[Development of a novel pharmacotherapy targeted at the N-methyl-D-aspartate receptor-D-serine system for...

Based upon the evidence that N-methyl-D-aspartate (NMDA) type glutamate receptor antagonists including phencyclidine cause schizophrenia-like treatment-resistant negative symptoms as well as antipsychotic-responsive dopamine-related positive symptoms, the facilitation of the NMDA receptor function has been considered to be a rational therapeutic approach to ameliorate both of the above schizophrenic symptomatologies. However, the direct stimulation of the NMDA receptor glycine modulation site by glycine, D-serine, D-alanine and D-cycloserine to perform the facilitation appears to run into difficulties due to their poor permeability to the brain, lack of selectivity to the receptor, or side effects such as peripheral toxicity. Because D-serine is a selective endogenous co-agonist for the NMDA receptor acting at the glycine site with a NMDA receptor-like distribution in the brain, we have alternatively been trying to find suitable target molecules or cells that are involved in the metabolism and functioning system of glia-derived neuromodulator D-serine to increase its signal for the NMDA receptor. To this end, we have been investigating the molecular and cellular mechanisms controlling the extracellular contents of D-serine and have found that the substances that are able to inhibit the transport or degradation of D-serine moderately elevated the extracellular D-serine levels in the rat frontal cortex.