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Heterozygous neuregulin 1 mice are more sensitive to the behavioural effects of Δ9-tetrahydrocannabinol

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Abstract

Rationale

Cannabis use may precipitate schizophrenia especially if the individual has a genetic vulnerability to this mental disorder. Human and animal research indicates that neuregulin 1 (Nrg1) is a susceptibility gene for schizophrenia.

Objectives

The aim of this study was to investigate whether dysfunction in the Nrg1 gene modulates the behavioural effects of Δ9-tetrahydrocannabinol (THC), the major psychotropic component of cannabis.

Materials and methods

Heterozygous Nrg1 transmembrane-domain knockout mice (Nrg1 HET) were treated with acute THC (0, 5 or 10 mg/kg i.p.) 30 min before being tested using open field (OF), hole board (HB), light-dark (LD), elevated plus maze (EPM), social interaction (SI) and prepulse inhibition (PPI) tests.

Results

Nrg1 HET mice showed differences in baseline behaviour with regard to locomotor activity, exploration and anxiety. More importantly, they were more sensitive to the locomotor suppressant actions of THC compared to wild type-like (WT) mice. In addition, Nrg1 HET mice expressed a greater THC-induced enhancement in % PPI than WT mice. The effects of THC on anxiety-related behaviour were task-dependent, with Nrg1 HET mice being more susceptible than WT mice to the anxiogenic effects of THC in LD, but not in the EPM, SI and OF tests.

Conclusions

Nrg1 HET mice were more sensitive to the acute effects of THC in an array of different behaviours including those that model symptoms of schizophrenia. It appears that variation in the schizophrenia-related neuregulin 1 gene alters the sensitivity to the behavioural effects of cannabinoids.

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Acknowledgements

This research was supported by NISAD, utilizing infrastructure funding from NSW Health, by the Sylvia and Charles Viertel Charitable Foundation, by the Deutsche Forschungsgemeinschaft (Forschungsstipendium: Ka 1837/1-1 and Ka 1837/1-2 awarded to TK), by the National Alliance for Research on Schizophrenia and Depression (Young Investigator Award awarded to TK) and by a Clive and Vera Ramaciotti Foundation Young Investigator Grant awarded to JCA. AAB was supported by a NISAD Postgraduate Research Scholarship. We thank Prof. Richard Harvey for providing the Nrg1 mice and the biological testing facility staff (especially J. Fisher, M. Pickering and K. Kerr) for their support. The critical comments by Jerry Tanda on the manuscript are gratefully acknowledged.

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Authors and Affiliations

  1. Neuroscience Institute of Schizophrenia and Allied Disorders (NISAD), 384 Victoria Street, Darlinghurst, NSW, 2010, Australia

    A. A. Boucher, J. C. Arnold, L. Duffy, P. R. Schofield & T. Karl

  2. Department of Pharmacology, University of Sydney, Sydney, NSW, 2006, Australia

    A. A. Boucher & J. C. Arnold

  3. Laboratoire de Neurosciences Cognitives, Université Bordeaux I, 33405, Talence, France

    A. A. Boucher & J. Micheau

  4. Neuroscience Research Program, Garvan Institute of Medical Research, Sydney, NSW, 2010, Australia

    L. Duffy & T. Karl

  5. Prince of Wales Medical Research Institute, Sydney, NSW, 2031, Australia

    P. R. Schofield

  6. University of New South Wales, Sydney, NSW, 2052, Australia

    P. R. Schofield

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  1. A. A. Boucher
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  2. J. C. Arnold
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Correspondence to T. Karl.

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Boucher, A.A., Arnold, J.C., Duffy, L. et al. Heterozygous neuregulin 1 mice are more sensitive to the behavioural effects of Δ9-tetrahydrocannabinol. Psychopharmacology 192, 325–336 (2007). https://doi.org/10.1007/s00213-007-0721-3

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