Vulnerability of I-a-Conotoxin MII Binding Sites to Nigrostriatal Damage in Monkey

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 I-a-conotoxin MII (CtxMII), a relatively new ligand that identifies a3 and/or a6 subunits containing nAChR subtypes. In brain from untreated monkeys, there was saturable I-a-CtxMII binding to a single population of high-affinity nicotinic sites (Kd 5 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 I-a-CtxMII sites were selectively reduced ($99%) in the basal ganglia and that the lesioninduced decreases correlated well with declines in the dopamine transporter, a marker of dopaminergic neuron integrity. These findings may indicate that most or all of I-aCtxMII-labeled nAChR subtypes in the basal ganglia are present on nigrostriatal dopaminergic neurons, in contrast to I-epibatidine sites. These data suggest that the development of ligands directed to nAChR subtypes containing a3 and/or a6 subunits may yield a novel treatment strategy for parkinsonian patients with nigrostriatal dopaminergic degeneration.