Milacemide, a glycine prodrug, enhances performance of learning tasks in normal and amnestic rodents

The N-methyl-D-aspartate receptor complex appears to play an important role in processes of learning and memory. The presence of a glycine modulatory site at this complex has recently been established and suggests that glycinergic neurotransmission may influence these cognitive functions. Increasing glycine concentrations in the brain by administration of a glycine prodrug, milacemide, is shown here to enhance performance of a shock-motivated passive avoidance task in rats, and to reverse drug-induced amnesia in a spontaneous alternation paradigm in mice. Prevention of the metabolism of milacemide to glycine by pretreatment with MAO-B inhibitors not only prevents the memory-enhancing effects of the drug, but appears to have a deleterious effect on memory formation suggesting an action of the prodrug itself on the brain. These studies indicate a role of glycinergic neurotransmission in memory processes, and support the therapeutic potential of glycinergic drugs in memory impairment.