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NEUROPHARMACOLOGY

Partial Recovery of Striatal Nicotinic Receptors in 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-Lesioned Monkeys with Chronic Oral Nicotine

The Parkinson's Institute, Sunnyvale, California (T.B., N.P., J.W.L., M.Q.); Department of Radiology, Johns Hopkins University School of Medicine, Baltimore, Maryland (H.F.); and Department of Biology and Psychiatry, University of Utah, Salt Lake City, Utah (J.M.M.)

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 [GenBank] ), 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 with 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 monkeys compared with unlesioned monkeys. This difference was not observed for 3/62^* nAChRs identified using ¹²⁵I--conotoxinMII. These data suggest that there are at least two striatal 3/62^* subtypes that 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.

Address correspondence to: Dr. Maryka Quik, The Parkinson's Institute, 1170 Morse Ave, Sunnyvale, CA 94089-1605. E-mail address: mquik{at}parkinsonsinstitute.org