Tolerance to nicotine's disruptive effects on operant responding develops rapidly over a 14-36 day repeated dosing period in both rats and mice. This occurred regardless of whether nicotine was administered pre- or post- to each behavioral exposure. Thus, tolerance development appeared to depend on both behavioral as well as pharmacological mechanisms. It is suggested that the pharmacological mechanism(s) involved in the development of tolerance may be related to an up-regulation of brain area nicotinic receptors. As observed with receptor binding studies, mecamylamine did not appear to attenuate the development of pharmacological tolerance to nicotine (does not attenuate nicotinic receptor up-regulation) even though this cholinergic antagonist will antagonize nicotine's acute behavioral disruptive effects completely. However, the fact that mecamylamine may induce some cross-tolerance to nicotine does complicate our interpretation of these data. The development of nicotine tolerance, in part, appears to depend upon an interaction at some acetylcholine-sensitive nicotinic receptor as evidenced by the ability of physostigmine to induce cross-tolerance to nicotine in both the rat and mouse. These data support the view that nicotine may be inducing its effects via at least two separate nicotinic receptors, one of which may be acetylcholine sensitive. Furthermore, binding data suggest that physostigmine's effects were related to a reduction of available central nicotinic receptor sites. In contrast to what humans experience, the rat does not appear as sensitive to nicotine-induced physical dependence, at least when operant behavior is utilized as the dependent variable used to measure withdrawal signs. Other approaches such as drug discrimination and conditioned avoidance paradigms may provide a better alternative to the evaluation of nicotine-induced dependence. Research utilizing schedule-controlled behavior in the mouse, on the other hand, has provided us with an additional model of a nicotine-induced withdrawal syndrome which may be of value in evaluating mechanisms of nicotine dependence. However, as with all of these findings, much work is needed to confirm and further characterize each model in so far as they may provide us with a reliable and specific measure of nicotine dependence.