THE BENZODIAZEPINES AND INOSINE ANTAGONIZE CAFFEINE-INDUCED SEIZURES

The induction of generalized tonic-clonic seizures in mice by the methylxanthine stimulant, caffeine, is described. These seizures are indistinguishable in quality from those induced by pentylenetetrazol (PTZ), and pretreatment with low doses of caffeine potentiates PTZ-induced seizures. Benzodiazepines (diazepam, clonazepam, flunitrazepam, chlordiazepoxide) inhibit caffeine-induced seizures with a rank order potency that parallels their affinities for the CNS benzodiazepine receptor in vitro. Inosine, a purine that is a competitive inhibitor of [3H] diazepam binding in vitro, antagonizes caffeine-induced seizures, while 7-methyl-inosine, a purine that lacks receptor binding inhibitory activity, has no effect on seizures. Since the benzodiazepines, inosine, caffeine and pentylenetetrazol all competitively inhibit [3H] diazepam binding and have marked effects on inducing or antagonizing seizures, further study of this receptor-ligand system may provide additional insights that concern possible biochemical mechanisms of seizures.