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NEUROPHARMACOLOGY

Cotinine Selectively Activates a Subpopulation of 3/6β2^* Nicotinic Receptors in Monkey Striatum

The Parkinson's Institute, Sunnyvale, California (K.O., N.P., M.Q.); and Departments of Biology and Psychiatry, University of Utah, Salt Lake City, Utah (J.M.M.)

The nicotine metabolite cotinine is an abundant long-lived bio-active compound that may contribute to the overall physiological effects of tobacco use. Although its mechanism of action in the central nervous system has not been extensively investigated, cotinine is known to evoke dopamine release in the nigrostriatal pathway through an interaction at nicotinic receptors (nAChRs). Because considerable evidence now demonstrates the presence of multiple nAChRs in the striatum, the present experiments were done to determine the subtypes through which cotinine exerts its effects in monkeys, a species that expresses similar densities of striatal 4β2^* (nAChR containing the 4 and β2 subunits, but not 3 or 6) and 3/6β2^* (nAChR composed of the 3 or 6 subunits and β2) nAChRs. Competition binding studies showed that cotinine interacts with both 4β2^* and 3/6β2^* nAChR subtypes in the caudate, with cotinine IC₅₀ values for inhibition of 5-[¹²⁵ I]iodo-3-[2(S)-azetinylmethoxy]pyridine-2HCl ([¹²⁵I]A-85380) and ¹²⁵I--conotoxinMII binding in the micromolar range. This interaction at the receptor level is of functional significance because cotinine stimulated both 4β2^* and 3/6β2^* nAChR [³H]dopamine release from caudate synaptosomes. Our results unexpectedly showed that nicotine evokes [³H]dopamine release from two 3/6β2^* nAChR populations, one of which was sensitive to cotinine and the other was not. This cotinine-insensitive subtype was only present in the medial caudate and was preferentially lost with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced nigrostriatal damage. In contrast, cotinine and nicotine elicited equivalent levels of 4β2^* nAChR-mediated dopamine release. These data demonstrate that cotinine functionally discriminates between two 3/6β2^* nAChRs in monkey striatum, with the cotinine-insensitive 3/6β2^* nAChR preferentially vulnerable to nigrostriatal damage.

Address correspondence to: Dr. Maryka Quik, The Parkinson's Institute, 675 Almanor Ave., Sunnyvale, CA 94085-2934. E-mail: mquik{at}parkinsonsinstitute.org

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