TAK-063, a phosphodiesterase 10A inhibitor, modulates neuronal activity in various brain regions in phMRI and EEG studies with and without ketamine challenge

Neuroscience. 2016 Dec 17;339:180-190. doi: 10.1016/j.neuroscience.2016.10.006. Epub 2016 Oct 8.

Abstract

TAK-063 is a selective phosphodiesterase 10A (PDE10A) inhibitor that produces potent antipsychotic-like and pro-cognitive effects at 0.3mg/kg (26% PDE10A occupancy in rats) or higher in rodents through the balanced activation of the direct and indirect pathways of striatal medium spiny neurons (MSNs). In this study, we evaluated the specific binding of TAK-063 using in vitro autoradiography (ARG) and the modulation of brain activity using pharmacological magnetic resonance imaging (phMRI) and electroencephalography (EEG). [3H]TAK-063 significantly accumulated in the caudate-putamen (CPu), ventral pallidum (VP), substantia nigra (SN), hippocampus (Hipp), and amygdala (Amy), but not in the frontal cortex (Fcx), brainstem (Bs), or cerebellum (Cb) in an ARG study using rat brain sections. [3H]TAK-063 accumulation in the CPu was more than eighteen-fold higher than that in the Hipp and Amy. TAK-063 at 0.3mg/kg increased the blood oxygenation level-dependent (BOLD) signal in the striatum and Amy, and decreased it in the Fcx in a phMRI study with anesthetized rats. TAK-063 at 0.3mg/kg significantly reduced the ketamine-induced increase in EEG gamma power both in awake and anesthetized rats. TAK-063 at 0.2mg/kg (35% PDE10A occupancy in monkeys) also reduced the ketamine-induced increase in EEG gamma power in awake monkeys. In line with the EEG data, TAK-063 at 0.3mg/kg reversed the ketamine-induced BOLD signal changes in the cortex, Bs, and Cb in a phMRI study with anesthetized rats. These data suggest that TAK-063 at about 30% PDE10A occupancy modulates activities of multiple brain regions through activation of neuronal circuits in rats and monkeys.

Keywords: EEG; PDE10A; TAK-063; phMRI.

MeSH terms

  • Anesthesia
  • Animals
  • Autoradiography
  • Brain / drug effects*
  • Brain / enzymology
  • Brain Mapping
  • Central Nervous System Agents / pharmacology*
  • Cerebrovascular Circulation / drug effects
  • Cerebrovascular Circulation / physiology
  • Drug Evaluation, Preclinical
  • Electroencephalography
  • Female
  • Ketamine / pharmacology*
  • Macaca fascicularis
  • Magnetic Resonance Imaging
  • Male
  • Neurons / drug effects*
  • Neurons / enzymology
  • Oxygen / blood
  • Phosphodiesterase Inhibitors / pharmacology*
  • Pyrazoles / pharmacology*
  • Pyridazines / pharmacology*
  • Rats, Sprague-Dawley
  • Rats, Wistar
  • Rest

Substances

  • 1-(2-fluoro-4-(1H-pyrazol-1-yl)phenyl)-5-methoxy-3-(1-phenyl-1H-pyrazol-5-yl)pyridazin-4(1H)-one
  • Central Nervous System Agents
  • Phosphodiesterase Inhibitors
  • Pyrazoles
  • Pyridazines
  • Ketamine
  • Oxygen