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.
Norris
D O
DO
Psychiatry Service, Department of Veterans Affairs Medical Center, Washington, D.C. 20422.
Mastropaolo
J
J
O'Connor
D A
DA
Cohen
J M
JM
Deutsch
S I
SI
D000081:Acetamides / Q000494:pharmacology; D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology*; D002220:Carbamazepine / Q000494:pharmacology; D003523:Cycloserine / Q000494:pharmacology; D016291:Dizocilpine Maleate / Q000494:pharmacology; D004357:Drug Synergism; D005479:Flurazepam / Q000494:pharmacology; D008297:Male; D051379:Mice; D011355:Prodrugs / Q000494:pharmacology; D018009:Receptors, Glycine / Q000187:drug effects*
D000081:Acetamides; D000927:Anticonvulsants; D011355:Prodrugs; D018009:Receptors, Glycine; C039332:milacemide; D002220:Carbamazepine; D016291:Dizocilpine Maleate; D003523:Cycloserine; D005479:Flurazepam