Loss of nicotinic receptors in monkey striatum after 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine treatment is due to a decline in alpha-conotoxin MII sites.
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 alpha2 to alpha6 subunits. 125I-Epibatidine binding sites are expressed throughout the control monkey brain, including the basal ganglia. The alpha3/alpha6-selective antagonist alpha-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 alpha-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 approximately 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 alpha-conotoxin MII-sensitive nAChRs. Monkeys with severe nigrostriatal damage (dopamine transporter levels < or = 5% of control) exhibited a 55 to 60% decrease in 125I-epibatidine binding, which seemed to be due to a complete loss of alpha-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 alpha-conotoxin MII discriminates between nAChR populations in the caudate and putamen, and that alpha-conotoxin MII-sensitive nAChRs are selectively decreased after MPTP-induced nigrostriatal damage.
Kulak
Jennifer M
JM
The Parkinson's Institute, Sunnyvale, California 94089-1605, USA.
McIntosh
J Michael
JM
Quik
Maryka
M
D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine / Q000494:pharmacology*; D000818:Animals; D001667:Binding, Competitive; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000494:pharmacology; D002421:Caudate Nucleus / Q000378:metabolism; D020916:Conotoxins / Q000378:metabolism; D003342:Corpus Striatum / Q000187:drug effects* / Q000378:metabolism; D015259:Dopamine Agents / Q000494:pharmacology*; D066298:In Vitro Techniques; D007457:Iodine Radioisotopes; D009043:Motor Activity / Q000187:drug effects; D018722:Nicotinic Agonists / Q000494:pharmacology; D011699:Putamen / Q000378:metabolism; D011725:Pyridines / Q000494:pharmacology; D011869:Radioligand Assay; D011978:Receptors, Nicotinic / Q000378:metabolism*; D012453:Saimiri
D019086:Bridged Bicyclo Compounds, Heterocyclic; D020916:Conotoxins; D015259:Dopamine Agents; D007457:Iodine Radioisotopes; D018722:Nicotinic Agonists; D011725:Pyridines; D011978:Receptors, Nicotinic; C098872:alpha-conotoxin MII; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; C082748:epibatidine