Received for publication January 22, 2008.
Revised February 20, 2008.
Accepted for publication February 25, 2008.

Cotinine selectively activates a subpopulation of 3/62* nicotinic receptors in monkey striatum

Abstract

Cotinine, the major metabolite of nicotine, is an abundant long-lived bioactive compound that may contribute to the overall physiological effects of tobacco use. Although its mechanism of action in the CNS has not been extensively investigated, cotinine is known to evoke dopamine release in the nigrostriatal pathway through an interaction at nicotinic receptors (nAChRs). Since 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 42* and 3/62* nAChRs. Competition binding studies showed that cotinine interacts with both 42* and 3/62* nAChR subtypes in caudate, with cotinine IC₅₀ values for inhibition of ¹²⁵I-A-85380 and ¹²⁵I--conotoxinMII binding in the µM range. This interaction at the receptor level is of functional significance as cotinine stimulated both 42* and 3/62* nAChR [³H]dopamine release from caudate synaptosomes. Unexpectedly, our results showed that nicotine evokes [³H]dopamine release from two 3/62* nAChRs populations, one which was sensitive to cotinine and the other not. This cotinine-insensitive subtype was present only in the medial caudate and was preferentially lost with MPTP-induced nigrostriatal damage. In contrast, cotinine and nicotine elicited equivalent levels of 42* nAChR-mediated DA release. These data demonstrate that cotinine functionally discriminates between two 3/62* nAChRs in monkey striatum, with the cotinine-insensitive 3/62* nAChR preferentially vulnerable to nigrostriatal damage.

Key words: MPTP, dopamine, neurotransmitter release assay, nicotine, nigrostriatal damage, radioligand binding