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The activation of the Akt/PKB signalling pathway in the brains of clozapine-exposed rats is linked to hyperinsulinemia and not a direct drug effect

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Abstract

The second generation antipsychotic drug clozapine is a much more effective therapy for schizophrenia than first generation compounds, but the reasons for this are poorly understood. We have previously shown that one distinguishing feature of clozapine is its ability to raise glucagon levels in animal models and thus causes prolonged hyperinsulinemia without inducing hypoglycaemia. Previous studies have provided evidence that defects in Akt/PKB and GSK3 signalling can contribute to development of psychiatric diseases. Clozapine is known to activate Akt/PKB in the brain, and some studies have indicated that this is due to a direct effect of the drug on the neurons. However, we provide strong evidence that elevated insulin levels induced by clozapine are in fact the real cause of the drug’s effects on Akt/PKB and GSK3 in the brain. This suggests that the elevated levels of insulin induced by clozapine may contribute to this drug’s therapeutic efficacy.

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Acknowledgments

This work was supported by funding from the Oakley Mental Health Research Foundation. GCS is funded by a Foundation for Research, Science and Technology Research Fellowship. HM is funded by a Maurice Wilkins Centre studentship.

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Authors and Affiliations

  1. Department of Molecular Medicine and Pathology, University of Auckland, Auckland, New Zealand

    G. C. Smith, H. McEwen & P. R. Shepherd

  2. Department of Pharmacology, University of New South Wales, Kensington, NSW, Australia

    G. C. Smith

  3. Singapore Bioimaging Consortium, Agency for Science, Technology and Research, 11 Biopolis Way, Singapore

    J. D. Steinberg

  4. The Maurice Wilkins Centre, Auckland, New Zealand

    H. McEwen & P. R. Shepherd

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  1. G. C. Smith
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  2. H. McEwen
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  3. J. D. Steinberg
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  4. P. R. Shepherd
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Correspondence to G. C. Smith.

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Smith, G.C., McEwen, H., Steinberg, J.D. et al. The activation of the Akt/PKB signalling pathway in the brains of clozapine-exposed rats is linked to hyperinsulinemia and not a direct drug effect. Psychopharmacology 231, 4553–4560 (2014). https://doi.org/10.1007/s00213-014-3608-0

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  • DOI: https://doi.org/10.1007/s00213-014-3608-0

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