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. ¹²⁵I-Epibatidine, [¹²⁵I]5-[¹²⁵I]iodo-3(2(S)-azetidinylmethoxy)-pyridine (A85380), and ¹²⁵I-α-conotoxinMII autoradiography was performed to evaluate changes in α4β2* and α3/α6β2* nAChRs, the major striatal subtypes. Nicotine treatment increased α4β2* nAChRs by ≥50% in striatum of both unlesioned and lesioned animals. This increase in α4β2* nAChRs was significantly greater in lesioned compared with unlesioned monkey striatum. Chronic nicotine treatment led to a small decrease in α3/α6β2* nAChR subtypes. The decline in α3/α6β2* subtypes, defined using α-conotoxinMII-sensitive ¹²⁵I-epibatidine or [¹²⁵I]A85380 binding, was significantly smaller in striatum of nicotine-treated lesioned monkeys compared with unlesioned monkeys. This difference was not observed for α3/α6β2* nAChRs identified using ¹²⁵I-α-conotoxinMII. These data suggest that there are at least two striatal α3/α6β2* subtypes that are differentially affected by chronic nicotine treatment in lesioned animals. In addition, the results showing an improvement in striatal α4β2* and select α3/α6β2* 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.