title: Long-term caffeine treatment leads to a decreased susceptibility to NMDA-induced clonic seizures in mice without changes in adenosine A1 receptor number.
abstract: 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.
authors.affiliation: Department of Pharmacology, Karolinska Institutet, Stockholm, Sweden.
authors.forename: V
authors.initials: V
authors.lastname: Georgiev
authors.forename: B
authors.initials: B
authors.lastname: Johansson
authors.forename: B B
authors.initials: BB
authors.lastname: Fredholm
mesh_terms: D000818:Animals; D001345:Autoradiography; D001522:Behavior, Animal / Q000187:drug effects; D002110:Caffeine / Q000494:pharmacology*; D004830:Epilepsy, Tonic-Clonic / Q000139:chemically induced* / Q000503:physiopathology; D006624:Hippocampus / Q000187:drug effects / Q000502:physiology; D008297:Male; D051379:Mice; D016202:N-Methylaspartate / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D011983:Receptors, Purinergic / Q000187:drug effects* / Q000502:physiology; D015430:Weight Gain / Q000187:drug effects; D014970:Xanthines / Q000097:blood
chemical_list: D011983:Receptors, Purinergic; D014970:Xanthines; D002110:Caffeine; D016202:N-Methylaspartate