Reduced levels of serotonin 2A receptors underlie resistance of EGR3-deficient mice to locomotor suppression by clozapine

Alison A. Williams, Wendy M. Ingram, Sarah Levine, Jack Resnik, Christy M. Kamel, James R. Lish, Diana I. Elizalde, Scott A. Janowski, Joseph Shoker, Alexey Kozlenkov, Javier González-Maeso, Amelia L. Gallitano

Research output: Contribution to journalArticle

29 Scopus citations

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 that Egr3-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 in Egr3-/- 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 of Egr3-/- 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 of Egr3-/- mice. Radioligand binding revealed nearly 70% reduction in 5HT2AR expression in the prefrontal cortex of Egr3-/- 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 of Egr3-/- 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 5HT 2AR in Egr3-/- 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 in EGR3 in humans may influence risk for schizophrenia.

Original languageEnglish (US)
Pages (from-to)2285-2298
Number of pages14
JournalNeuropsychopharmacology
Volume37
Issue number10
DOIs
StatePublished - Sep 1 2012

Keywords

  • 5HT2A receptor
  • Egr3
  • clozapine
  • immediate early gene
  • locomotor activity
  • schizophrenia/antipsychotics

ASJC Scopus subject areas

  • Pharmacology
  • Psychiatry and Mental health

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    Williams, A. A., Ingram, W. M., Levine, S., Resnik, J., Kamel, C. M., Lish, J. R., Elizalde, D. I., Janowski, S. A., Shoker, J., Kozlenkov, A., González-Maeso, J., & Gallitano, A. L. (2012). Reduced levels of serotonin 2A receptors underlie resistance of EGR3-deficient mice to locomotor suppression by clozapine. Neuropsychopharmacology, 37(10), 2285-2298. https://doi.org/10.1038/npp.2012.81