EFFECT OF THE GLYCINE NMDA RECEPTOR PARTIAL AGONIST, D-CYCLOSERINE, ON SEIZURE THRESHOLD AND SOME PHARMACODYNAMIC EFFECTS OF MK-801 IN MICE/

Acute treatment of mice with D-cycloserine (a high efficacy, partial a gonist at strychnine-insensitive glycine receptors) resulted in dose- and time-dependent increases in the threshold for electrically induced tonic seizures. This anticonvulsant effect was observed at doses whic h did not induce motor impairment, as determined by the rotarod test. Despite the relatively high intrinsic efficacy of D-cycloserine at gly cine receptors, this drug did not produce proconvulsant effects in mic e at any of the doses (5-320 mg/kg) or time points examined. Prolonged treatment with D-cycloserine led to a reduction of its anticonvulsant effect. Similar to D-cycloserine, the uncompetitive N-methyl-D-aspart ate (NMDA) receptor antagonist, MK-801 (dizocilpine), dose dependently increased the electroconvulsive threshold. Combined treatment with MK -801 and D-cycloserine led to significant anticonvulsant effects, but these effects were simply additive and not synergistic. In contrast to anticonvulsant activity, the motor impairing effect of MK-801 was mar kedly potentiated by D-cycloserine. The data substantiate that high ef ficacy glycine/NMDA receptor partial agonists such as D-cycloserine ex ert anticonvulsant activity at non-toxic doses. The finding that motor impairing but not anticonvulsant effects of MK-801 were potentiated b y D-cycloserine suggests that different pharmacodynamic actions of NMD A receptor antagonists are differentially modulated by the glycine rec eptor, which could be related to the regional heterogeneity of the NMD A receptor complex in the brain.