Long-term caffeine treatment leads to a decreased susceptibility to NMDA-induced clonic seizures in mice without changes in adenosine A1 receptor number.

The effects of long-term caffeine treatment on N-methyl-D-aspartate (NMDA)-induced seizures in mice were studied. Caffeine was added (0.3 g/l) to drinking water for 14 days and the mice ingested 60-70 mg/kg/day. During the treatment, the plasma concentrations of methylxanthines (caffeine, theophylline and/or paraxanthine, theobromine) were measured. NMDA (150 mg/kg i.p.) was administered to control mice and to mice during and after the caffeine administration. A1 adenosine receptor density in the gyrus dentatus of hippocampus, measured by quantitative receptor autoradiography with [3H]cyclohexyl adenosine as the ligand, was not significantly altered after long-term caffeine treatment. NMDA-induced clonic seizures, wet dog shakes and mortality were significantly reduced at the end of long-term caffeine treatment but returned towards control at 1 and 2 days after withdrawal. At the end of caffeine treatment, tonic seizures were also absent. These results show that long-term treatment with caffeine in a dose that gives plasma levels of 6-10 microM decreases the effects of NMDA on e.g. seizure susceptibility, and that this effect cannot be ascribed to changes of A1 adenosine receptor density.