The P50 is an early component of auditory evoked potentials and a measure of sensory gating deficits. This evoked potential component is thought to be an important endophenotype candidate for schizophrenia. Recent research suggests that instead of the P50 ratio, S1 and S2 amplitudes should be evaluated for sensory gating. However, no studies have focused on the relationship between cognitive dysfunction and P50 sensory gating deficits using S1 and S2 amplitudes. The purpose of the present study was to investigate the association between the P50 ratio (S2/S1), S1 and S2 amplitudes, and neuropsychological cognitive domains using stepwise multiple linear regression analyses. Results demonstrated a significant relationship between executive functioning and the P50 ratio and between sustained attention and S2 amplitude, respectively. Our findings suggest that the P50 ratio and S2 amplitude reflect distinct neurophysiological substrates associated with different cognitive functions.

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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). [H]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. [H]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.

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