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The Journal of Neuroscience, August 1, 2001, 21(15):5494-5500
Vulnerability of 125I- -Conotoxin MII Binding Sites
to Nigrostriatal Damage in Monkey
Maryka
Quik1,
Yelena
Polonskaya1,
Jennifer M.
Kulak1, and
J. Michael
McIntosh2
1 The Parkinson's Institute, Sunnyvale, California
94089, and 2 Department of Biology and Psychiatry,
University of Utah, Salt Lake City, Utah 84112
Parkinson's disease, a neurodegenerative movement disorder
characterized by selective degeneration of nigrostriatal dopaminergic neurons, affects ~1% of the population over 50. Because nicotinic acetylcholine receptors (nAChRs) may represent an important therapeutic target for this disorder, we performed experiments to elucidate the
subtypes altered with nigrostriatal damage in parkinsonian monkeys. For
this purpose we used 125I- -conotoxin MII
(CtxMII), a relatively new ligand that identifies 3 and/or
6 subunits containing nAChR subtypes. In brain from untreated
monkeys, there was saturable 125I--CtxMII binding
to a single population of high-affinity nicotinic sites
(Kd = 0.9 nM), primarily
localized in the visual, habenula-interpeduncular, and
nigrostriatal-mesolimbic pathways. Administration of the selective dopaminergic neurotoxin
1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine resulted in damage
to the nigrostriatal system and parkinsonism. Autoradiographic analysis
showed that 125I--CtxMII sites were selectively reduced
( 99%) in the basal ganglia and that the lesion-induced decreases
correlated well with declines in the dopamine transporter, a marker of
dopaminergic neuron integrity. These findings may indicate that most or
all of 125I--CtxMII-labeled nAChR subtypes in the basal
ganglia are present on nigrostriatal dopaminergic neurons, in contrast
to 125I-epibatidine sites. These data suggest that the
development of ligands directed to nAChR subtypes containing 3
and/or 6 subunits may yield a novel treatment strategy for
parkinsonian patients with nigrostriatal dopaminergic degeneration.
Key words:
-conotoxin MII; 3 nAChRs; 6 nAChRs; MPTP; monkeys; autoradiography; nigrostriatal system; dopamine; Parkinson's
disease
Copyright © 2001 Society for Neuroscience 0270-6474/01/21155494-07$05.00/0
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