Received for publication May 8, 2006.
Revised July 7, 2006.
Accepted for publication July 10, 2006.

Partial recovery of striatal nicotinic receptors in 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 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-A85380 and ¹²⁵I--conotoxinMII autoradiography was performed to evaluate changes in 42* and 3/62* nAChRs, the major striatal subtypes. Nicotine treatment increased 42* nAChRs by > 50% in striatum of both unlesioned and lesioned animals. This increase in 42* nAChRs was significantly greater in lesioned compared to unlesioned monkey striatum. Chronic nicotine treatment led to a small decrease in 3/62* nAChR subtypes. The decline in 3/62* subtypes, defined using -conotoxinMII-sensitive ¹²⁵I-epibatidine or ¹²⁵I-A85380 binding, was significantly smaller in striatum of nicotine-treated lesioned compared to unlesioned monkeys. This difference was not observed for 3/62* nAChRs identified using ¹²⁵I--conotoxinMII. These data suggest there are at least two striatal 3/62* subtypes, which are differentially affected by chronic nicotine treatment in lesioned animals. In addition, the results showing an improvement in striatal 42* and select 3/62* 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.

Key words: MPTP, Nicotinic, alpha-conotoxinMII, epibatidine, nicotine, striatum