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Enhancement of latent inhibition by two 5-HT2A receptor antagonists only when given at both pre-exposure and conditioning

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Abstract

Rationale.

Clozapine-like atypical antipsychotic drugs, such as olanzapine, risperidone and sertindole, bind most strongly to 5-HT2A receptors, which may contribute to their antipsychotic effects. Antipsychotic drugs, such as clozapine and haloperidol, have been found to enhance latent inhibition (LI) in humans and rats. LI is a process of learning to ignore irrelevant stimuli that is disrupted in acute, positive-symptom schizophrenia, and can be modelled in animals.

Objectives.

The aim of this study was to determine the effects of two selective 5-HT2A receptor antagonists, SR 46,349B and ICI 169,369, on LI, as a test of their antipsychotic potential.

Methods.

Doses of the 5-HT2A receptor antagonists that were sufficient for receptor blockade were determined in 5-HT behavioural syndrome tests. SR 46,349B and ICI 169,369 were then tested for enhancement of LI and reversal of amphetamine-induced attenuation of LI in a conditioned suppression paradigm.

Results.

SR 46,349B (0.6–2.4 mg kg–1 i.p.) and ICI 169,369 (10–40 mg kg–1 i.p.) antagonised 5-hydroxytryptophan (5-HTP)-induced head twitches and wet dog shakes, which are mediated by 5-HT2A receptors, but had no effect on mCPP-induced hypolocomotion, which is mediated by 5-HT2C receptors. Neither SR 46,349B (1.2 mg kg–1 i.p.) nor ICI 169,369 (40 mg kg–1 i.p) affected 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT)-induced forepaw treading, suggesting that they were not in vivo 5-HT1A receptor antagonists. SR 46,349B (2.4 mg kg–1 i.p.) and ICI 169,369 (40 mg kg–1 i.p.) enhanced LI when given at both the pre-exposure and conditioning stages of the paradigm, but not when given at either pre-exposure or conditioning only. Both drugs also reversed the disruption of LI induced by D-amphetamine (1 mg kg–1 i.p.).

Conclusions.

The profile of SR 46,349B and ICI 169,369 in LI differs from that of clozapine and haloperidol in LI, which both enhance LI when given only at the conditioning stage of the paradigm.

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Acknowledgements.

We would like to thank Glavkos Ioannou and Dominic Grisé for their expert assistance with developing and building new behavioural equipment, Dr Sophia Rabé for statistical advice and Dr Natalia Lawrence for help with inter-observer reliability ratings. Thanks are also due to Sanofi-Synthélabo, AstraZeneca Pharmaceuticals, Sandoz (now Novartis) and DuPont Merck for gifts of drugs used in this study. We would also like to thank Dr Hans Kalkman of Sandoz for his advice on the mCPP-induced hypolocomotion paradigm. Particular thanks are due to the Wellcome Trust, who supported this work with the award of a Wellcome Prize Studentship to LMM. We also wish to thank the University of Leicester for providing study leave support to PMM.

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Authors and Affiliations

  1. Department of Psychology, Institute of Psychiatry, De Crespigny Park, London SE5 8AF, UK

    L. M. McDonald, P. M. Moran, G. N. Vythelingum, M. H. Joseph, J. D. Stephenson & J. A. Gray

  2. Department of Neuroscience, Institute of Psychiatry, De Crespigny Park, London SE5 8AF, UK

    J. D. Stephenson

  3. Merck Sharp and Dohme Research Laboratories, The Neuroscience Research Centre, Terlings Park, Harlow, Essex CM20 2QR, UK

    L. M. McDonald

  4. Behavioural Neuroscience Group, School of Psychology, University of Leicester, University Road, Leicester LE1 7RH, UK

    P. M. Moran & M. H. Joseph

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  1. L. M. McDonald
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  2. P. M. Moran
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  3. G. N. Vythelingum
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  4. M. H. Joseph
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  6. J. A. Gray
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Correspondence to L. M. McDonald.

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McDonald, L.M., Moran, P.M., Vythelingum, G.N. et al. Enhancement of latent inhibition by two 5-HT2A receptor antagonists only when given at both pre-exposure and conditioning. Psychopharmacology 169, 321–331 (2003). https://doi.org/10.1007/s00213-002-1173-4

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