TY - JOUR
T1 - TAK-063, a phosphodiesterase 10A inhibitor, modulates neuronal activity in various brain regions in phMRI and EEG studies with and without ketamine challenge
AU - Tomimatsu, Yoshiro
AU - Cash, Diana
AU - Suzuki, Motohisa
AU - Suzuki, Kazunori
AU - Bernanos, Michel
AU - Simmons, Camilla
AU - Williams, Steven C R
AU - Kimura, Haruhide
PY - 2016/12/17
Y1 - 2016/12/17
N2 - TAK-063 is a selective phosphodiesterase 10A (PDE10A) inhibitor that produces potent antipsychotic-like and pro-cognitive effects at 0.3 mg/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 0.3 mg/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 0.3 mg/kg significantly reduced the ketamine-induced increase in EEG gamma power both in awake and anesthetized rats. TAK-063 at 0.2 mg/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 0.3 mg/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.
AB - TAK-063 is a selective phosphodiesterase 10A (PDE10A) inhibitor that produces potent antipsychotic-like and pro-cognitive effects at 0.3 mg/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 0.3 mg/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 0.3 mg/kg significantly reduced the ketamine-induced increase in EEG gamma power both in awake and anesthetized rats. TAK-063 at 0.2 mg/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 0.3 mg/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.
KW - PDE10A
KW - TAK-063
KW - phMRI
KW - EEG
UR - http://www.scopus.com/inward/record.url?scp=84992323225&partnerID=8YFLogxK
U2 - 10.1016/j.neuroscience.2016.10.006
DO - 10.1016/j.neuroscience.2016.10.006
M3 - Article
SN - 0306-4522
VL - 339
SP - 180
EP - 190
JO - Neuroscience
JF - Neuroscience
ER -