title: The transcription factor NGFI-B (Nur77) and retinoids play a critical role in acute neuroleptic-induced extrapyramidal effect and striatal neuropeptide gene expression.
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.
authors: 1Neuroscience Unit, CHUQ Research Center (CHUL), Quebec, Canada.
authors: Isabelle
authors: I
authors: Ethier
authors: Geneviève
authors: G
authors: Beaudry
authors: Michel
authors: M
authors: St-Hilaire
authors: Jeff
authors: J
authors: Milbrandt
authors: Claude
authors: C
authors: Rouillard
authors: Daniel
authors: D
authors: Lévesque
mesh_terms: D000077556:Alitretinoin; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D014150:Antipsychotic Agents / Q000009:adverse effects / Q000494:pharmacology*; D001345:Autoradiography; D001480:Basal Ganglia Diseases / Q000139:chemically induced / Q000235:genetics* / Q000378:metabolism; D001522:Behavior, Animal; D001665:Binding Sites; D002375:Catalepsy / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism; D003342:Corpus Striatum / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics / Q000502:physiology*; D004281:Docosahexaenoic Acids / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004338:Drug Combinations; D004347:Drug Interactions; D005786:Gene Expression Regulation / Q000187:drug effects*; D006220:Haloperidol / Q000494:pharmacology; D017403:In Situ Hybridization; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009479:Neuropeptides / Q000235:genetics / Q000378:metabolism*; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1; D012333:RNA, Messenger / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear; D018168:Receptors, Retinoic Acid / Q000235:genetics / Q000378:metabolism; D011987:Receptors, Steroid; D047488:Retinoid X Receptors; D012176:Retinoids / Q000819:agonists / Q000502:physiology*; D013997:Time Factors; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D014212:Tretinoin / Q000494:pharmacology
chemical_list: D000970:Antineoplastic Agents; D014150:Antipsychotic Agents; D004268:DNA-Binding Proteins; D004338:Drug Combinations; D009479:Neuropeptides; C539818:Nr4a1 protein, mouse; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1; D012333:RNA, Messenger; D018160:Receptors, Cytoplasmic and Nuclear; D018168:Receptors, Retinoic Acid; D011987:Receptors, Steroid; D047488:Retinoid X Receptors; D012176:Retinoids; D014157:Transcription Factors; D000077556:Alitretinoin; D004281:Docosahexaenoic Acids; D014212:Tretinoin; D006220:Haloperidol