Pharmacological modulation of the neural basis underlying inhibition of return (IOR) in the human 5-HT2A agonist and NMDA antagonist model of psychosis

Abstract

Attentional deficits are common symptoms in schizophrenia. Recent evidence suggests that schizophrenic patients show abnormalities in spatial orienting of attention, particularly a deficit of inhibition of return (IOR). IOR is mostly thought to reflect an automatic, inhibitory mechanism protecting the organism from redirecting attention to previously scanned, insignificant locations. Pharmacologic challenges with hallucinogens have been used as models for psychosis. The aim of this study was to investigate the neural correlates underlying orienting of attention in the human N-methyl-D-aspartic acid antagonist and 5-HT2A agonist models of psychosis. Fourteen healthy volunteers participated in a randomized, double-blind, cross-over event-related functional magnetic resonance imaging (fMRI) study with dimethyltryptamine (DMT) and S-ketamine. We administered a covert orienting of attention task with nonpredictive peripheral cues, and we scanned the subjects on two separate days at least 14 days apart with a placebo and a verum condition on each day. DMT, but not S-ketamine, slowed down reaction times significantly. IOR was blunted after DMT, but not after S-ketamine. Relative to placebo, S-ketamine increased activation in the IOR condition in the right superior frontal gyrus, left superior temporal gyrus, and right midfrontal frontal gyrus. The discrepancy between the behavioral and functional imaging outcome indicates that pharmacological fMRI might be a sensitive tool to detect drug-modulated blood oxygenation level-dependent signal changes in the absence of behavioral abnormalities. Our findings might help to further clarify the contradictory findings of IOR in schizophrenic patients and might, thus, shed more light on possible differential pathomechanisms of schizophrenic symptoms.