Several studies have evaluated the effects of D-serine itself and enzymes related to its metabolism. D-Amino acid oxidase (DAAO) inhibitors would inhibit the metabolism of D-serine and would raise the levels of D-serine in a manner similar to the mechanism of RG1478 on glycine. DAAO inhibitors were the subject of two recent ‘position papers’ [39,40] that outlined the rationale for potential use in schizophrenia, and reviewed the thus far inconsistent results. As reviewed, at least one DAAO inhibitor has entered phase I trials, albeit with a neuropathic pain focus. A recently published preclinical study [41] added to the inconsistent findings, finding that, although DAAO inhibition did not cause measurable increases in D-serine in forebrain, it did affect hippocampal and cortical activity, as measured by electrophysiology. In a separate study [42], however, knockout of serine racemase, an enzyme responsible for conversion of L-serine to D-serine, significantly disrupted representation of order memory, although novel object detection, relational memory and normal sociability, and preference for social novelty remained intact.
