Tolerance to oral and IP caffeine: locomotor activity and pharmacokinetics.

Locomotor activity increase was a bitonic function of acute caffeine IP doses (2.5-40 mg/kg) in rats. When the schedule-induced polydipsic, orally self-administered dose of caffeine was increased over blocks of daily 3 h sessions from 9.3 to 36.5 mg/kg, postsession activity increased monotonically as a function of dose. The rate of tolerance development to the increase in locomotor activity produced by caffeine depended on the route of administration. Tolerance onset occurred on the fourth day of chronic IP doses, but remained incomplete after 21 doses. With the highest dose level of oral caffeine self-administration, tolerance developed on day 13, but remained incomplete even after 17 doses. Acute tolerance occurred for each of the IP doses, whereas a linear relation between locomotor activity and serum caffeine concentration was obtained after oral self-administration. There were two- to threefold higher locomotor activity AUCs(4 h) with oral caffeine at three dose levels compared to the activity AUCs(4 h) for IP doses.