Chronic intermittent nicotine delivery with lung alveolar region-targeted aerosol technology produces circadian blood pharmacokinetics in rats resembling human smokers

Abstract

IntroductionCigarette smoke is an aerosol containing microparticles that carry nicotine into lung alveolar region where nicotine is rapidly absorbed into circulation. Nicotine exposure in smokers is a chronic intermittent process, with intake during wakefulness and abstinence during sleep resulting in circadian fluctuation of blood nicotine levels. Here we present a smoking-relevant nicotine exposure device and rodent model.\n\nMethodsWe developed a computer controlled integrated platform where freely moving rodents can be exposed to episodic nicotine aerosol on an investigator-designed schedule. Rats were exposed to nicotine aerosol once every half hr in the dark phase of 12/12-hr dark/light cycles for 10 days. Plasma nicotine and its metabolite cotinine levels were determined with a LC-MS/MS method.\n\nResultsWe characterized the aerosol in the breathing zone of the rodent exposure chamber. The droplet size distribution was within the respirable diameter range. The system can generate a wide range of nicotine concentrations in air that meet a variety of experimental needs. We optimized the parameters of aerosol generation and exposure: plasma nicotine and cotinine concentrations reached 30-35 ng/ml and 190-240 ng/ml, respectively. The nicotine levels and circadian patterns resembled the pharmacokinetic pattern of human smokers.\n\nConclusionsWe developed an aerosol system that can produce chronic intermittent nicotine exposure in unanesthetized and unrestrained rodents with route of administration and circadian blood pharmacokinetics resembling human smokers. This methodology is a novel tool for studies of behavior, pharmacology and toxicology of chronic nicotine exposure, nicotine addiction, tobacco-related diseases, teratogenicity, and for discovery of therapeutics.\n\nImplicationsWe developed a method and an alveolar region-targeted aerosol system that provides chronic intermittent nicotine exposure in rodents. The method produces clinically relevant animal models with the route of administration and circadian pharmacokinetics resembling human smokers. This method is a novel tool for understanding the health effects of chronic nicotine exposures such as with tobacco cigarettes, E-cigarettes and other tobacco products, for studies of pharmacology, toxicology, nicotine addiction, tobacco-related diseases, and for discovery of medications.