Behavioral characterization of caffeine and adenosine agonists during chronic caffeine exposure.

Many of the behavioral actions of caffeine are mediated by its blockade of adenosine receptors, a notion that may have implications for tolerance and supersensitivity associated with chronic caffeine exposure. To examine possible interactions between chronic caffeine and adenosine-related actions of several drugs, the acute effects of caffeine and three adenosine agonists on behavior maintained by a Multiple Fixed-Interval (FI), Duration > 5 s schedule of reinforcement were studied using rats chronically consuming either 0 (tap water control), 0.5 mg/ml, or 1.0 mg/ml of caffeine in their drinking water. 5'-(N-cyclopropyl)-carboxamidoadenosine [CPCA (preferential A2 agonist)], 5'-N-ethylcarboxamidoadenosine [NECA (about equal agonist activity at A1 and A2 receptors)], and R(-)N6-(2-phenylisopropyl)adenosine [R-PIA (preferential A1 agonist)], as well as caffeine (nonspecific adenosine antagonist), were administered acutely i.p. after behavior stabilized. Dose-related decreases in overall response rate were produced by all adenosine agonists. Acute administration of all adenosine agonists and higher doses of caffeine increased average lever-press durations under the FI schedule from about 0.3 s to between 1 and 3 s, a three- to 10-fold increase. CPCA and NECA were 10 times more potent than R-PIA on all measures. Caffeine increased overall response rate under the FI schedule at doses of 3-30 mg/kg in nontolerant rats, and decreased rates at higher doses, which also increased lever-press durations. Insurmountable tolerance was seen to the rate-increasing effects of caffeine on behavior under the FI schedule, in rats exposed chronically to caffeine. Modest evidence of surmountable tolerance was seen in the rate-decreasing effects on the Duration > 5 s schedule. No tolerance to increases in lever-press durations or decreases in response rates was detected. Chronic exposure to caffeine did not alter the acute effects of the adenosine agonists: on all measures and with all adenosine agonists, the dose-effect curves for the three caffeine-exposure groups were indistinguishable from one another. The relative potencies suggest that the acute actions of adenosine agonists are related to A2 receptors. This is consistent with the failure to detect supersensitivity, since upregulation associated with chronic caffeine exposure appears primarily in A1 receptors.