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

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.

N-甲基-D-天冬氨酸（NMDA）受体拮抗剂，如MK-801、苯环利定（phencyclidine）与氯胺酮（ketamine），已被用于建立精神分裂症动物模型。本团队此前已有研究报道，快速解离型磷酸二酯酶10A（phosphodiesterase 10A, PDE10A）抑制剂TAK-063（而非慢速解离型PDE10A抑制剂MP-10）可改善MK-801诱导的前脉冲抑制缺陷，并降低啮齿类动物中氯胺酮诱导的皮层脑电图伽马功率升高。由此可见，快速与慢速解离型PDE10A抑制剂或许可差异性调控前额叶皮层（PFC）的功能——该脑区的PDE10A表达水平较低。本研究中，我们评估了快速解离型PDE10A抑制剂TAK-063与慢速解离型PDE10A抑制剂T-609，对苯环利定诱导的大鼠纹状体、前额叶皮层及海马体神经激活的影响。实验结果显示，TAK-063（而非T-609）可剂量依赖性地抑制大鼠前额叶皮层中苯环利定诱导的脑电图伽马功率升高。对苯环利定处理大鼠的c-fos与Npas4 mRNA诱导情况进行评估后发现，TAK-063与T-609均可在纹状体中诱导剂量依赖性的神经激活；而仅TAK-063（而非T-609）可剂量依赖性且显著地（或呈现出抑制趋势）抑制大鼠前额叶皮层与海马体中苯环利定诱导的c-fos及/或Npas4 mRNA表达。综上，快速解离特性或许是TAK-063能够抑制大鼠前额叶皮层中苯环利定诱导的过度神经激活的关键特征。