Original article| Volume 60, ISSUE 6, P538-547, September 15, 2006

Nur77 Gene Knockout Alters Dopamine Neuron Biochemical Activity and Dopamine Turnover


      Transcription factors of the Nur family (Nurr1, Nur77, and Nor-1) are orphan nuclear receptors closely associated with dopamine neurotransmission in the central nervous system. Nur77 expression is strongly modulated by antipsychotic and ant-parkinsonian drugs in dopaminoceptive brain areas. However, the role of Nur77 in dopamine neuron activity and turnover remains elusive.


      We compared various behavioral and biochemical parameters between Nur77 knockout −/− and wild-type +/+ mice in basal and haloperidol-challenged conditions.


      We report here that Nur77-deficient mice display enhanced spontaneous locomotor activity, greater sensitivity to a small dose of the dopamine D2 receptor agonist quinpirole acting mainly at autoreceptor sites, and higher levels of the dopamine metabolite DOPAC relative to wild-type mice. Dopamine turnover disturbances are also found after acute challenge with haloperidol, a dopamine D2 receptor antagonist. These alterations are associated with increased tyrosine hydroxylase expression and activity, and reduced catechol-O-methyltransferase expression.


      Taken together, these results are consistent with the involvement of Nur77 in dopamine neuron biochemical activity and dopamine turnover.

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        • Beaudry G.
        • Langlois M.-C.
        • Weppe I.
        • Rouillard C.
        • Lévesque D.
        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. 2000; 75: 1694-1702
        • Bhardwaj S.K.
        • Beaudry G.
        • Quirion R.
        • Lévesque D.
        • Srivastava L.K.
        Neonatal ventral hippocampus lesion leads to reductions in nerve growth factor inducible-B mRNA in the prefrontal cortex and increased amphetamine response in the nucleus accumbens and dorsal striatum.
        Neuroscience. 2003; 122: 669-676
        • Bilder R.M.
        • Volavka J.
        • Lachman H.M.
        • Grace A.A.
        The catechol-O-methyltransferase polymorphism: Relations to the tonic-phasic dopamine hypothesis and neuropsychiatric phenotypes.
        Neuropsychopharmacology. 2004; 29: 1943-1961
        • Boja J.W.
        • Cadet J.L.
        • Kopajtic T.A.
        • Lever J.
        • Seltzman H.H.
        • Wyrick C.D.
        • et al.
        Selective labeling of the dopamine transporter by the high affinity ligand 3 β-(4-[125I]iodophenyl)tropane-2 β-carboxylic acid isopropyl ester.
        Mol Pharmacol. 1995; 47: 779-786
        • Carboni E.
        • Silvagni A.
        Dopamine reuptake by norepinephrine neurons: Exception or rule?.
        Crit Rev Neurobiol. 2004; 16: 121-128
        • Cossette M.
        • Parent A.
        • Lévesque D.
        Tyrosine hydroxylase-positive neurons intrinsic to the human striatum express the transcription factor Nurr1.
        Eur J Neurosci. 2004; 20: 2089-2095
        • Di Paolo T.
        • Lévesque D.
        • Daigle M.
        A physiological dose of progesterone affects rat striatum biogenic amine metabolism.
        Eur J Pharmacol. 1986; 125: 11-16
        • Egan M.F.
        • Chrapusta S.
        • Karoum F.
        • Lipska B.K.
        • Wyatt R.J.
        Effects of chronic neuroleptic treatment on dopamine release: insights from studies using 3-methoxytyramine.
        J Neural Transm. 1996; 103: 777-805
        • Egan M.F.
        • Chrapusta S.J.
        • Karoum F.
        • Wyatt R.J.
        The effects of acute and chronic haloperidol treatment on dopamine release mediated by the medial forebrain bundle in the striatum and nucleus accumbens.
        Neuropsychopharmacology. 1996; 14: 211-223
        • Eilam D.
        • Szechtman H.
        Biphasic effect of D-2 agonist quinpirole on locomotion and movements.
        Eur J Pharmacol. 1989; 161: 151-157
        • Ethier I.
        • Beaudry G.
        • St-Hilaire M.
        • Milbrandt J.
        • Rouillard C.
        • Lévesque D.
        The transcription factor NGFI-B (Nur77) and retinoids play a critical role in acute neuroleptic-induced extrapyramidal effect and striatal neuropeptide gene expression.
        Neuropsychopharmacology. 2004; 29: 335-346
        • Ethier I.
        • Kagechika H.
        • Shudo K.
        • Rouillard C.
        • Lévesque D.
        Docosahexaenoic acid reduces haloperidol-induced dyskinesias in mice: Involvement of Nur77 and retinoid receptors.
        Biol Psychiatry. 2004; 56: 522-526
        • Evans R.
        A transcriptional basis for physiology.
        Nat Med. 2004; 10: 1022-1026
        • Garris P.A.
        • Budygin E.A.
        • Phillips P.E.M.
        • Venton B.J.
        • Robinson D.L.
        • Bergström B.P.
        • et al.
        A role for presynaptic mechanisms in the actions of nomifensine and haloperidol.
        Neuroscience. 2003; 118: 819-829
        • Gogos J.A.
        • Morgan M.
        • Luine V.
        • Santha M.
        • Ogawa S.
        • Pfaff D.
        • Karayiorgou M.
        Catechol-O-methyltransferase-deficient mice exhibit sexually dimorphic changes in catecholamine levels and behavior.
        Proc Natl Acad Sci USA. 1998; 95: 9991-9996
        • Gronemeyer H.
        • Gustafsson J.A.
        • Laudet V.
        Principles for modulation of the nuclear receptor superfamily.
        Nat Rev Drug Discov. 2004; 3: 950-964
        • Hermanson E.
        • Joseph B.
        • Castro D.
        • Lindqvist E.
        • Aarnisalo P.
        • Wallen A.
        • et al.
        Nurr1 regulates dopamine synthesis and storage in MN9D dopamine cells.
        Exp Cell Res. 2003; 288: 324-334
        • Hung A.C.
        • Huang H.M.
        • Tsay H.J.
        • Lin T.N.
        • Kuo J.S.
        • Sun S.H.
        ATP-stimulated c-fos and zif268 mRNA expression is inhibited by chemical hypoxia in a rat brain-derived type 2 astrocyte cell line, RBA-2.
        J Cell Biochem. 2000; 77: 323-332
        • Huotari M.
        • Gogos J.A.
        • Karayiorgou M.
        • Koponen O.
        • Forsberg M.
        • Raasmaja A.
        • et al.
        Brain catecholamine metabolism in catechol-O-methyltransferase (COMT)-deficient mice.
        Eur J Neurosci. 2002; 15: 246-256
        • Iwawaki T.
        • Kohno K.
        • Kobayashi K.
        Identification of a potential Nurr1 response element that activates the tyrosine hydroxylase gene promoter in cultured cells.
        Biochem Biophys Res Commun. 2000; 274: 590-595
        • Jonkers N.
        • Sarre S.
        • Ebinger G.
        • Michotte Y.
        Benserazide decreases central AADC activity, extracellular dopamine levels and levodopa decarboxylation in striatum of the rat.
        J Neural Transm. 2001; 108: 559-570
        • Karhunen T.
        • Tilgmann C.
        • Ulmanen I.
        • Panula P.
        Neuronal and non-neuronal catechol-O-methyltransferase in primary cultures of rat brain cells.
        Int J Dev Neurosci. 1995; 13: 825-834
        • Lee S.L.
        • Wesselschmidt R.L.
        • Linette G.P.
        • Kanagawa O.
        • Russell J.H.
        • Milbrandt J.
        Unimpaired thymic and peripheral T cell death in mice lacking the nuclear receptor NGFI-B (Nur77).
        Science. 1995; 269: 532-535
        • Li Z.
        • Ichikawa J.
        • Huang M.
        • Prus A.J.
        • Dai J.
        • Meltzer H.Y.
        ACP-103, a 5-HT2A/2C inverse agonist, potentiates haloperidol-induced dopamine release in rat medial prefrontal cortex and nucleus accumbens.
        Psychopharmacology (Berl). 2005; 183: 144-153
        • Lindley S.E.
        • She X.H.
        • Schatzberg A.F.
        Monoamine oxidase and catechol-O-methyltransferase enzyme activity and gene expression in response to sustained glucocorticoids.
        Psychoneuroendocrinology. 2005; 30: 785-790
        • Lowry O.H.
        • Rosebrough N.J.
        • Farr A.L.
        • Randall R.J.
        Protein measurement with the folin phenol reagent.
        J Biol Chem. 1951; 193: 265-275
        • Maheux J.
        • Ethier I.
        • Rouillard C.
        • Lévesque D.
        Induction patterns of transcription factors of the Nur family (Nurr1, Nur77 and Nor-1) by typical and atypical antipsychotics in the mouse brain: Implication for their mechanism of action.
        J Pharmacol Exp Ther. 2005; 313: 460-473
        • Maira M.
        • Martens C.
        • Philips A.
        • Drouin J.
        Heterodimerization between members of the Nur subfamily of orphan nuclear receptors as a novel mechanism for gene activation.
        Mol Cell Biol. 1999; 19: 7549-7557
        • Mannisto P.T.
        • Kaakkola S.
        Catechol-O-methyltransferase (COMT): biochemistry, molecular biology, pharmacology, and clinical efficacy of the new selective COMT inhibitors.
        Pharmacol Rev. 1999; 51: 593-628
        • Matsumoto M.
        • Weickert C.S.
        • Beltaifa S.
        • Kolachana B.
        • Chen J.S.
        • Hyde T.M.
        • et al.
        Catechol O-methyltransferase (COMT) mRNA expression in the dorsolateral prefrontal cortex of patients with schizophrenia.
        Neuropsychopharmacology. 2003; 28: 1521-1530
        • Morissette M.
        • Di Paolo T.
        Acute effect of 17β-estradiol and lithium on ovariectomized rat brain biogenic amines metabolism.
        J Psychiat Res. 1996; 30: 95-107
        • Nissbrandt H.
        • Sundström E.
        • Jonsson G.
        • Hjorth S.
        • Carlsson A.
        Synthesis and release of dopamine in rat brain: comparison between substantia nigra pars compacts, pars reticulata, and striatum.
        J Neurochem. 1989; 52: 1170-1182
        • Olson L.
        • Cheng H.
        • Zetterström R.H.
        • Solomin L.
        • Jansson L.
        • Giménez-Llort L.
        • et al.
        On CNS repair and protection strategies: novel approaches with implications for spinal cord injury and Parkinson’s disease.
        Brain Res Brain Res Rev. 1998; 26: 302-305
        • Paulsen R.F.
        • Granas K.
        • Johnsen H.
        • Rolseth V.
        • Sterri S.
        Three related brain nuclear receptors, NGFI-B, Nurr1, and NOR-1, as transcriptional activators.
        J Mol Neurosci. 1995; 6: 249-255
        • Perlmann T.
        • Jansson L.
        A novel pathway for vitamin A signaling mediated by RXR heterodimerization with NGFI-B and NURR1.
        Genes Dev. 1995; 9: 769-782
        • Philips A.
        • Lesage S.
        • Gingras R.
        • Maira M.-H.
        • Gauthier Y.
        • Hugo P.
        • Drouin J.
        Novel dimeric Nur77 signaling mechanism in endocrine and lymphoid cells.
        Mol Cell Biol. 1997; 17: 5946-5951
        • Sacchetti P.
        • Mitchell T.R.
        • Granneman J.G.
        • Bannon M.J.
        Nurr1 enhances transcription of the human dopamine transporter gene through a novel mechanism.
        J Neurochem. 2001; 76: 1565-1572
        • Sakurada K.
        • Ohshima-Sakurada M.
        • Palmer T.D.
        • Gage F.H.
        Nurr1, an orphan nuclear receptor, is a transcriptional activator of endogenous tyrosine hydroxylase in neural progenitor cells derived from the adult brain.
        Development. 1999; 126: 4017-4026
        • Schmitz Y.
        • Benoit-Marand M.
        • Gonon F.
        • Sulzer D.
        Presynaptic regulation of dopaminergic neurotransmission.
        J Neurochem. 2003; 87: 273-289
        • Sharman D.F.
        The turnover of catecholamines.
        in: Pycock C.J. Taberner P.V. Central Neurotransmitter Turnover. Croom Helm, London1985: 20-58
        • St-Hilaire M.
        • Landry É.
        • Lévesque D.
        • Rouillard C.
        Denervation and repeated L-DOPA induce a coordinate expression of the transcription factor NGFI-B in striatal projection pathways in hemi-parkinsonian rats.
        Neurobiol Dis. 2003; 14: 98-109
        • St-Hilaire M.
        • Tremblay P.-O.
        • Lévesque D.
        • Barden N.
        • Rouillard C.
        Effects of cocaine on c-fos and NGFI-B mRNA expression in transgenic mice underexpressing glucocorticoid receptors.
        Neuropsychopharmacology. 2003; 28: 478-489
        • Werme M.
        • Olson L.
        • Brené S.
        NGFI-B and Nor1 mRNAs are upregulated in brain reward pathways by drugs of abuse: Different effects in Fischer and Lewis rats.
        Mol Brain Res. 2000; 76: 18-24
        • Werme M.
        • Ringholm A.
        • Olson L.
        • Brené S.
        Differential patterns of induction of NGFI-B, Nor1 and c-fos mRNAs in striatal subregions by haloperidol and clozapine.
        Brain Res. 2000; 863: 112-119
        • Zetterström R.H.
        • Solomin L.
        • Jansson L.
        • Hoffer B.J.
        • Olson L.
        • Perlmann T.
        Dopamine neuron agenesis in Nurr1-deficient mice.
        Science. 1997; 276: 248-250
        • Zetterström R.H.
        • Williams R.
        • Perlmann T.
        • Olson L.
        Cellular expression of the immediate-early transcription factors Nurr1 and NGFI-B suggests a gene regulatory role in several brain regions including the nigrostriatal dopamine system.
        Mol Brain Res. 1996; 41: 111-120
        • Zetterström T.
        • Sharp T.
        • Ungerstedt U.
        Effect of neuroleptic drugs on striatal dopamine release and metabolism in the awake rat studied by intracerebral dialysis.
        Eur J Pharmacol. 1984; 106: 27-37