[Advances in the Pathophysiology and Drug Discovery of Novel Therapeutics for Attention-Deficit/hyperactivity...

Attention-deficit/hyperactivity disorder (ADHD) is a neurodevelopmental disorder characterized by inattention, hyperactivity and impulsivity. Psychostimulants such as methylphenidate are first-line treatments, but carry risks of severe side effects and addiction. Therefore, further research and the discovery of non-psychostimulant medications with novel mechanisms are urgently needed. We previously reported that juvenile stroke-prone spontaneously hypertensive rats (SHRSP/Ezo) are a suitable animal model of ADHD, and we identified N-methyl-D-aspartate (NMDA) receptor dysfunction in the prefrontal cortex of SHRSP/Ezo. D-Serine, a co-agonist for the glycine binding site of NMDA receptors, is synthesized from L-serine by serine racemase (SR) and degraded by D-amino acid oxidase (DAAO). Although D-serine dysregulation is implicated in psychiatric disorders, its pathophysiological role in ADHD is unclear. We measured D-serine in the medial prefrontal cortex (mPFC) of SHRSP/Ezo and addressed SR and DAAO expression. Additionally, we assessed cognitive function following DAAO inhibitor microinjection into the mPFC. SHRSP/Ezo showed a reduced D-serine/total serine (DL) ratio in the mPFC compared with the genetic control, Wistar Kyoto rat/Ezo (WKY/Ezo). DAAO expression in the mPFC was higher in SHRSP/Ezo rats compared with WKY/Ezo, however there was no difference in SR expression. The microinjection of a DAAO inhibitor into the mPFC of SHRSP/Ezo rats increased the DL ratio and ameliorated ADHD-like behaviors in the Y-maze test. These results suggest an association between abnormal D-serine metabolism and ADHD-like behaviors based on NMDA receptor dysfunction in the mPFC. Our findings provide insight into ADHD pathogenesis and should advance the development of new therapeutic approaches for the disorder.