Partial recovery of striatal nicotinic receptors in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned monkeys with chronic oral nicotine.
Recent studies in nonhuman primates show that chronic nicotine treatment protects against nigrostriatal degeneration, with a partial restoration of neurochemical and functional measures in the striatum. The present studies were done to determine whether long-term nicotine treatment also protected against striatal nicotinic receptor (nAChR) losses after nigrostriatal damage. Monkeys were administered nicotine in the drinking water for 6 months and subsequently lesioned with the dopaminergic neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) over several months while nicotine was continued. (125)I-Epibatidine, [(125)I]5-[(125)I]iodo-3(2(S)-azetidinylmethoxy)-pyridine (A85380), and (125)I-alpha-conotoxinMII autoradiography was performed to evaluate changes in alpha4beta2* and alpha3/alpha6beta2* nAChRs, the major striatal subtypes. Nicotine treatment increased alpha4beta2* nAChRs by > or =50% in striatum of both unlesioned and lesioned animals. This increase in alpha4beta2* nAChRs was significantly greater in lesioned compared with unlesioned monkey striatum. Chronic nicotine treatment led to a small decrease in alpha3/alpha6beta2* nAChR subtypes. The decline in alpha3/alpha6beta2* subtypes, defined using alpha-conotoxinMII-sensitive (125)I-epibatidine or [(125)I]A85380 binding, was significantly smaller in striatum of nicotine-treated lesioned monkeys compared with unlesioned monkeys. This difference was not observed for alpha3/alpha6beta2* nAChRs identified using (125)I-alpha-conotoxinMII. These data suggest that there are at least two striatal alpha3/alpha6beta2* subtypes that are differentially affected by chronic nicotine treatment in lesioned animals. In addition, the results showing an improvement in striatal alpha4beta2* and select alpha3/alpha6beta2* nAChR subtypes, combined with previous work, demonstrate that chronic nicotine treatment restores and/or protects against the loss of multiple molecular markers after nigrostriatal damage. Such findings suggest that nicotine or nicotinic agonists may be of therapeutic value in Parkinson's disease.
Bordia
Tanuja
T
The Parkinson's Institute, 1170 Morse Ave, Sunnyvale, CA 94089-1605, USA.
Parameswaran
Neeraja
N
Fan
Hong
H
Langston
J William
JW
McIntosh
J Michael
JM
Quik
Maryka
M
D000818:Animals; D001384:Azetidines / Q000378:metabolism; D001665:Binding Sites; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000378:metabolism; D020916:Conotoxins / Q000378:metabolism; D003342:Corpus Striatum / Q000187:drug effects*; D005260:Female; D020267:MPTP Poisoning / Q000378:metabolism*; D009538:Nicotine / Q000494:pharmacology* / Q000627:therapeutic use; D010300:Parkinson Disease / Q000188:drug therapy; D011725:Pyridines / Q000378:metabolism; D011978:Receptors, Nicotinic / Q000032:analysis / Q000145:classification / Q000187:drug effects*; D012453:Saimiri
C104288:A 85380; D001384:Azetidines; D019086:Bridged Bicyclo Compounds, Heterocyclic; D020916:Conotoxins; D011725:Pyridines; D011978:Receptors, Nicotinic; C098872:alpha-conotoxin MII; D009538:Nicotine; C082748:epibatidine