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Subunit Composition of Nicotinic Receptors in Monkey Striatum: Effect of Treatments with 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine or L-DOPA

The Parkinson's Institute, Sunnyvale, California (M.Q., T.B., J.M.K.); Consiglio Nazionale delle Ricerche, Institute of Neuroscience, Cellular and Molecular Pharmacology, Department of Medical Pharmacology, University of Milan, Milan, Italy (S.V., F.C., C.G.); Department of Radiology, The 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.).

Nicotinic acetylcholine receptors (nAChRs) represent an important modulator of striatal function both under normal conditions and in pathological states such as Parkinson's disease. Because different nAChR subtypes may have unique functions, immunoprecipitation and ligand binding studies were done to identify their subunit composition. As in the rodent, 2, 4, 6, 2, and 3 nAChR subunit immunoreactivity was identified in monkey striatum. However, distinct from the rodent, the present results also revealed the novel presence of 3 nAChR subunit-immunoreactivity in this same region, but not that for 5 and 4. Relatively high levels of 2 and 3 subunits were also identified in monkey cortex, in addition to 4 and 2. Experiments were next done to determine whether striatal subunit expression was changed with nigrostriatal damage. 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine treatment decreased 6 and 3 subunit immunoreactivity by 80% in parallel with the dopamine transporter, suggesting that they are predominantly expressed on nigrostriatal dopaminergic projections. In contrast, 3, 4, and 2 subunit immunoreactivity was decreased 50%, whereas 2 was not changed. These data, together with those from dual immunoprecipitation and radioligand binding studies ([³H]cytisine, ¹²⁵I--bungarotoxin, and ¹²⁵I--conotoxin MII) suggest the following: that 623, 6423, and 32^* nAChR subtypes are present on dopaminergic terminals and that the 42 subtype is localized on both dopaminergic and nondopaminergic neurons, whereas 22^* and 7 receptors are localized on nondopaminergic cells in monkey striatum. Overall, these results suggest that drugs targeting non-7 nicotinic receptors may be useful in the treatment of disorders characterized by nigrostriatal dopaminergic damage, such as Parkinson's disease.

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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