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Vol. 61, Issue 1, 230-238, January 2002
-Conotoxin MII Sites
The Parkinson's Institute, Sunnyvale, California (J.M.K., M.Q.);
and Departments of Biology and Psychiatry, University of Utah, Salt
Lake City, Utah (J.M.M.).
Nicotinic acetylcholine receptors (nAChRs) in the basal ganglia
are a potential target for new therapeutics for Parkinson's disease. As an approach to detect expression of nAChRs in
monkeys, we used 125I-epibatidine, an agonist at nAChRs
containing 
2 to 6 subunits. 125I-Epibatidine binding
sites are expressed throughout the control monkey brain, including the
basal ganglia. The 3/6-selective antagonist -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 -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 -conotoxin MII-sensitive nAChRs. Monkeys
with severe nigrostriatal damage (dopamine transporter levels 
5% of
control) exhibited a 55 to 60% decrease in
125I-epibatidine binding, which seemed to be due to a
complete loss of -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 -conotoxin MII discriminates between nAChR populations in the
caudate and putamen, and that -conotoxin MII-sensitive nAChRs are
selectively decreased after MPTP-induced nigrostriatal damage.
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