A glycinergic intervention potentiates the antiseizure efficacies of MK-801, flurazepam, and carbamazepine

Twenty four hours after mice were forced to swim for up to 10 minutes in cold water, there was a reduction in the ability of MK-801 to antagonize the electrical precipitation of tonic hindlimb extension. Milacemide, a lipophilic prodrug of glycine, restored the antiseizure efficacy of MK-801 to the same level observed in unstressed animals treated with milacemide and MK-801. Stimulation of the glycine-gated chloride ionophore subsequent to the liberation of free glycine could explain milacemide's pharmacologic action as an adjuvant to MK-801. Consistent with this interpretation, milacemide was able to potentiate the antiseizure effects of flurazepam, a benzodiazepine agonist, in stressed and unstressed mice and carbamazepine in unstressed animals. D-cycloserine, a partial glycine agonist with greater specificity for the strychnine-insensitive modulatory site on the NMDA receptor complex, was examined for its effect on MK-801's antiseizure efficacy. At a high dose (320 mg/kg), D-cycloserine alone had an anticonvulsant effect. Moreover, this dose of D-cycloserine administered with MK-801 showed a significantly greater anticonvulsant efficacy than MK-801 alone. The data support the development of glycinergic interventions as adjunctive agents in the pharmacotherapy of seizure disorders.