Anticonvulsive activity of several excitatory amino acid antagonists against barbital withdrawal-induced spontaneous convulsions

Abstract

Several excitatory amino acid antagonists were tested for an ability to prevent spontaneous convulsions seen during the barbital abstinence syndrome in rats. Barbital-dependent animals were continuously infused intracerebroventricularly (i.c.v.) for the first 48 h following barbital withdrawal with either saline, 2-amino-7-phosphonoheptanoic acid (APH), magnesium sulfate, glutamyldiethyl ester (GDEE) or cis-2,3-piperidine dicarboxylic acid (PDA) using the highest dosages which did not affect normal behavior of the rats. All animals were observed continuously from 12 to 48 h postwithdrawal and the number of spontaneous convulsions observed in each animal was recorded. After this time, animals were killed by focused microwave irradiaton and the cerebellas were collected for determination of cyclic guanosine monophosphate (cGMP) levels. While both APH and MgSO 4 dramatically prevented convulsions, only APH prevented the withdrawal-induced elevation of cerebellar cGMP. PDA and GDEE had no statistically significant effect on either cerebellar cGMP levels or on convulsive activity. Although the effect of GDEE was not statistically significant, the number of convulsions was reduced to 1 3 those seen in control animals. These data implicate N-methyl-d-aspartate (NMDA) receptor-mediated pathways in seizure activity associated with the barbital abstinence syndrome and show that the withdrawal-induced elevation of cerebellar cGMP can occur without the induction of convulsions.