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 D2/D3 antagonist is completely abolished in NGFI-B-deficient mice whereas the cataleptic response to SCH 23390, a dopamine D1 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 RXRγ1 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.
Similar content being viewed by others
Log in or create a free account to read this content
Gain free access to this article, as well as selected content from this journal and more on nature.com
or
References
Allison DB, Casey DE (2001). Antipsychotic-induced weight gain: a review of the literature. J Clin Psychiatry 62(Suppl 7): 22–31.
Augood SJ, Westmore K, Emson PC (1997). Phenotypic characterization of neurotensin messenger RNA-expressing cells in the neuroleptic-treated rat striatum: a detailed cellular co-expression study. Neuroscience 76: 763–774.
Beaudry G, Langlois M-C, Weppe I, Rouillard C, Lévesque D (2000). Contrasting patterns and cellular specificity of transcriptional regulation of the nuclear receptor nerve growth factor-inducible B by haloperidol and clozapine in the rat forebrain. J Neurochem 75: 1694–1702.
Castillo SO, Xiao Q, Kostrouch Z, Dozin B, Nikodem VM (1998). A divergent role of COOH-terminal domains in Nurr1 and Nur77 transactivation. Gene Exp 7: 1–12.
Chambon P (1996). A decade of molecular biology of retinoic acid receptors. FASEB J 10: 940–954.
Chan RM, Stewart MJ, Crabb DW (1997). A direct repeat (DR-1) element in the first exon modulates transcription of the preproenkephalin A gene. Brain Res Mol Brain Res 45: 50–58.
Cheng LE, Chan FK, Cado D, Winoto A (1997). Functional redundancy of the Nur77 and Nor-1 orphan steroid receptors in T-cell apoptosis. EMBO J 16: 1865–1875.
Crawford PA, Sadovsky Y, Woodson K, Lee SL, Milbrandt J (1995). Adrenocortical function and regulation of the steroid 21-hydroxylase gene in NGFI-B-deficient mice. Mol Cell Biol 15: 4331–4336.
Dawson MI, Hobbs PD, Peterson VJ, Leid M, Lange CW, Feng K-C et al (2001). Apoptosis induction in cancer cells by a novel analogue of 6-[3-(1-adamantyl)-4-hydroxyphenyl]-2-naphthalene-carboxylic acid lacking retinoid receptor transcriptional activation activity. Cancer Res 61: 4723–4730.
de Urquiza AM, Liu S, Sjöberg M, Zetterström RH, Griffiths W, Sjövall J et al (2000). Docosahexaenoic acid, a ligand for the retinoid X receptor in mouse brain. Science 290: 2140–2144.
Dobner PR, Fadel J, Deitemeyer N, Carraway RE, Deutch AY (2001). Neurotensin-deficient mice show altered responses to antipsychotic drugs. Proc Natl Acad Sci USA 98: 8048–8053.
Egea PF, Mitschler A, Moras D (2002). Molecular recognition of agonist ligands by RXRs. Mol Endocrinol 16: 987–997.
Gerfen CR, Mahan LC, Susel Z, Chase TN, Monsma Jr FJ, Sibley DR (1990). D1 and D2 dopamine receptor-regulated gene expression of striatonigral and striatopallidal neurons. Science 250: 1429–1432.
Gervais J, Soghomonian J-J, Richard D, Rouillard C (1999). Dopamine and serotonin interactions in the modulation of the expression of the immediate-early transcription factor, nerve growth factor-inducible B, in the striatum. Neuroscience 91: 1045–1054.
Goodman AB (1998). Three independent lines of evidence suggest retinoids as causal to schizophrenia. Proc Natl Acad Sci USA 95: 7240–7244.
Hazel TG, Nathans D, Lau LF (1988). A gene inducible by serum growth factors encodes a member of the steroid and thyroid hormone receptor superfamily. Proc Natl Acad Sci USA 85: 8444–8448.
Herdegen T, Leah JD (1998). Inducible and constitutive transcription factors in the mammalian nervous system: control of gene expression by Jun, Fos and Krox, and CREB/ATF proteins. Brain Res Brain Res Rev 28: 370–490.
Hernandez-Lopez S, Tkatch T, Perez-Garci E, Galarraga E, Bargas J, Hamm H et al (2000). D2 dopamine receptors in striatal medium spiny neurons reduce L-type Ca2+ currents and excitability via a novel PLCβ1-IP3-calcineurin-signaling cascade. J Neurosci 20: 8987–8995.
Heyman RA, Mangelsdorf DJ, Dyck JA, Stein RB, Eichele G, Evans RM et al (1992). 9-cis retinoic acid is a high affinity ligand for the retinoid X receptor. Cell 68: 397–406.
Hiroi N, Graybiel AM (1996). Atypical and typical neuroleptic treatments induce distinct programs of transcription factor expression in the striatum. J Comp Neurol 374: 70–83.
Hoffman DC, Donovan H (1995). Catalepsy as a rodent model for detecting antipsychotic drugs with extrapyramidal side effect liability. Psychopharmacology (Berl) 120: 128–133.
Kane JM (2001). Extrapyramidal side effects are unacceptable. Eur Neuropsychopharmacol 11: S397–S403.
Kovalovsky D, Refojo D, Liberman AC, Hochbaum D, Paez-Pereda M, Coso OA et al (2002). Activation and induction of NUR77/NURR1 in corticotrophs by CRH/cAMP: involvement of calcium, protein kinase A, and MAPK pathways. Mol Endocrinol 16: 1638–1651.
Krezel W, Ghyselinck N, Samad TA, Dupé V, Kastner P, Borrelli E et al (1998). Impaired locomotion and dopamine signaling in retinoid receptor mutant mice. Science 279: 863–867.
Krezel W, Kastner P, Chambon P (1999). Differential expression of retinoid receptors in the adult mouse central nervous system. Neuroscience 89: 1291–1300.
LaMantia A-S (1999). Forebrain induction, retinoic acid, and vulnerability to schizophrenia: insights from molecular and genetic analysis in developing mice. Biol Psychiatry 46: 19–30.
Langlois M-C, Beaudry G, Zekki H, Rouillard C, Lévesque D (2001). Impact of antipsychotic drug administration on the expression of nuclear receptors in the neocortex and striatum of the rat brain. Neuroscience 106: 117–128.
Le Moine C, Bloch B (1995). D1 and D2 dopamine receptor gene expression in the rat striatum: sensitive cRNA probes demonstrate prominent segregation of D1 and D2 mRNAs in distinct neuronal populations of the dorsal and ventral striatum. J Comp Neurol 355: 418–426.
Lee SL, Wesselschmidt RL, Linette GP, Kanagawa O, Russell JH, Milbrandt J (1995). Unimpaired thymic and peripheral T cell death in mice lacking the nuclear receptor NGFI-B (Nur77). Science 269: 532–535.
Leveque J-C, Macias W, Rajadhyaksha A, Carlson RR, Barczak A, Kang S et al (2000). Intracellular modulation of NMDA receptor function by antipsychotic drugs. J Neurosci 20: 4011–4020.
Leysen JE, Janssen PM, Schotte A, Luyten WH, Megens AA (1993). Interaction of antipsychotic drugs with neurotransmitter receptor sites in vitro and in vivo in relation to pharmacological and clinical effects: role of 5-HT2 receptors. Psychopharmacology (Berl) 112: S40–S54.
Liu Z-G, Smith SW, McLaughlin KA, Schwartz LM, Osborne BA (1994). Apoptotic signals delivered through the T-cell receptor of a T-cell hybrid require the immediate-early gene Nur77. Nature 367: 281–284.
Maden M (2002). Retinoid signalling in the development of the central nervous system. Nat Rev Neurosci 3: 843–853.
Maira M, Martens C, Batsché E, Gauthier Y, Drouin J (2003). Dimer-specific potentiation of NGFI-B (Nur77) transcriptional activity by the protein kinase A pathway and AF-1-dependent coactivator recruitment. Mol Cell Biol 23: 763–776.
Maltais A, Labelle Y (2000). Structure and expression of the mouse gene encoding the orphan nuclear receptor TEC. DNA Cell Biol 19: 121–130.
Meltzer HY (1995). Atypical antipsychotic drugs. In: Bloom FE, Kupfer DJ (eds). Psychopharmacology: The Fourth Generation of Progress. Raven Press: New York. pp 1277–1286.
Milbrandt J (1988). Nerve growth factor induces a gene homologous to the glucocorticoid receptor gene. Neuron 1: 183–188.
Nilsson S, Makela S, Treuter E, Tujague M, Thomsen J, Andersson G et al (2001). Mechanisms of estrogen action. Physiol Rev 81: 1535–1565.
Paulsen RF, Granas K, Johnsen H, Rolseth V, Sterri S (1995). Three related brain nuclear receptors, NGFI-B, Nurr1, and NOR-1, as transcriptional activators. J Mol Neurosci 6: 249–255.
Perlmann T, Jansson L (1995). A novel pathway for vitamin A signaling mediated by RXR heterodimerization with NGFI-B and NURR1. Genes Dev 9: 769–782.
Saga Y, Kobayashi M, Ohta H, Murai N, Nakai N, Oshima M et al (1999). Impaired extrapyramidal function caused by the targeted disruption of retinoid X receptor RXRγ1 isoform. Genes Cells 4: 219–228.
Seeman P (1995). Dopamine receptors: clinical correlates. In: Bloom FE, Kupfer DJ (eds). Psychopharmacology: The Fourth Generation of Progress. Raven Press: New York. pp 295–302.
Slagsvold HH, Ostvold A-C, Fallgren AB, Paulsen RE (2002). Nuclear receptor and apoptosis initiator NGFI-B is a substrate for kinase ERK2. Biochem Biophys Res Commun 291: 1146–1150.
Steiner H, Gerfen CR (1998). Role of dynorphin and enkephalin in the regulation of striatal output pathways and behavior. Exp Brain Res 123: 60–76.
Tremblay M, Rouillard C, Lévesque D (1999). Dopamine D3 receptor antisense administration reduces basal c-fos and NGFI-B mRNA levels in the rat forebrain. Synapse 32: 51–57.
Vivat V, Zechel C, Wurtz J-M, Bourguet W, Kagechika H, Umemiya H et al (1997). A mutation mimicking ligand-induced conformational change yields a constitutive RXR that senses allosteric effects in heterodimers. EMBO J 16: 5697–5709.
Wagner E, Luo T, Dräger UC (2002). Retinoic acid synthesis in the postnatal mouse brain marks distinct developmental stages and functional systems. Cereb Cortex 12: 1244–1253.
Wansa KD, Harris JM, Muscat GE (2002). The activation function-1 domain of Nur77/NR4A1 mediates trans-activation, cell specificity, and coactivator recruitment. J Biol Chem 277: 33001–33011.
Werme M, Ringholm A, Olson L, Brené S (2000). Differential patterns of induction of NGFI-B, Nor-1 and c-fos mRNAs in striatal subregions by haloperidol and clozapine. Brain Res 863: 112–119.
Woronicz JD, Calnan B, Ngo V, Winoto A (1994). Requirement for the orphan steroid receptor Nur77 in apoptosis of T-cell hybridomas. Nature 367: 277–281.
Zetterström RH, Lindqvist E, de Urquiza AM, Tomac A, Eriksson U, Perlmann T et al (1999). Role of retinoids in the CNS: differential expression of retinoid binding proteins and receptors and evidence for presence of retinoic acid. Eur J Neurosci 11: 407–416.
Zetterström RH, Solomin L, Mitsiadis T, Olson L, Perlmann T (1996). Retinoid X receptor heterodimerization and developmental expression distinguish the orphan nuclear receptors NGFI-B, Nurr1, and Nor1. Mol Endocrinol 10: 1656–1666.
Acknowledgements
We thank Dr Pierre-Paul Rompré and Pierre Blanchet for very stimulating and helpful discussions and Dr Yves Labelle from the SFA Research Center (Québec, Canada) for generously providing us with Nor-1 knockout mice. DL holds a scholarship from the Fonds de la Recherche en Santé du Québec (FRSQ) and IE holds a fellowship from the Laval University Neuroscience Research Center.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Éthier, I., Beaudry, G., St-Hilaire, M. et al. The Transcription Factor NGFI-B (Nur77) and Retinoids Play a Critical Role in Acute Neuroleptic-Induced Extrapyramidal Effect and Striatal Neuropeptide Gene Expression. Neuropsychopharmacol 29, 335–346 (2004). https://doi.org/10.1038/sj.npp.1300318
Received:
Revised:
Accepted:
Published:
Issue date:
DOI: https://doi.org/10.1038/sj.npp.1300318
Keywords
This article is cited by
-
Paliperidone and aripiprazole differentially affect the strength of calcium-secretion coupling in female pituitary lactotrophs
Scientific Reports (2015)
-
Patrolling monocytes play a critical role in CX3CR1-mediated neuroprotection during excitotoxicity
Brain Structure and Function (2015)
-
The transcription factors Nur77 and retinoid X receptors participate in amphetamine-induced locomotor activities
Psychopharmacology (2009)
