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

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Abstract

Rationale

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.

Objectives

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.

Materials and methods

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.

Results

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.

Conclusions

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.

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Acknowledgements

This work was supported by a grant to E. Gouzoulis-Mayfrank from the German Research Foundation (Deutsche Forschungsgemeinschaft DFG, Project No. 6 of a DFG clinical researcher group KFO 112/1/-1, Go 717/5-1).

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All authors certify that there is no actual or potential financial interest in relation to the subject matter or materials discussed in this manuscript.

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Authors and Affiliations

  1. Department of Psychiatry and Psychotherapy, University of Cologne, Kerpener Strasse 62, 50924, Cologne, Germany

    Jörg Daumann, Karsten Heekeren, Anna Neukirch & Euphrosyne Gouzoulis-Mayfrank

  2. Institute of Medicine, Jülich Research Centre, Jülich, Germany

    Christiane M. Thiel

  3. Department of Radiology, University of Cologne, Cologne, Germany

    Walter Möller-Hartmann

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  1. Jörg Daumann
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  2. Karsten Heekeren
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  6. Euphrosyne Gouzoulis-Mayfrank
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Daumann, J., Heekeren, K., Neukirch, A. et al. Pharmacological modulation of the neural basis underlying inhibition of return (IOR) in the human 5-HT2A agonist and NMDA antagonist model of psychosis. Psychopharmacology 200, 573–583 (2008). https://doi.org/10.1007/s00213-008-1237-1

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