CHLORMETHIAZOLE ANTAGONIZES SEIZURES INDUCED BY N-METHYL-DL-ASPARTATE WITHOUT INTERACTING WITH THE NMDA-RECEPTOR COMPLEX

Administration to mice of N-methyl-DL-aspartate (NMDLA; 680-3400 mu mol/kg IP) produced a behavioural syndrome of scratching, running, pawing, clonus, loss of righting and tonic convulsions. Measures of latency to appearance of the behaviours and percentage of animals displaying the behaviour (frequency) indicated that the latency to appearance of running behaviour, clonus and tonic convulsions were all dose dependant. Chlormethiazole (155-622 mu mol/kg IP) given 15 min before NMDLA (3400 mu mol/kg) dose-dependently inhibited all the behaviours, increasing the latency to appearance of scratching, running and clonus and reducing the incidence of pawing, loss of righting and tonic convulsions. Tonic seizures induced by NMDLA (3400 mu mol/kg) were inhibited by the following drugs (ED(50) values in mu mol/kg in brackets): chlormethiazole (210); pentobarbitone (67); dizocilpine (0.9). The diazepam value (38) was estimated as complete inhibition was not obtained. Chlormethiazole (1 mM) did not affect the binding of [H-3]-dizocilpine to rat cortical membranes or the stimulation uf this binding by glutamate (10 mu M), glycine (10 mu M) or spermidine (100 mu M). It is therefore concluded that whilst chlormethiazole effectively antagonises the convulsive behavioural syndrome induced by injection of NMDLA, it does not do so by interacting with the NMDA receptor complex but more probably by its known interaction with the GABA(A) receptor complex.