Biol. Pharm. Bull. 28(9) 1561—1565 (2005)

brain between 1990 and 1991 by the present author with my collaborators at the National Institute of Neuroscience, NCNP, in Tokyo and other institutes, was a consequence of my research project on the pathophysiology and novel pharmacotherapy of schizophrenia using D-serine and D-alanine, which facilitate the N-methyl-D-aspartate (NMDA) glutamate receptor function via its glycine site (Fig. 1), by noting the induction of schizophrenia-like psychosis by the glutamate receptor antagonists such as phencyclidine (PCP). According to this author’s idea to overcome the low ability of these polar D-amino acids to cross through the blood brain barrier (BBB) that their apolar compounds could easily permeate the BBB and improve the schizophrenic symptoms by their systemic administration, Dr. Hibino at Nippon Oil and Fats, Co., Ltd., designed and synthesized for our experiments, N-myristoyl-D-serine and N-myristoyl-D-alanine, which were shown to ameliorate an animal model of schizophrenia, PCP-induced abnormal behavior, following their intraperitoneal injection. During the process of the verification of the expected presence of free D-serine or D-alanine in the brain of animals treated with their fatty acid compounds by collaboration with the late Dr. Hayashi at the National Institute of Neuroscience and Dr. Fujii at Tsukuba University, we provided the first evidence that free D-serine is constantly maintained at a high concentration in the mammalian brain although D-amino acids were believed to be uncommon in mammalian tissues based on previous studies. Through immediate confirmations of our findings, subsequent studies on endogenous D-serine have been gradually extended in a variety of aspects. In this article, the present status and future problems are discussed.