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Decrease in 3^*/6^* Nicotinic Receptors but Not Nicotine-Evoked Dopamine Release in Monkey Brain after Nigrostriatal Damage

The Parkinson's Institute, Sunnyvale, California (S.E.M., N.P., T.B., M.Q.); Institute for Behavioral Genetics, University of Colorado, Denver, Colorado (S.R.G.); and Department of Biology and Psychiatry, University of Utah, Salt Lake City, Utah (J.M.M.)

Nicotinic acetylcholine receptors (nAChRs) are decreased in the striata of patients with Parkinson's disease (PD) or in experimental models after nigrostriatal damage. Because presynaptic nAChRs on striatal dopamine terminals mediate dopamine release, receptor loss may contribute to behavioral deficits in PD. The present experiments were done to determine whether nAChR function is affected by nigrostriatal damage in nonhuman primates, because this model shares many features with PD. Initial characterization of nicotine-evoked [³H]dopamine release from monkey striatal synaptosomes revealed that release was calcium-dependent and inhibited by selective nAChR antagonists. It is noteworthy that a greater proportion (70%) of release was inhibited by the 3^*/6^* antagonist -conotoxinMII (-CtxMII) compared with rodents. Monkeys were lesioned with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), and [³H]dopamine release, dopamine transporter, and nAChRs were measured. As anticipated, lesioning decreased the transporter and 3^*/6^* nAChRs in caudate and putamen. In contrast, 3^*/6^* nAChR-evoked [³H]dopamine release was reduced in caudate but not putamen, demonstrating a dissociation between nAChR sites and function. A different pattern was observed in the mesolimbic dopamine system. Dopamine transporter levels in nucleus accumbens were not reduced after MPTP, as expected; however, there was a 50% decline in 3^*/6^* nAChR sites with no decrease in 3^*/6^* receptor-evoked dopamine release. No declines in -CtxMII-resistant nAChR (4^*) binding or nicotine-evoked release were observed in any region. These results show a selective preservation of 3^*/6^* nAChR-mediated function in the nigrostriatal and mesolimbic dopamine systems after nigrostriatal damage. Maintenance of function in putamen, a region with a selective loss of dopaminergic terminals, may be important in PD.

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

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