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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 (K_d = 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

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Copyright © 2001 Society for Neuroscience  0270-6474/01/21155494-07$05.00/0

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