CAFFEINE TREATMENT AND WITHDRAWAL IN MICE - RELATIONSHIPS BETWEEN DOSAGE, CONCENTRATIONS, LOCOMOTOR-ACTIVITY AND A(1) ADENOSINE RECEPTOR-BINDING

Relationships between caffeine dose, methylxanthine tissue concentrati ons, adenosine receptor binding and locomotor activity were examined i n CD-1 mice. A method of caffeine infusion via s.c. pumps provided con stant steady-state methylxanthine concentrations. Mice receiving caffe ine doses of 97 mg/kg/day (with mean plasma concentration of 2.7 mug/m l) demonstrated motor activity depression for 6 days after pump implan tation (vs. vehicle-treated controls). Mice receiving caffeine doses o f 194 mg/kg/day (mean plasma concentration of 7.1 mug/ml) demonstrated motor stimulation 4 and 24 hr after implantation. Mice receiving this dose for 6 days developed motor depression. A reduction in the stimul ant effects of acute caffeine (20 mg/kg i.p.) was found in mice receiv ing caffeine infusions (1 94 mg/kg/day for 6 days) as compared to thos e receiving vehicle infusions, suggestive of drug tolerance. These dos e- and time-dependent behavioral effects during caffeine-infusion were associated with decreases between 20 and 69% in specific binding of A 1 adenosine radioligand 1,3-[H-3]dipropyl-8-cyclopentylxanthine in viv o. Behavioral alterations during caffeine infusion appear to be mediat ed by A1 adenosine receptor occupancy. Increasing motor depression dev eloped on days 1 and 2 after pump removal with values returning to con trol levels by days 4 and 6. Behavioral alterations were associated wi th in vivo binding increases of 98 and 324%, respectively, and a retur n to control values on days 4 and 6. In vivo binding alterations were not associated with ex vivo A1 receptor binding changes. Caffeine tole rance and withdrawal effects in this animal model appear to be mediate d by chronic occupancy of A1 adenosine receptors. The behavioral and i n vivo receptor binding alterations observed after caffeine discontinu ation follow a time course similar to caffeine withdrawal in humans.