up of the kinetics of striatal denervation in this, and similar, experimental models is now needed with a view to developing early diagnosis tools and symptomatic therapies that might enhance endogenous compensatory mechanisms.
Key words: threshold for symptom appearance; early D2 dopaminergic receptor upregulation; substantia nigra; striatum; dopaminergic homeostasis; compensatory mechanisms
Copyright © 2001 Society for Neuroscience 0270-6474/01/21176853-09$05.00/0
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