Introduction The major substrate underlying amphetamine (AMPH)-induced locomotor activity is associated with dopamine forebrain circuits. Brain regions associated with AMPH-induced locomotor activity express high levels of retinoid receptors. However, the role of these transcription factors in dopamine-mediated effects remains poorly understood. Two nuclear receptor families, the retinoic acid receptors (RAR) and the retinoid X receptors (RXR), transduce retinoic acid signal. RARs are specifically involved in retinoid signaling, whereas RXRs also participate in other signaling pathways as partners for other nuclear receptors such as Nur77 , an orphan member of the nuclear receptor family expresses in dopamine system. Materials and methods To explore the role of retinoid receptors and Nur77 in AMPH-induced locomotor activity, we administered selective retinoid receptor drugs in combination with AMPH in adult wild-type and Nur77 -deficient mice. At a low dose, AMPH similarly increased ambulatory activity in wild-type and Nur77 -deficient mice, while it did not alter non-ambulatory activity. Results and discussion At a high dose, AMPH did not alter ambulatory activity anymore, while non-ambulatory activity strongly increased in wild-type mice. Nur77 -deficient mice still displayed a higher ambulatory activity with no change in non-ambulatory activity. HX531, a synthetic RXR antagonist, blocks AMPH-induced ambulatory activity, whereas RAR drugs tested remained without effect. Interestingly, the effect of HX531 was abolished in Nur77 -deficient mice, suggesting that this orphan nuclear receptor is essential for the action of the RXR drug. Conclusion This study shows that RXR and Nur77 participate in AMPH-induced locomotor activity and prompts for further investigations on the role of Nur77 and RXR in addiction and reward-related behaviors.

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 D-2 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.

Accumulating evidence suggests an important role of oxidation in pathologies such as Parkinson's disease. Here, we investigated the effects of cystamine, which has shown neuroprotection in animal models of Huntington's disease, in a parkinsonian mouse generated by the toxin MPTP. Aged mice (16 months of age) were assigned to either a 10 or 50 mg/kg/day cystamine treatment administered (1) 2 days prior, during and 14 days after MPTP lesioning or (2) beginning on the day of the MPTP lesion and for the subsequent 14 days. Pre-treatment with lower doses of cystamine (10 mg/kg) revealed increased levels of tyrosine hydroxylase (TH) positive striatal fiber (p < 0.01), increased density of TH-immunoreactive cells (p < 0.01), increased substantia nigra Nurr1 mRNA levels (p < 0.001), and increased density of substantia nigra cells expressing the dopamine transporter (p < 0.001) as compared to MPTP treated mice. These results provide strong evidence for neuroprotective properties of cystamine in this animal model of Parkinson's disease.

We have previously shown that dopamine (DA) denervation and repeated L-DOPA treatment modulate the pattern of Nur77 mRNA expression in the striatum. However, the exact role of this nuclear receptor in L-DOPA-induced molecular and behavioural adaptations observed in animal models of Parkinson's disease is still unknown. In the present study, we investigated the effects of Nur77 gene deletion on the development of behavioural sensitization and on changes in the regulation of neuropeptides and DA D(3) receptor expression following DA denervation and repeated L-DOPA treatment in Nur77+/+ and Nur77-/- hemiparkinsonian mice. One week postsurgery, hemiparkinsonian mice were treated with L-DOPA (10 mg/kg) plus benserazide (3 mg/kg) once a day for 7 days. Despite similar extents of nigrostriatal denervation, L-DOPA-induced rotational response was exacerbated in Nur77-/- mice compared to Nur77+/+ ones. However, the rate of increase of the rotational behaviour after repeated L-DOPA injections was similar in the two mouse strains. Lesioning the nigrostriatal pathway increased enkephalin (ENK) and neurotensin (NT) mRNA levels in both mouse strains. However, the up-regulation of these neuropeptides was significantly reduced in Nur77-/- mice. There was no difference in the modulation of D3 receptor density and dynorphin (DYN) mRNA expression between the two mouse strains. The present results suggest that Nur77 is involved in setting the threshold level for L-DOPA-induced rotational behaviour, rather than controlling the development of behavioural sensitization. This specific behavioural change is associated with a selective regulation of neuropeptide expression specifically in the indirect striatal output pathway.