N-methyl-D-aspartate (NMDA) receptor activation requires the binding of a co-agonist
on the glycine-binding site. D-serine is the main endogeneous co-agonist of NMDA receptors,
and its availability significantly depends on the activity of the metabolic enzyme
D-amino acid oxidase (DAAO). Inhibition of DAAO increases the brain levels of D-serine,
and modulates a variety of physiological functions including cognitive behavior.Here,
we examined the effects of a novel 4‑hydroxypyridazin-3(2H)‑one derivative DAAO inhibitor,
Compound 30 (CPD30) on passive avoidance learning and on neuronal firing activity
in rats.D-serine administration was applied as reference, which increased cognitive
performance and enhanced hippocampal firing activity and responsiveness to NMDA after
both local and systemic application. Similarly to D-serine, CPD30 (0.1 mg/kg) effectively
reversed MK-801 induced memory impairment in the passive avoidance test. Furthermore,
local iontophoretic application of CPD30 in the vicinity of hippocampal pyramidal
neurons significantly increased firing rate, and enhanced their responses to locally
applied NMDA. Compound 30 also enhanced hippocampal firing activity after systemic
administration. In 0.1-1.0 mg/kg doses, CPD30 increased spontaneous and NMDA-evoked
firing activity of the neurons. Effects of CPD30 on NMDA-responsiveness emerged faster
(at 10 min post-injection) when 1.0 mg/kg dose was applied compared to the onset of
the effects of 0.1 mg/kg CPD30 (at 30 min post-injection).The present results confirm
that the inhibition of DAAO enzyme is an effective strategy for cognitive enhancement.
Our findings further facilitate the understanding of the cellular mechanisms underlying
the behavioral effects of DAAO inhibition in the mammalian brain.
