both humans and animals, although there is lesser dose-dependency than other drugs in animals, and the curve is somewhat flat for humans (Corrigall, 1999). Nonetheless, reduced nicotine self-administration in humans is observed with nicotine preloading and compensation with changing nicotine doses in cigarettes. Speed of nicotine delivery also plays a role in the extent to which nicotine is self-administered. Rapid bolus injections of nicotine result in greater self-administration than a slow infusion (Wakasa et al., 1995). Self-administration can be blocked by mecamylamine, a nonspecific nAchR antagonist or by dopamine receptor antagonists (see earlier discussion of the biological basis of addiction). Self-administration can be facilitated not only by the dosing characteristics of cigarettes or nicotine but also by the sensory characteristics of cigarettes (Henningfield and Goldberg, 1983; Rose and Corrigall, 1997).

Smokers tend to report dose-related subjective effects such as drug liking, drug strength, head rush, and feeling dizzy or aroused as a result of inhaled, buccal (smokeless tobacco), intravenous, or nasal spray nicotine administration (Fant et al., 1999; Henningfield et al., 1985; Jones et al., 1999; Perkins et al., 1994a, 1994b). Smokers who have a history of drug dependence exhibit a similar dose-related increase in “liking” and other subjective responses for intravenously administered nicotine as observed for cocaine, amphetamine, morphine, pentobarbitol, and heroin (Jasinski et al., 1984; Jones et al., 1999; Keenan et al., 1994). Findings from another study also revealed that intravenous nicotine was misidentified as cocaine or amphetamine by the study participants who had histories of drug use (Henningfield et al., 1985; Jones et al., 1999). Subjective responses to nicotine gum, patch, spray and inhaler have been less pronounced than responses to cigarettes or intravenous nicotine (deWit and Zacny, 1995; Henningfield and Keenan, 1993; Schuh et al., 1997).

The occurrence of withdrawal symptoms after cessation of continuous nicotine infusion in rodents has been demonstrated (Malin et al., 1992). In humans, withdrawal symptoms upon cigarette smoking cessation has also been well established (Hughes et al., 1990a). However, fewer studies have been conducted with other tobacco products or nicotine replacement agents. Cessation of smokeless tobacco use generally produces less intense withdrawal symptoms than cessation of cigarette smoking (Hatsukami et al., 1987; Keenan et al., 1989). However, in a population of smokeless tobacco users enrolled in clinical trials, the severity and number of withdrawal symptoms from smokeless tobacco were comparable to those experienced by cigarette smokers who were trying to quit (Hatsukami et al., 2000). Nicotine gum withdrawal symptoms also tend to be significantly less intense in number and severity than cigarette withdrawal symptoms (Hatsukami et al., 1991, 1993, 1995), and higher doses of gum produce greater withdrawal than lower doses of gum (Hatsukami



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