TAK-063, a selective phosphodiesterase 10A inhibitor with faster off-rate, but not T-609 a slower off-rate phosphodiesterase 10A inhibitor, suppresses phencyclidine-induced excessive neural activation in the rat prefrontal cortex

Published: 8 November 2018| Version 1 | DOI: 10.17632/vknh9m5m6y.1
Atsushi Nakatani, Yoshiro Tomimatsu, Sayuri Nakamura, Haruhide Kimura


N-methyl-D-aspartate receptor antagonists, such as MK-801, phencyclidine, and ketamine, have been used to establish animal models of schizophrenia. We previously reported that a faster off-rate phosphodiesterase 10A (PDE10A) inhibitor TAK-063, but not a slower off-rate PDE10A inhibitor MP-10, improved MK-801-induced prepulse inhibition deficits and reduced a ketamine-induced increase in the cortical electroencephalography gamma power in rodents. Thus, faster and slower off-rate PDE10A inhibitors may differentially modulate the function of the prefrontal cortex (PFC) where the PDE10A expression level is low. In this study, we evaluated the effects of a faster off-rate PDE10A inhibitor TAK-063 and a slower off-rate PDE10A inhibitor T-609 on phencyclidine-induced neural activation in the striatum, PFC, and hippocampus in rats. TAK-063, but not T-609, dose-dependently suppressed the phencyclidine-induced electroencephalography gamma power in the rat PFC. Assessment of c-fos and Npas4 mRNAs induction in phencyclidine-treated rats revealed that both TAK-063 and T-609 induced dose-dependent neural activation in the striatum, while TAK-063, but not T-609, showed dose-dependent and significant, or a tendency toward, the suppression of phencyclidine-induced c-fos and/or Npas4 mRNAs expression in the rat PFC and hippocampus. Therefore, a faster off-rate may be a critical characteristic of TAK-063 that suppresses phencyclidine-induced excessive neural activation in the rat PFC.