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Neuropsychopharmacology
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Reduced Levels of Serotonin 2A Receptors Underlie Resistance ofEgr3-Deficient Mice to Locomotor Suppression by Clozapine

Neuropsychopharmacologyvolume 37, pages2285–2298 (2012)Cite this article

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Abstract

The immediate-early gene early growth response 3 (Egr3) is associated with schizophrenia and expressed at reduced levels in postmortem patients' brains. We have previously reported thatEgr3-deficient (Egr3−/−) mice display reduced sensitivity to the sedating effects of clozapine compared with wild-type (WT) littermates, paralleling the heightened tolerance of schizophrenia patients to antipsychotic side effects. In this study, we have used a pharmacological dissection approach to identify a neurotransmitter receptor defect inEgr3−/− mice that may mediate their resistance to the locomotor suppressive effects of clozapine. We report that this response is specific to second-generation antipsychotic agents (SGAs), as first-generation medications suppress the locomotor activity ofEgr3−/− and WT mice to a similar degree. Further, in contrast to the leading theory that sedation by clozapine results from anti-histaminergic effects, we show that H1 histamine receptors are not responsible for this effect in C57BL/6 mice. Instead, selective serotonin 2A receptor (5HT2AR) antagonists ketanserin and MDL-11939 replicate the effect of SGAs, repressing the activity in WT mice at a dosage that fails to suppress the activity ofEgr3−/− mice. Radioligand binding revealed nearly 70% reduction in 5HT2AR expression in the prefrontal cortex ofEgr3−/− mice compared with controls.Egr3−/− mice also exhibit a decreased head-twitch response to 5HT2AR agonist 1-(2,5-dimethoxy 4-iodophenyl)-2-amino propane (DOI). These findings provide a mechanism to explain the reduced sensitivity ofEgr3−/− mice to the locomotor suppressive effects of SGAs, and suggest that 5HT2ARs may also contribute to the sedating properties of these medications in humans. Moreover, as the deficit in cortical 5HT2AR inEgr3−/− mice aligns with numerous studies reporting decreased 5HT2AR levels in the brains of schizophrenia patients, and the gene encoding the 5HT2AR is itself a leading schizophrenia candidate gene, these findings suggest a potential mechanism by which putative dysfunction inEGR3 in humans may influence risk for schizophrenia.

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Acknowledgements

We are grateful to L Muppana, MS, for animal colony maintenance and technical assistance; to W Rodriguez for experimental assistance; to B Appelhans, PhD, Rush University Medical Center, for statistics consultation; to H Meltzer, MD, Northwestern University, for his donation of ACP-103 and his advice throughout the project; and to both H Meltzer, MD, and D Kupfer, MD, University of Pittsburgh, for their critical reading of the manuscript. Ki determinations, receptor binding profiles, and agonist and/or antagonist functional data, were generously provided by the National Institute of Mental Health's Psychoactive Drug Screening Program, Contract No. HHSN-271-2008-00025-C (NIMH PDSP). The NIMH PDSP is Directed by Bryan L Roth MD, PhD at the University of North Carolina at Chapel Hill and Project Officer Jamie Driscol at NIMH, Bethesda MD, USA. This work was supported by a NARSAD/Sidney R Baer Jr Foundation Young Investigator Award (to ALG), an Arizona Biomedical Research Commission grant (to ALG), and by NIH Grant R01 MH084894 (to JGM). Additional support from Science Foundation Arizona (to AAW), and from the Howard Hughes Medical Institute through the Undergraduate Science Education program and the School of Life Sciences at Arizona State University, is gratefully acknowledged.

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Authors and Affiliations

  1. School of Life Sciences, Arizona State University, Tempe, AZ, USA

    Alison A Williams

  2. Department of Molecular and Cell Biology, Life Sciences Addition, University of California, Berkeley, CA, USA

    Wendy M Ingram

  3. University of Arizona College of Medicine—Tucson, Tucson, AZ, USA

    Sarah Levine & Scott A Janowski

  4. Department of Basic Medical Sciences and Psychiatry, University of Arizona College of Medicine—Phoenix, Phoenix, AZ, USA

    Jack Resnik, Christy M Kamel, James R Lish, Diana I Elizalde, Joseph Shoker & Amelia L Gallitano

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

    Alexey Kozlenkov & Javier González-Maeso

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

    Javier González-Maeso

Authors
  1. Alison A Williams
  2. Wendy M Ingram
  3. Sarah Levine
  4. Jack Resnik
  5. Christy M Kamel
  6. James R Lish
  7. Diana I Elizalde
  8. Scott A Janowski
  9. Joseph Shoker
  10. Alexey Kozlenkov
  11. Javier González-Maeso
  12. Amelia L Gallitano

Corresponding author

Correspondence toAmelia L Gallitano.

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Supplementary Information accompanies the paper on the Neuropsychopharmacology website

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Williams, A., Ingram, W., Levine, S.et al. Reduced Levels of Serotonin 2A Receptors Underlie Resistance ofEgr3-Deficient Mice to Locomotor Suppression by Clozapine.Neuropsychopharmacol37, 2285–2298 (2012). https://doi.org/10.1038/npp.2012.81

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