Tolerance to behavioral effects of caffeine in rats

Tolerance develops to three behavioral effects of caffeine in rats treated daily with the drug: stimulation of locomotor activity, rate-decreasing effect on food-reinforced operant responding, and discriminative stimulus effects. Tolerance induced by caffeine to stimulation of locomotor activity: (1) develops rapidly, being nearly maximal 24 hr after the start of daily treatment with 35-40 mg/kg in four divided oral doses; (2) is insurmountable (i.e., complete) so that rats are unresponsive, even to high doses of caffeine, and dose-response curves are displaced downward and flattened; (3) is pharmacologically specific, extending to other methylxanthines but not to nonxanthine psychomotor stimulants. Tolerance to the other two behavioral effects of caffeine: (1) appears to develop gradually; (2) is surmountable so that dose-response curves are displaced to the right; (3) extends to nonxanthine psychomotor stimulants, methylphenidate, in the case of discriminative effects. Thus, at least two distinct types of tolerance to behavioral effects of caffeine in the rat can be identified. The potency of an adenosine analog, R(-)-PIA, in depressing locomotor activity does not increase during or 24 hr after termination of chronic daily treatment with caffeine when rats are completely tolerant to caffeine-induced stimulation of locomotor activity. These results do not support the view that enhanced functional sensitivity of central adenosine systems (e.g., up-regulation of receptors) is the mechanism of tolerance to the stimulant effect of caffeine on locomotor activity.