The transcription factor NGFI-B (Nur77) and retinoids play a critical role in acute neuroleptic-induced extrapyramidal effect and striatal neuropeptide gene expression

Authors: Éthier, IsabelleBeaudry, GenevièveSt-Hilaire, Michel; Milbrandt, Jeff; Rouillard, ClaudeLévesque, Daniel
Abstract: Despite extensive investigation, the cellular mechanisms responsible for neuroleptic actions remain elusive. We have previously shown that neuroleptics modulated the expression of some members of the ligand-activated transcription factors (nuclear receptors) including the nerve-growth factor inducible gene B (NGFI-B or Nur77) and retinoid X receptor (RXR) isoforms. Using genetic and pharmacological approaches, we investigated the role of NGFI-B and retinoids in acute behavioral and biochemical responses to dopamine antagonists. NGFI-B knockout (KO) mice display a profound alteration of haloperidol-induced catalepsy and striatal neuropeptide gene expression. Haloperidol-induced increase of striatal enkephalin mRNA is totally abolished in NGFI-B KO mice whereas the increase of neurotensin mRNA expression is reduced by 50%. Interestingly, catalepsy induced by raclopride, a specific dopamine D(2)/D(3) antagonist is completely abolished in NGFI-B-deficient mice whereas the cataleptic response to SCH 23390, a dopamine D(1) agonist, is preserved. Accordingly, the effects of haloperidol on striatal c-fos, Nor-1, and dynorphin mRNA expression are also preserved in NGFI-B-deficient mice. The cataleptic response and the increase of enkephalin mRNA expression induced by haloperidol can also be suppressed by administration of retinoid ligands 9-cis retinoic acid and docosahexaenoic acid. In addition, we demonstrate that haloperidol enhances colocalization of NGFI-B and RXRgamma1 isoform mRNAs, suggesting that both NGFI-B and a RXR isoform are highly coexpressed after haloperidol administration. Our data demonstrate, for the first time, that NGFI-B and retinoids are actively involved in the molecular cascade induced by neuroleptic drugs.
Document Type: Article de recherche
Issue Date: 5 November 2003
Open Access Date: Restricted access
Document version: VoR
This document was published in: Neuropsychopharmacology, Vol. 29 (2), 335–346 (2004)
American College of Neuropsychopharmacology
Alternative version: 10.1038/sj.npp.1300318
Collection:Articles publiés dans des revues avec comité de lecture

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