Partial recovery of striatal nicotinic receptors in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned monkeys with chronic oral nicotine.

Abstract

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.

• Authors: Tanuja Bordia, Neeraja Parameswaran, Hong Fan, J William Langston, J Michael McIntosh, Maryka Quik
• Journal: The Journal of pharmacology and experimental therapeutics (J Pharmacol Exp Ther) Vol. 319 Issue 1 Pg. 285-92 (Oct 2006) ISSN: 0022-3565 [Print] United States
• PMID: 16837557 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• A 85380
• Azetidines
• Bridged Bicyclo Compounds, Heterocyclic
• Conotoxins
• Pyridines
• Receptors, Nicotinic
• alpha-conotoxin MII
• Nicotine
• epibatidine

Topics

• Animals
• Azetidines (metabolism)
• Binding Sites
• Bridged Bicyclo Compounds, Heterocyclic (metabolism)
• Conotoxins (metabolism)
• Corpus Striatum (drug effects)
• Female
• MPTP Poisoning (metabolism)
• Nicotine (pharmacology, therapeutic use)
• Parkinson Disease (drug therapy)
• Pyridines (metabolism)
• Receptors, Nicotinic (analysis, classification, drug effects)
• Saimiri