Brain Uptake Kinetics of Nicotine and Cotinine after Chronic Nicotine Exposure

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Abstract
Blood-brain barrier (BBB) nicotine transfer has been well documented in view of the fact that this alkaloid is a cerebral blood flow marker. However, limited data are available that describe BBB penetration of the major tobacco alkaloids after chronic nicotine exposure. This question needs to be addressed, given long-term nicotine exposure alters both BBB function and morphology. In contrast to nicotine, it has been reported that cotinine (the major nicotine metabolite) does not penetrate the BBB, yet cotinine brain distribution has been well documented after nicotine exposure. Surprisingly, therefore, the literature indirectly suggests that central nervous system cotinine distribution occurs secondarily to nicotine brain metabolism. The aims of the current report are to define BBB transfer of nicotine and cotinine in naive and nicotine-exposed animals. Using an in situ brain perfusion model, we assessed the BBB uptake of [3H]nicotine and [3H]cotinine in naive animals and in animals exposed chronically to S-(–)nicotine (4.5 mg/kg/day) through osmotic minipump infusion. Our data demonstrate that 1) [3H]nicotine BBB uptake is not altered in the in situ perfusion model after chronic nicotine exposure, 2) [3H]cotinine penetrates the BBB, and 3) similar to [3H]nicotine, [3H]cotinine BBB transfer is not altered by chronic nicotine exposure. To our knowledge, this is the first report detailing the uptake of nicotine and cotinine after chronic nicotine exposure and quantifying the rate of BBB penetration by cotinine.