Personne :
Rouillard, Claude

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Université Laval. Faculté de médecine
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Voici les éléments 1 - 10 sur 21
  • Publication
    Accès libre
    Nur77 gene knockout alters dopamine neuron biochemical activity and dopamine turnover
    (Society of Biological Psychiatry, 2006-09-15) St-Hilaire, Michel; Paquet, Brigitte; Morissette, Marc; Gilbert, François; Di Paolo, Thérèse; Lévesque, Daniel; Rouillard, Claude
    Background: 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. Methods: We compared various behavioral and biochemical parameters between Nur77 knockout −/− and wild-type +/+ mice in basal and haloperidol-challenged conditions. Results: 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. Conclusion: Taken together, these results are consistent with the involvement of Nur77 in dopamine neuron biochemical activity and dopamine turnover.
  • Publication
    Accès libre
    Nur77 mRNA levels and L-Dopa-induced dyskinesias in MPTP monkeys treated with docosahexaenoic acid
    (Blackwell Science, 2009-07-25) Mahmoudi, Souha; Ouattara, Bazoumana; Morissette, Marc; Gilbert, François; Di Paolo, Thérèse; Lévesque, Daniel; Rouillard, Claude; Grégoire, Laurent; Samadi, Pershia
    We have previously shown that docosahexaenoic acid (DHA) significantly reduced L-Dopa-induced dyskinesia (LID) in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) monkeys (Samadi et al., Ann. Neurol. 59:282–288, 2006). In the present study, we measured for the first time mRNA levels of Nur77, an orphan nuclear receptor that participates to adaptive and/or aberrant dopamine-related behaviors, and retinoid X receptor γ1 (RXRγ1), a putative brain receptor for DHA and transcriptional partner of Nur77, in MPTP monkeys treated with L-Dopa and DHA. The RXRγ1 mRNA is strongly expressed in monkey caudate nucleus and putamen, but no change in levels of RXRγ1 was observed following MPTP and L-Dopa treatments. On the other hand, denervation reduced Nur77 mRNA levels, whereas chronic L-Dopa treatment strongly induced Nur77 transcripts. These modulations are taking place in substance P positive cells and are associated with both caudate-putamen matrix and striosome compartments. Interestingly, combination of L-Dopa with DHA further increases Nur77 mRNA levels in the anterior caudate-putamen, and mainly in striosomes. This is accompanied by a significant inverse correlation between Nur77 mRNA levels and dyskinetic scores. Taken together, our results show that Nur77 expression is modulated following dopamine denervation and chronic L-Dopa therapy in a non-human primate model of Parkinson's disease, and suggest that strong modulation of Nur77 expression might be linked to a reduced risk to develop LIDs.
  • Publication
    Differences between subacute and chronic MPTP mice models: investigation of dopaminergic neuronal degeneration and alpha-synuclein inclusions
    (Raven Press, 2009-05-12) Bousquet, Mélanie; Gibrat, Claire; Saint-Pierre, Martine; Lévesque, Daniel; Rouillard, Claude; Cicchetti, Francesca
    Animal models are invaluable tools to study neurodegenerative disorders but a general consensus on the most accurate rodent model of Parkinson’s disease has not been reached. Here, we examined how different methods of MPTP administration influence the degeneration of the dopaminergic (DA) system. Adult male C57BL/6 mice were treated with the same cumulative dose of MPTP following four distinct procedures: (i) subacute i.p. injections; (ii) 28-day chronic s.c. infusion; (iii) 28-day chronic i.p. infusion; and (iv) 14-day chronic i.p. infusion. Subacute MPTP treatment significantly affected all aspects of the DA system within the nigral and striatal territories. In contrast, the 28-day chronic s.c. infusion did not significantly alter any components of the DA system. The 28- and 14-day chronic i.p. infusions induced loss of tyrosine hydroxylase (TH)-positive cells correlated with a decrease in Nurr1 mRNA levels, but no significant decrease in the density of TH striatal fibers. Importantly, however, only the 14-day chronic MPTP i.p. infusion protocol promoted the formation of neuronal inclusions as noted by the expression of α-synuclein protein within the cytoplasm of TH nigral neurons. Overall, we found that the 14-day chronic MPTP i.p. infusion reproduces more accurately the pathological characteristics of early stage Parkinson’s disease.
  • Publication
    Accès libre
    Nur77 and retinoid X receptors : critical factors in dopamine-related neuroadaptation
    (Elsevier Science Publishers, 2006-11-28) Lévesque, Daniel; Rouillard, Claude
    Dopaminergic systems in the brain adapt in response to various stimuli from the internal and external world, but the mechanisms underlying this process are incompletely understood. Here, we review recent evidence that certain types of transcription factor of the nuclear receptor family, specifically Nur77 and retinoid X receptors, have important roles in adaptation and homeostatic regulation of dopaminergic systems. These findings call for a reassessment of our fundamental understanding of the molecular and cellular basis of dopamine-mediated transmission. Given that diseases such as Parkinson's disease and schizophrenia are thought to involve adaptation of dopamine signalling, these findings might provide new insight into these pathologies and offer new avenues for drug development.
  • Publication
    Accès libre
    Modulation of haloperidol-induced patterns of the transcription factor Nur77 and Nor-1 expression by serotonergic and adrenergic drugs in the mouse brain
    (Oxford Academic, 2012-05-01) Maheux, Jérôme; Vuillier, Laura; Lévesque, Daniel; Mahfouz, Mylène; Rouillard, Claude
    Different patterns of expression of the transcription factors of Nur77 and Nor-1 are induced following acute administration of typical and atypical antipsychotic drugs. The pharmacological profile of atypical antipsychotics suggests that serotonergic and/or adrenergic receptors might contribute to these reported differences. In order to test this possibility, we examined the abilities of serotonin 5-HT1A and 5-HT2A/2C, and α1- and α2-adrenergic receptor drugs to modify the pattern of Nur77 (NR4A1) and Nor-1 (NR4A3) mRNA expression induced by haloperidol. Various groups of mice were treated with either saline, DOI, a 5-HT2A/2C agonist, MDL11939, a 5-HT2A antagonist, 8-OH-DPAT, a 5-HT1A agonist, prazosin, an α1-adrenergic antagonist and idazoxan, an α2-adrenergic antagonist, alone or in combination with haloperidol. The 5-HT2A/2C agonist DOI alone significantly increased Nur77 expression in the medial striatum and nucleus accumbens. DOI reduced Nor-1 expression, while MDL11939 increased the expression of this transcript in the cortex. Prazosin reduced Nur77 expression in the dorsal striatum and nucleus accumbens. Interestingly, 8-OH-DPAT and MDL11939 partially prevented haloperidol-induced Nur77 up-regulation, while MDL11939 completely abolished Nor-1 expression in the striatum. In addition, MDL11939 decreased haloperidol-induced Nur77 and Nor-1 mRNA levels in the ventral tegmental area. On the contrary, idazoxan (α2 antagonist) consistently potentiated haloperidol-induced Nur77, but not Nor-1 mRNA levels in the striatum, whereas prazosin (α1 antagonist) remained without effect. Taken together, these results show the ability of a 5-HT1A agonist or a 5-HT2A antagonist to reduce haloperidol-induced Nur77 and Nor-1 striatal expression, suggesting that these serotonin receptor subtypes participate in the differential pattern of gene expression induced by typical and atypical antipsychotic drugs.
  • Publication
    Estrogen receptors and lesion-induced response of striatal dopamine receptors
    (Elsevier Ltd., 2013-01-25) Al-Sweidi, Sara; Morissette, Marc; Di Paolo, Thérèse; Rouillard, Claude
    Neuroprotection by 17β-estradiol and an estrogen receptor (ER) agonist against 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) lesion were shown to implicate protein kinase B (Akt) signaling in mice. In order to evaluate the associated mechanisms, this study compared estrogen receptor alpha (ERα) and estrogen receptor beta (ERβ) intact or knockout (KO) and wild-type (WT) C57Bl/6 male mice following MPTP treatment of 7, 9, 11 mg/kg and/or 17β-estradiol. Striatal D1 and D2 dopamine (DA) receptors were measured by autoradiography with the specific ligands [3H]-SCH 23390 and [3H]-raclopride, respectively and signaling by Western blot for Akt, glycogen synthase kinase 3β (GSK3β) and extracellular-regulated signal kinases (ERK1 and ERK2). Control ERKOβ mice had lower striatal [3H]-SCH 23390 specific binding than WT and ERKOα mice; both KO mice had lower [3H]-raclopride specific binding. Striatal D1 receptors decreased with increasing doses of MPTP in correlation with striatal DA concentrations in ERKOα mice and remained unchanged in WT and ERKOβ mice. Striatal D2 receptors decreased with increasing doses of MPTP in correlation with striatal DA concentrations in WT and ERKOα mice and increased in ERKOβ mice. In MPTP-lesioned mice, 17β-estradiol treatment increased D1 receptors in ERKOα and ERKOβ mice and D2 receptors in WT and ERKOβ mice. MPTP did not affect striatal pAkt/Akt and pGSK3β/GSK3β levels in WT and ERKOα mice, while in vehicle-treated ERKOβ mice these levels were higher and increased with MPTP lesioning. Striatal pERK1/ERK1 and pERK2/ERK2 levels showed to a lesser extent a similar pattern. In conclusion, ERs affected the response of striatal DA receptors to a MPTP lesion and post receptor signaling.
  • Publication
    Cystamine prevents MPTP-induced toxicity in young adult mice via the up-regulation of the brain-derived neurotrophic factor
    (Elsevier, 2009-11-11) Bousquet, Mélanie; Calon, Frédéric; Gibrat, Claire; Saint-Pierre, Martine; Lévesque, Daniel; Rouillard, Claude; Cicchetti, Francesca
    Preclinical data suggest that cystamine stands as a promising neuroprotective agent against Huntington's and Parkinson's diseases. To decipher the mechanisms of action of cystamine, we investigated the effects of various doses of cystamine (10, 50, and 200 mg/kg) on the regulation of the brain-derived neurotrophic factor (BDNF), its receptor tropomyosin-receptor-kinase B (TrkB) and on the heat shock protein 70 (Hsp70) brain mRNA expression in relation to the time after administration. We have determined that the lower cystamine dose is the most efficient to promote putative neuroprotective effects. Indeed, an acute administration of 10 mg/kg of cystamine increased the expression of BDNF mRNA in the substantia nigra compacta (SNc), although it did not significantly influence TrkB or Hsp70 mRNA. Higher cystamine doses resulted in the absence of activation of any of these markers or led to non-specific effects. We have also substantiated the neuroprotective effect of a 21-day treatment of 10 mg/kg/day of cystamine in young adult mice against MPTP-induced loss of tyrosine hydroxylase-striatal fiber density, nigral dopamine cells and nigral Nurr1 mRNA expression. The neuroprotective action of cystamine in the same animals was associated with an up-regulation of BDNF in the SNc. Taken together, these results strengthen the neuroprotective potential of cystamine in the treatment of Parkinson's disease and point towards the up-regulation of BDNF as an important mechanism of action.
  • Publication
    Accès libre
    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
    (American Society for Pharmacology and Experimental Therapeutics, 2004-12-22) Maheux, Jérôme; Lévesque, Daniel; Éthier, Isabelle.; Rouillard, Claude
    Monitoring gene expression has been intensively used to identify neurobiological and neuroanatomical substrates associated with administration of antipsychotic drugs. Transcription factors of the Nur family (Nurr1, Nur77, and Nor-1) are orphan nuclear receptors that have been recently associated with dopamine neurotransmission. Nurr1 is involved in midbrain dopamine neuron development. Nur77 and Nor-1 are expressed in dopaminoceptive areas such as the striatum, nucleus accumbens, and prefrontal cortex. To better understand the relationship between Nur and antipsychotic drug effects, we conducted a comprehensive evaluation of the effect of various typical and atypical antipsychotic drugs on the modulation of Nur mRNA levels. We show that differential patterns of Nur expression can be obtained with typical and atypical antipsychotic drugs. Modulation of Nur77 and Nor-1 mRNA expression by antipsychotics can be used to calculate an index that is predictive of the typical or atypical profile of antipsychotic drugs. Inductions of Nur by anti-psychotic drugs are correlated with dopamine D2 receptor in the striatum and D2 and D3 receptor subtypes in the nucleus accumbens. The 5-hydroxytryptamine 2A/D2 affinity ratio of antipsychotics can also predict these patterns of inductions. In addition to classical gene patterns induced in the striatal complex (striatum, accumbens) and cortex, most antipsychotic drugs tested strongly induced Nur77, Nor-1, and increased Nurr1 mRNA levels in the substantia nigra and ventral tegmental area. These data suggest that typical and atypical antipsychotic drugs might induce in multiple brain regions distinct Nur-dependent transcriptional activities, which may contribute to their pharmacological effects.
  • Publication
    NR4A orphan nuclear receptors in glucose homeostasis : a minireview
    (Elsevier Masson, 2013-09-26) Close, Anne-Françoise; Rouillard, Claude; Buteau, Jean
    Type 2 diabetes mellitus is a disorder characterized by insulin resistance and a relative deficit in insulin secretion, both of which result in elevated blood glucose. Understanding the molecular mechanisms underlying the pathophysiology of diabetes could lead to the development of new therapeutic approaches. An ever-growing body of evidence suggests that members of the NR4A family of nuclear receptors could play a pivotal role in glucose homeostasis. This review aims to present and discuss advances so far in the evaluation of the potential role of NR4A in the regulation of glucose homeostasis and the development of type 2 diabetes.
  • Publication
    Extracellular signal-regulated kinases (ERK) and protein kinase C (PKC) activities are involved in the modulation of Nur77 and Nor-1 expression by dopaminergic drugs
    (Raven Press, 2008-07-04) Bourhis, Emmanuelle; Maheux, Jérôme; Lévesque, Daniel; Rouillard, Claude
    The dopamine system is the main target of antipsychotic and psychostimulant drugs. These drugs induce intracellular events that culminate in the transcription of immediate early genes, such as c-fos. Another class of transcription factors, namely, the nuclear receptor subgroup called Nurs (Nur77, Nurr1 and Nor-1), has recently been associated with behavioral and biochemical effects mediated by dopamine. However, the signaling cascade leading to modulation of Nur mRNA levels in the brain has never been investigated. In the present study, we explore in vivo using specific kinase inhibitors the role of mitogen-associated and extracellular signal-regulated kinases (MEK) and protein kinase C (PKC) in the modulation of Nur expression induced by dopamine receptor drugs. Modulation of Nur77 expression by a dopamine D2 receptor antagonist is associated with MEK and PKC activities, whereas only the PKC activity participates in the modulation of Nor-1 expression. Both MEK and PKC activities also participate in the modulation of Nur77 mRNA levels induced by dopamine receptor agonists, whereas a selective MEK activity is associated with the modulation of Nor-1 mRNA levels. Interestingly, modulation of dopamine drug-induced locomotor activities by kinase inhibitors is in accordance with the effects on Nur77, but not Nor-1, expression. Taken together, the results indicate that signaling events leading to modulation of Nur77 and Nor-1 expression following dopamine receptor interacting drugs are distinct. Considering that orphan nuclear receptors of the Nur subgroup display an important ligand-independent constitutive activity, characterization of the signaling cascades involved in the regulation of their expression represents an important step for understanding their role in dopamine system physiology and pathophysiology.