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Abnormally persistent latent inhibition induced by MK801 is reversed by risperidone and by positive modulators of NMDA receptor function: differential efficacy depending on the stage of the task at which they are administered

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Abstract

Rationale

Latent inhibition (LI) is the poorer conditioning to a stimulus resulting from its nonreinforced preexposure. LI indexes the ability to ignore irrelevant stimuli and is used extensively to model attentional impairments in schizophrenia (SZ). We showed that rats and mice treated with the N-methyl-d-aspartic acid (NMDA) receptor antagonist MK801 expressed LI under conditions preventing LI expression in controls. This abnormally persistent LI was reversed by the atypical antipsychotic drug (APD) clozapine and by compounds enhancing NMDA transmission via the glycineB site, but not by the typical APD haloperidol, lending the MK801 LI model predictive validity for negative/cognitive symptoms.

Objective

To test additional representatives from the two classes of drugs and show that the model can dissociate between atypical APDs and glycinergic drugs are the objectives of the study.

Materials and methods

LI was measured in a conditional emotional response procedure. Atypical APD risperidone, selective 5HT2A antagonist M100907, and three glycinergic drugs were administered in preexposure or conditioning.

Results

Rats treated with MK801 (0.05 mg/kg) exhibited LI under conditions that disrupted LI in controls. This abnormality was reversed by risperidone (0.25 and 0.067 mg/kg) and M100907 (1 mg/kg) given in preexposure. Glycine (0.8 g/kg), d-cycloserine (DCS;15 and 30 mg/kg), and glycyldodecylamide (GDA; 0.05 and 0.1 g/kg.) counteracted MK801-induced LI persistence when given in conditioning.

Conclusions

These results support the validity of MK801-induced persistent LI as a model of negative/cognitive symptoms in SZ and indicate that this model may have a unique capacity to discriminate between typical APDs, atypical APDs, and glycinergic compounds, and thus, foster the identification of novel treatments for SZ.

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Acknowledgements

We thank Merck Research Laboratories, USA, Novartis, Switzerland, Sanofi-Aventis, USA, and Janssen, Belgium, for their generous gifts of MK801, clozapine, M100907 and haloperidol, respectively, and Uriel Heresco-Levy and Daniel Javitt for their generous gifts of glycine and GDA, respectively. We are indebted to Morris Beneveniste for his invaluable input on the structure and function of NMDA receptors.

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  1. I. Gaisler-Salomon

    Present address: Department of Psychiatry/ Molecular Therapeutics, Columbia University, NYC, NY, USA

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  1. Department of Psychology, Tel Aviv University, Tel Aviv, Israel

    I. Gaisler-Salomon, L. Diamant, C. Rubin & I. Weiner

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Gaisler-Salomon, I., Diamant, L., Rubin, C. et al. Abnormally persistent latent inhibition induced by MK801 is reversed by risperidone and by positive modulators of NMDA receptor function: differential efficacy depending on the stage of the task at which they are administered. Psychopharmacology 196, 255–267 (2008). https://doi.org/10.1007/s00213-007-0960-3

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  • DOI: https://doi.org/10.1007/s00213-007-0960-3

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