Loss of Nicotinic Receptors in Monkey Striatum after 1-Methyl-4-Phenyl-1,2,3,6-Tetrahydropyridine Treatment Is Due to a Decline in α-Conotoxin MII Sites

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Abstract
Nicotinic acetylcholine receptors (nAChRs) in the basal ganglia are a potential target for new therapeutics for Parkinson9s disease. As an approach to detect expression of nAChRs in monkeys, we used 125I-epibatidine, an agonist at nAChRs containing α2 to α6 subunits. 125I-Epibatidine binding sites are expressed throughout the control monkey brain, including the basal ganglia. The α3/α6-selective antagonist α-conotoxin MII maximally inhibited 50% of binding in the caudate-putamen and had no effect on 125I-epibatidine binding in the frontal cortex or thalamus. In contrast, inhibition experiments with nicotine, cytisine, and 3-(2(S)-azetidinylmethoxy)pyridine·2HCl (A85380) showed a complete block of 125I-epibatidine binding in all regions investigated and did not discriminate between the α-conotoxin MII-sensitive and -insensitive populations in the striatum. To assess the effects of nigrostriatal damage, monkeys were rendered parkinsonian with the dopaminergic neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Animals with moderate striatal damage (dopamine transporter levels ∼30% of control) had a 40 to 50% decrease in 125I-epibatidine binding. Inhibition studies showed that the decrease in epibatidine binding was due to loss of α-conotoxin MII-sensitive nAChRs. Monkeys with severe nigrostriatal damage (dopamine transporter levels ≤5% of control) exhibited a 55 to 60% decrease in125I-epibatidine binding, which seemed to be due to a complete loss of α-conotoxin MII nAChRs and a partial loss of other nAChR subtypes. These results show that nAChRs expressed in the primate striatum have similar affinities for nicotine, cytisine, and A85380, that α-conotoxin MII discriminates between nAChR populations in the caudate and putamen, and that α-conotoxin MII-sensitive nAChRs are selectively decreased after MPTP-induced nigrostriatal damage.