Effects of milacemide, a glycine prodrug, on ethanol's antiseizure efficacy

A variety of in vitro data suggest that ethanol interferes with N-methyl-D-aspartate (NMDA)-stimulated calcium ion conductance. This effect occurs at ethanol concentrations in blood associated with acute intoxication in the nontolerant human (less than 50 mM) and may involve its selective action at the strychnine-insensitive glycine binding site on the NMDA receptor complex. Moreover, there are in vitro data showing that glycinergic interventions can attenuate ethanol's inhibitory actions on NMDA-mediated transmission. The relevance of these in vitro findings to the intact animal was tested in an incremental electroconvulsive shock (IECS) paradigm using milacemide, a lipophilic prodrug of glycine. In this paradigm, the influence of milacemide on ethanol's ability to antagonize the electrical precipitation of seizures was tested. Doses of 3.2 and 32.0 mg/kg did not change ethanol's antiseizure efficacy, whereas 320.0 mg/kg potentiated ethanol's antiseizure efficacy. The mechanism of potentiation of ethanol's antiseizure efficacy by milacemide is unknown. Potentiation could result from stimulation of chloride ion conductance in the brainstem by glycine liberated from the lipophilic prodrug and acting at the strychnine-sensitive site. Alternatively, unmetabolized milacemide, which accumulates at the highest administered dose, may antagonize NMDA-mediated neural transmission. The latter explanation would be consistent with a role for receptor-gated calcium ion conductance in the mediation of ethanol's actions.