smokeless tobacco, switching to products with greater nicotine delivery may also contribute to nicotine dose escalation (US DHHS

Animal studies have proved useful in establishing the actual development of tolerance to nicotine, the magnitude of such tolerance, and mechanisms that underlie this tolerance. The majority of these studies have used the rat and mouse as experimental subjects. Most of the chronic tolerance studies using the rat have focused on the effects of nicotine on locomotor activity. Depression of locomotor activity typically occurs following the injection of nicotine in doses exceeding 0.2 mg/kg in drug-naive rats. Tolerance to this depression develops following chronic treatment (Keenan and Johnson 1972; Stolerman, Fink, Jarvik 1973; Stolerman, Bunker, Jarvik 1974). The magnitude of this tolerance is influenced by the dose and dosing interval. Tolerance persists for greater than 90 days when nicotine is injected chronically. Tolerance to the effects of injected nicotine on depression of locomotor activity could also be produced with nicotine administered in the rats’ drinking water or through subcutaneously implanted reservoirs (Stolerman, Fink, Jarvik 1973). Under certain experimental conditions, rats treated chronically with nicotine exhibit an increase in locomotor activity following nicotine challenge (Morrison and Stephenson 1972; BaA5ttig et al. 1976; Clarke and Kumar 1983a,b). A careful analysis of the response to an acute challenge dose of nicotine demonstrated that soon after the first dose of nicotine, depressed locomotor activity was observed; after 40 min or more, increased locomotor activity became apparent (Clarke and Kumar 1983b). Chronically injected rats exhibited this enhanced activity progressively earlier postinjection. More recently, Ksir and others (1985, 1987) demonstrated that chronic nicotine injections may result in enhanced locomotor activity immediately after nicotine injection if the rats were acclimated to the test apparatus for 1 hr before nicotine injection. These findings indicate that in the rat, tolerance develops to the depressant effects of nicotine and that this tolerance uncovers a latent stimulatory action. If mice are injected chronically with nicotine, tolerance develops to the locomotor depressant effects elicited by a challenge dose of nicotine (Hatchell and Collins 1977). The degree and rate of development of tolerance appear to be influenced by the sex, as well as the strain, of the animals. Tolerance development has been studied by continuously infusing mice of several inbred strains with nicotine and assessing tolerance by measuring locomotor activity, body temperature, respiratory rate, heart rate, and acoustic startle response following nicotine challenge. Such studies have demonstrated that: (1) Tolerance to nicotine increases with the nicotine