NEUROTOXIC CONVULSIONS INDUCED BY HISTAMINE H-2-RECEPTOR ANTAGONISTS IN MICE

Convulsive potency was evaluated to investigate the mechanism of neuro toxic convulsion induced by histamine H-2 receptor antagonists (H-2 bl ockers). Four H-2 blockers, cimetidine (721-1236 nmol), ranitidine (47 7-954 nmol), famotidine (7.4-44 nmol), and nizatidine (226-603 nmol) w ere administered intracerebrally (ic) to mice. Dose dependency of clon ic and/or tonic convulsion was observed, and the ED50 values of convul sive occurrence for cimetidine, ranitidine, famotidine, and nizatidine were 997, 662, 23.4, and 404 nmol, respectively. Intraperitoneal pret reatment of muscimol, aminooxy acetic acid, diazepam, (+/-)2-amino-7-p hosphono-heptanoic acid (APH), or (+)MK801 suppressed the tonic convul sion after ic administration of ranitidine, but had no effect on cloni c convulsion. Furthermore, the convulsive threshold concentration in t he brain determined by constant rate infusion of ranitidine was not af fected by the pretreatment of muscimoll diazepam, APH, and MK801. ED50 values for convulsive occurrence after ic administration of four H-2 blockers correlated well with the EC50 values for gastric acid secreti on inhibition. The convulsive threshold concentrations of cimetidine a nd ranitidine in the brain were 11 and 2.5 mu M, respectively, which w ere similar to the dissociation constants determined from the inhibiti on of gastric acid output in mice. From these results, tonic convulsio n induced by H-2 blockers can be suppressed by GABAergic or glutamater gic anticonvulsants, while clonic convulsion induced by H-2 blockers m ay be associated with the blockade of H-2 receptor in the brain and no t be directly associated with the GABA and glutamate-mediated neurotra nsmission. (C) 1996 Academic Press, Inc.