統合失調症の認知機能障害における前頭前野皮質の制御機構

1. Dopamine transporter knockout (DAT KO) mice display deficits in sensorimotor gating that are manifested by reduced prepulse inhibition (PPI) of the acoustic startle reflex. Since PPI deficits may model some of the cognitive dysfunctions identified in certain neuropsychiatric patients, we have studied the effects of transporter blockers on PPI in wild-type and DAT KO mice. Treatments with high dose psychostimulants that block DAT as well as the norepinephrine (NET) and serotonin (SERT) transporters significantly impaired PPI in wild-type mice. By contrast, these treatments significantly ameliorated the PPI deficits observed in untreated DAT KO mice. In studies with more selective transport inhibitors, the selective NET inhibitor nisoxetine also significantly reversed PPI deficits in DAT KO mice. By contrast, while the SERT inhibitor fluoxetine normalized these PPI deficits in DAT KO mice, citalopram failed to do so. The 'paradoxical' effects of cocaine and methylphenidate in DAT KO mice are thus likely to be mediated, at least in part by the ability of these drugs to block NET, although serotonin systems may also have some role. Together with recent microdialysis data,-these results support the hypothesis that prefrontal cortical NET blockade and consequent enhancement of prefrontal cortical extracellular dopamine mediates the reversal of PPI deficits in DAT KO mice.

2. Prepulse inhibition of perceived stimulus intensity (PPI-PSI) is a robust, stable, and convenient method for measurement of sensory gating which is relatively unaffected by a number of biological variables, e.g., sex differences, menstrual cycle, or personality dimensions, in healthy individuals. Patients with schizophrenia showed significantly less PPI-PSI compared with control subjects. The PPI-PSI deficits were significantly correlated with the "thought-disorder" schizophrenia score extracted from the Brief Psychiatric Rating Scale (BPRS). These results provide additional evidence for the notion that schizophrenia is characterized by sensory gating deficits. In addition, PPI-PSI was found to be correlated with integrated clinical symptoms typical of schizophrenia. Our findings suggested that PPI-PSI could be useful for assessing the severity of schizophrenia.