Nicotine, a major component of tobacco, is highly addictive, underlying the fact that smokers quickly become addicted��about 1,200 per day in the United States (NIH/NIDA, 2008)��and have great difficulty quitting. To understand the numerous selleck effects of nicotine and to develop more effective and safer medications for smoking cessation as well as for treatment of tobacco-related diseases, animal models relevant to human nicotine exposure are required. In smokers (and often in those exposed secondhand), exposure to nicotine is chronic and intermittent. Cigarette smoke is an aerosol containing tiny particles within the respirable diameter range (Gowadia, Oldham, & Dunn-Rankin, 2009; Hinds, 1978). Respirable diameter is defined as the aerodynamic diameter of particles capable of reaching the gas exchange region in the lungs (the alveoli) for the organism under study (OECD, 2009).

Cigarette smoke particles deposit in the alveoli, where nicotine crosses the pulmonary membrane into the circulation. Inhalation of cigarette smoke leads to a rapid increase in arterial blood nicotine concentrations. When a human smokes one cigarette (takes ~5min), their arterial blood nicotine concentration reaches its maximum (C max) of 20�C60ng/ml in 3�C5min (T max), which then declines over the next 20min due to rapid distribution to all body tissues; the venous blood nicotine reaches C max of 15�C30ng/ml in T max of 5�C8min (Benowitz, Porchet, Sheiner, & Jacob, 1988; Henningfield, Stapleton, Benowitz, Grayson, & London, 1993; Hukkanen, Jacob, & Benowitz, 2005; Rose, Behm, Westman, & Coleman, 1999).

Nicotine reaches the brain within ~8�C10 s of inhalation (Matta et al., 2007) and it accumulates in the brain to its maximum value within 3�C5min (Rose, Mukhin, et al., 2010). Episodic exposure to nicotine in this pharmacokinetic pattern strongly stimulates brain nicotine receptors, inducing numerous psychological and behavioral effects and, eventually, nicotine dependence. For drug abuse studies with animal models to be relevant to humans, the routes of drug administration as well as the blood pharmacokinetics and target tissue concentrations should be comparable between humans and animals (Brent, 2004; Matta et al., 2007). Commonly used nicotine administration methods for in vivo animal models include the following: (a) Oral application, for example, nicotine dissolved in drinking water.

In this case, 70% of nicotine is metabolized in the liver, with only ~30% entering the systemic circulation (Matta Dacomitinib et al., 2007). Moreover, oral nicotine absorption is slow compared to that during smoking. (b) Intraperitoneal (i.p.), subcutaneous (s.c.), or intravenous (i.v.) injection of nicotine. These methods are invasive and inconvenient for chronic intermittent exposure. In addition, i.p. nicotine delivery is affected by the first-pass liver metabolism.