Declines in different beta2* nicotinic receptor populations in monkey striatum after nigrostriatal damage.

Abstract

In the present study we used the nicotinic ligand 5-iodo-A-85380 [5-iodo-3(2(S)-azetidinylmethoxy)pyridine], which selectively binds to beta2-containing nicotinic acetylcholine receptors, to elucidate the nicotinic receptor subtypes affected by nigrostriatal damage in the monkey. Autoradiographic studies in control monkeys showed that 5-[(125)I]A-85380 ([(125)I]A-85380) binds throughout the brain with the characteristics of a nicotinic receptor ligand. Competition experiments with cytisine and nicotine yielded K(i) values of approximately 1 and 10 nM, respectively, with complete inhibition of [(125)I]A-85380 binding at a 10(-6) M concentration of these ligands. In contrast, alpha-conotoxin MII blocked radioligand binding in the striatum by 30% at the highest concentrations, suggesting that a subset of striatal [(125)I]A-85380 sites are alpha-conotoxin MII-sensitive. Monkeys treated with the nigrostriatal neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine showed a selective decrease in striatal [(125)I]A-85380 sites, with a 42% reduction in the caudate and putamen of animals with moderate nigrostriatal lesioning and a 53% decline in the striatum of severely lesioned animals. Our previous work had demonstrated that there were two populations of nicotinic receptors eliminated after nigrostriatal damage, an alpha-conotoxin MII-sensitive and an alpha-conotoxin MII- resistant subtype. Analysis of both striatal [(125)I]A-85380 and [(125)I]epibatidine competition studies extend our earlier studies by demonstrating that the alpha-conotoxin MII-sensitive sites eliminated after moderate nigrostriatal lesioning appear to be composed of two nicotinic receptor subtypes. The data may be important for potential therapeutic approaches because they suggest that there are at least three populations of nicotinic receptors in monkey striatum, of which two are selectively vulnerable to nigrostriatal damage, while the third is more resistant.