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Persistent effects of chronic clozapine on the cellular and behavioral responses to LSD in mice

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Abstract

Rationale

In schizophrenia patients, optimal treatment with antipsychotics requires weeks to months of sustained drug therapy. However, single administration of antipsychotic drugs can reverse schizophrenia-like behavioral alterations in rodent models of psychosis. This raises questions about the physiological relevance of such antipsychotic-like activity.

Objective

This study evaluates the effects of chronic treatment with clozapine on the cellular and behavioral responses induced by the hallucinogenic serotonin 5-HT2A receptor agonist lysergic acid diethylamide (LSD) as a mouse model of psychosis.

Method

Mice were treated chronically (21 days) with 25 mg/kg/day clozapine. Experiments were conducted 1, 7, 14, and 21 days after the last clozapine administration. [3H]Ketanserin binding and 5-HT 2A mRNA expression were determined in mouse somatosensory cortex. Head-twitch behavior, expression of c-fos, which is induced by all 5-HT2A agonists, and expression of egr-1 and egr-2, which are LSD-like specific, were assayed.

Results

Head-twitch response was decreased and [3H]ketanserin binding was downregulated in 1, 7, and 14 days after chronic clozapine. 5-HT 2A mRNA was reduced 1 day after chronic clozapine. Induction of c-fos, but not egr-1 and egr-2, was rescued 7 days after chronic clozapine. These effects were not observed after short treatment (2 days) with clozapine or chronic haloperidol (1 mg/kg/day).

Conclusion

Our findings provide a murine model of chronic atypical antipsychotic drug action and suggest downregulation of the 5-HT2A receptor as a potential mechanism involved in these persistent therapeutic-like effects.

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Acknowledgments

NIMH 5R01MH084894 (J.G.M.), NIDA P01 DA12923 (S.C.S.), NARSAD (J.G.M.), the Mortimer D. Sackler Foundation Award (J.G.M.), and Dainippon Sumitomo Pharma (J.G.M.) participated in the funding of this study.

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Authors and Affiliations

  1. Department of Psychiatry, Mount Sinai School of Medicine, New York, NY, 10029, USA

    José L. Moreno, Terrell Holloway, Adrienne Umali, Vinayak Rayannavar & Javier González-Maeso

  2. Department of Neurology, Mount Sinai School of Medicine, New York, NY, 10029, USA

    Stuart C. Sealfon & Javier González-Maeso

  3. Center for Translational Systems Biology, Mount Sinai School of Medicine, New York, NY, 10029, USA

    Stuart C. Sealfon

  4. Friedman Brain Institute, Mount Sinai School of Medicine, New York, NY, 10029, USA

    Stuart C. Sealfon & Javier González-Maeso

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  1. José L. Moreno
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  2. Terrell Holloway
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  3. Adrienne Umali
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  4. Vinayak Rayannavar
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  5. Stuart C. Sealfon
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  6. Javier González-Maeso
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Correspondence to Javier González-Maeso.

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Moreno, J.L., Holloway, T., Umali, A. et al. Persistent effects of chronic clozapine on the cellular and behavioral responses to LSD in mice. Psychopharmacology 225, 217–226 (2013). https://doi.org/10.1007/s00213-012-2809-7

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  • DOI: https://doi.org/10.1007/s00213-012-2809-7

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