The orphan nuclear receptor Nor1/Nr4a3 is a negative regulator of ß-cell mass.

The Nr4a subfamily of nuclear receptor comprises three members in mammalian cells: Nur77/Nr4a1, Nurr1/Nr4a2, and Nor1/Nr4a3. Nr4a proteins play key roles in the regulation of glucose homeostasis in peripheral metabolic tissues. However, their biological functions in ß-cells remain relatively uncharacterized. Here we sought to investigate the potential role of Nor1 in the regulation of ß-cell mass and, in particular, ß-cell survival/apoptosis. We used histological analysis to examine the consequences of genetic deletion of either Nur77 and Nor1 on ß-cell mass, investigated the expression patterns of Nr4as in human islets and INS cells and performed gain- and loss-of-function experiments to further characterize the role of Nor1 in ß-cell apoptosis. Surprisingly, Nor1 knockout mice displayed increased ß-cell mass, whereas mice with genetic deletion of Nur77 did not exhibit any significant differences compared with their WT littermates. The increase in ß-cell mass in Nor1 knockout mice was accompanied by improved glucose tolerance. A gene expression study performed in both human islets and INS cells revealed that Nor1 expression is significantly increased by pro-inflammatory cytokines and, to a lesser extent, by elevated concentrations of glucose. Nor1 overexpression in both INS and human islet cells caused apoptosis, whereas siRNA-mediated Nor1 knockdown prevented cytokine-induced ß-cell death. Finally, Nor1 expression was up-regulated in islets of individuals with type 2 diabetes. Altogether, our results uncover that Nor1 negatively regulates ß-cell mass. Nor1 represents a promising molecular target in diabetes treatment to prevent ß-cell destruction.

The highly selective mGlu2 receptor positive allosteric modulator LY-487,379 alleviates l-DOPA-induced dyskinesia in the 6-OHDA-lesioned rat model of Parkinson's disease.

l-3,4-Dihydroxyphenylalanine (l-DOPA) is the most effective treatment for Parkinson's disease (PD), but its use over a long period is marred by motors complications such as dyskinesia. We previously demonstrated that selective metabotropic glutamate 2/3 (mGlu2/3 ) receptor activation with LY-354,740 alleviates dyskinesia in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned marmoset and the 6-hydroxydopamine (6-OHDA)-lesioned rat. Here, we sought to determine the role played by selective mGlu2 activation in the anti-dyskinetic effect of mGlu2/3 stimulation and have investigated the effect of the highly selective mGlu2 positive allosteric modulator LY-487,379 at alleviating established, and preventing the development of, l-DOPA-induced dyskinesia in the 6-OHDA-lesioned rat. First, dyskinetic 6-OHDA-lesioned rats were administered l-DOPA in combination with LY-487,379 (0.1, 1 and 10 mg/kg) or vehicle, and the severity of dyskinesia was determined. Second, 6-OHDA-lesioned rats were administered LY-487,379 (0.1 or 1 mg/kg), started concurrently with l-DOPA, once daily for 22 days, and dyskinesia severity was evaluated weekly for four consecutive weeks. We also assessed the effect of LY-487,379 on l-DOPA anti-parkinsonian effect. We found that acute challenges of LY-487,379 0.1 mg/kg in combination with l-DOPA, significantly diminished dyskinesia severity, by ≈54% (p < .01), when compared to vehicle. Moreover, animals treated with l-DOPA/LY-487,379 0.1 and 1 mg/kg during the dyskinesia induction phase exhibited milder dyskinesia, by ≈74% and ≈61%, respectively (both p < .01), when compared to l-DOPA/vehicle. LY-487,379 did not impair l-DOPA anti-parkinsonian activity. These results suggest that mGlu2 activation may be an effective and promising therapeutic strategy to alleviate the severity and prevent the development of dyskinesia.

The Stress-Induced Transcription Factor NR4A1 Adjusts Mitochondrial Function and Synapse Number in Prefrontal Cortex.

The energetic costs of behavioral chronic stress are unlikely to be sustainable without neuronal plasticity. Mitochondria have the capacity to handle synaptic activity up to a limit before energetic depletion occurs. Protective mechanisms driven by the induction of neuronal genes likely evolved to buffer the consequences of chronic stress on excitatory neurons in prefrontal cortex (PFC), as this circuitry is vulnerable to excitotoxic insults. Little is known about the genes involved in mitochondrial adaptation to the buildup of chronic stress. Using combinations of genetic manipulations and stress for analyzing structural, transcriptional, mitochondrial, and behavioral outcomes, we characterized NR4A1 as a stress-inducible modifier of mitochondrial energetic competence and dendritic spine number in PFC. NR4A1 acted as a transcription factor for changing the expression of target genes previously involved in mitochondrial uncoupling, AMP-activated protein kinase activation, and synaptic growth. Maintenance of NR4A1 activity by chronic stress played a critical role in the regressive synaptic organization in PFC of mouse models of stress (male only). Knockdown, dominant-negative approach, and knockout of Nr4a1 in mice and rats (male only) protected pyramidal neurons against the adverse effects of chronic stress. In human PFC tissues of men and women, high levels of the transcriptionally active NR4A1 correlated with measures of synaptic loss and cognitive impairment. In the context of chronic stress, prolonged expression and activity of NR4A1 may lead to responses of mitochondria and synaptic connectivity that do not match environmental demand, resulting in circuit malfunction between PFC and other brain regions, constituting a pathological feature across disorders.SIGNIFICANCE STATEMENT The bioenergetic cost of chronic stress is too high to be sustainable by pyramidal prefrontal neurons. Cellular checkpoints have evolved to adjust the responses of mitochondria and synapses to the buildup of chronic stress. NR4A1 plays such a role by controlling the energetic competence of mitochondria with respect to synapse number. As an immediate-early gene, Nr4a1 promotes neuronal plasticity, but sustained expression or activity can be detrimental. NR4A1 expression and activity is sustained by chronic stress in animal models and in human studies of neuropathologies sensitive to the buildup of chronic stress. Therefore, antagonism of NR4A1 is a promising avenue for preventing the regressive synaptic reorganization in cortical systems in the context of chronic stress.

Modulation of haloperidol-induced patterns of the transcription factor Nur77 and Nor-1 expression by serotonergic and adrenergic drugs in the mouse brain.

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-HT(1A) and 5-HT(2A/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-HT(2A/2C) agonist, MDL11939, a 5-HT(2A) antagonist, 8-OH-DPAT, a 5-HT(1A) agonist, prazosin, an α1-adrenergic antagonist and idazoxan, an α2-adrenergic antagonist, alone or in combination with haloperidol. The 5-HT(2A/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-HT(1A) agonist or a 5-HT(2A) 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.

Brain morphometry in adults with gambling disorder.

Little is known regarding the brain substrates of Gambling Disorder, including surface brain morphometry, and whether these are linked to the clinical profile. A better understanding of the brain substrates will likely help determine targets to treat patients. Hence, the aim of this study was two-fold, that is to examine surface-based morphometry in 17 patients with gambling disorder as compared to norms of healthy individuals (2713 and 2790 subjects for cortical and subcortical anatomical scans, respectively) and to assess the clinical relevance of morphometry in patients with Gambling Disorder. This study measured brain volume, surface and thickness in Gambling Disorder. We compared these measures to those of a normative database that controlled for factors such as age and sex. We also tested for correlations with gambling-related behaviors, such as gambling severity and duration, impulsivity, and depressive symptoms (assessed using the South Oaks Gambling Screen, years of gambling, Barratt Impulsiveness Scale, and Beck Depression Inventory, respectively). Patients displayed thinner prefrontal and parietal cortices, greater volume and thickness of the occipital and the entorhinal cortices, and greater volume of subcortical regions as compared to the norms of healthy individuals. There were positive correlations between surface area of occipital regions and depressive symptoms. This work contributes to better characterize the brain substrates of Gambling Disorder, which appear to resemble those of substance use disorders and Internet Gaming Disorder.

Concurrent Transcranial Direct Current Stimulation and Resting-State Functional Magnetic Resonance Imaging in Patients with Gambling Disorder.

Background/Introduction: Transcranial direct current stimulation (tDCS) delivered over the dorsolateral prefrontal cortex (DLPFC) while patients are at rest can decrease craving in patients with substance-related and addictive disorders. Yet, the effects of tDCS on resting-state brain activity remain unknown in this population. This study examined the effects of tDCS on resting-state functional connectivity (rsFC) with concurrent stimulation and functional magnetic resonance imaging in patients with gambling disorder. Methods: This was a randomized, sham-controlled, double-blind, crossover study. The anodal and cathodal electrodes were applied over the right and left DLPFC, respectively. Patients received 30 min of active and sham stimulation on separate days. rsFC was assessed before and during stimulation with seed-based analyses. Results: There was a significant increase of rsFC between the right DLPFC seed and the right superior parietal lobule during active stimulation as compared to during sham stimulation (p = 0.0059, corrected for multiple comparisons). There was also a positive correlation between rsFC change of this frontoparietal network and brain volume of the right DLPFC (p = 0.0042, corrected for multiple comparisons). Discussion: A single session of tDCS targeting the DLPFC strengthened functional connectivity in a frontoparietal circuit, known to be implicated in cognitive control, especially in patients with a greater volume of the region under the anode electrode. Impact statement Transcranial direct current stimulation increased the functional connectivity of a frontoparietal circuit in patients with gambling disorder. These changes were larger in patients with greater volume of the dorsolateral prefrontal cortex. Transcranial direct current stimulation strengthened the connectivity of a brain network known to be associated with cognitive control.

Nurr1 is required for maintenance of maturing and adult midbrain dopamine neurons.

Transcription factors involved in the specification and differentiation of neurons often continue to be expressed in the adult brain, but remarkably little is known about their late functions. Nurr1, one such transcription factor, is essential for early differentiation of midbrain dopamine (mDA) neurons but continues to be expressed into adulthood. In Parkinson's disease, Nurr1 expression is diminished and mutations in the Nurr1 gene have been identified in rare cases of disease; however, the significance of these observations remains unclear. Here, a mouse strain for conditional targeting of the Nurr1 gene was generated, and Nurr1 was ablated either at late stages of mDA neuron development by crossing with mice carrying Cre under control of the dopamine transporter locus or in the adult brain by transduction of adeno-associated virus Cre-encoding vectors. Nurr1 deficiency in maturing mDA neurons resulted in rapid loss of striatal DA, loss of mDA neuron markers, and neuron degeneration. In contrast, a more slowly progressing loss of striatal DA and mDA neuron markers was observed after ablation in the adult brain. As in Parkinson's disease, neurons of the substantia nigra compacta were more vulnerable than cells in the ventral tegmental area when Nurr1 was ablated at late embryogenesis. The results show that developmental pathways play key roles for the maintenance of terminally differentiated neurons and suggest that disrupted function of Nurr1 and other developmental transcription factors may contribute to neurodegenerative disease.

Cystamine metabolism and brain transport properties: clinical implications for neurodegenerative diseases.

Cystamine has shown significant neuroprotective properties in preclinical studies of Parkinson's disease (PD) and Huntington's disease (HD). Cysteamine, its FDA-approved reduced form, is scheduled to be tested for clinical efficacy in HD patients. Here, we studied the key cystamine metabolites, namely cysteamine, hypotaurine and taurine, as well as cysteine, in order to identify which one is more distinctively responsible for the neuroprotective action of cystamine. After a single administration of cystamine (10, 50 or 200 mg/kg), naïve mice were perfused with phosphate-buffered saline (PBS) at 1, 3, 12, 24 or 48 h post-injection and brain and plasma samples were analyzed by two distinct HPLC methods. Although plasma levels remained under the detection threshold, significant increases in cysteamine brain levels were detected with the 50 and 200 mg/kg doses in mice perfused 1 and 3 h following cystamine injection. To further assess cysteamine as the candidate molecule for pre-clinical and clinical trials in PD, we evaluated its capacity to cross the blood brain barrier. Using an in situ cerebral perfusion technique, we determined that the brain transport coefficient (Clup) of cysteamine (259 µM) was 0.15 ± 0.02 µL/g/s and was increased up to 0.34 ± 0.07 µL/g/s when co-perfused in the presence of cysteine. Taken together, these results strongly suggest that cysteamine is the neuroactive metabolite of cystamine and may further support its therapeutic use in neurodegenerative diseases, particularly in HD and PD.

Differences between subacute and chronic MPTP mice models: investigation of dopaminergic neuronal degeneration and alpha-synuclein inclusions.

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 alpha-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.

Nur77 mRNA levels and L-Dopa-induced dyskinesias in MPTP monkeys treated with docosahexaenoic acid.

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 gamma1 (RXRgamma1), a putative brain receptor for DHA and transcriptional partner of Nur77, in MPTP monkeys treated with L-Dopa and DHA. The RXRgamma1 mRNA is strongly expressed in monkey caudate nucleus and putamen, but no change in levels of RXRgamma1 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.

Nur77 and retinoid X receptors: crucial factors in dopamine-related neuroadaptation.

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.

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.

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.

Role of spinal 5-HT2 receptor subtypes in quipazine-induced hindlimb movements after a low-thoracic spinal cord transection.

A role of serotonin receptors (5-HTRs) in spinal rhythmogenesis has been proposed several years ago based mainly upon data showing that bath-applied 5-HT could elicit locomotor-like rhythms in in vitro isolated spinal cord preparations. Such a role was partially confirmed in vivo after revealing that systemically administered 5-HTR(2) agonists, such as quipazine, could induce some locomotor-like movements (LM) in completely spinal cord-transected (Tx) rodents. However, given the limited binding selectivity of currently available 5-HTR(2) agonists, it has remained difficult to determine clearly if one receptor subtype is specifically associated with LM induction. In situ hybridization, data using tissues from L1-L2 spinal cord segments, where critical locomotor network elements have been identified in mice, revealed greater 5-HTR(2A) mRNA levels in low-thoracic Tx than non-Tx animals. This expression level remained elevated for several days, specifically in the lateral intermediate zone, where peak values were detected at 1 week post-Tx and returned to normal at 3 weeks post-Tx. Behavioral and kinematic analyses revealed quipazine-induced LM in 1-week Tx mice either non-pretreated or pretreated with selective 5-HTR(2B) and/or 5-HTR(2C) antagonists. In contrast, LM completely failed to be induced by quipazine in animals pretreated with selective 5-HTR(2A) antagonists. Altogether, these results provide strong evidence suggesting that 5-HTR(2A) are specifically associated with spinal locomotor network activation and LM generation induced by quipazine in Tx animals. These findings may contribute to design drug treatments aimed at promoting locomotor function recovery in chronic spinal cord-injured patients.

Membrane cholesterol removal and replenishment affect rat and monkey brain monoamine transporters.

The dopamine transporter (DAT) is abundantly expressed in the striatum where it removes extracellular dopamine into the cytosol of presynaptic nerve terminals. It is the target of drugs of abuse and antidepressants. There is a loss of the DAT in Parkinson's disease affecting release of levodopa implicated in levodopa-induced dyskinesias. This study investigated the effect of cholesterol on DAT, serotonin transporter (SERT) and vesicular monoamine transporter 2 (VMAT2) in monkey and rat brains in vitro. DAT protein levels measured by Western blot remained unchanged with in vitro methyl-ß-cyclodextrin (MCD) incubations to remove membrane cholesterol or with incubations to increase membrane cholesterol content. By contrast, striatal DAT specific binding labelled with [125I]RTI-121 or with [125I]RTI-55 decreased with increasing concentrations of MCD and increased with cholesterol loading. Moreover, [125I]RTI-121 specific binding of striatal membranes depleted of cholesterol with MCD was restored to initial DAT content with addition of cholesterol showing its rapid and reversible effect. By contrast, striatal VMAT2 and SERT specific binding showed no or limited changes by cholesterol manipulations. Similar results were obtained for monkey caudate nucleus, putamen and nucleus accumbens. Membrane microviscosity was assessed by fluorescence polarization spectroscopy, using the probe 1,6-diphenyl-1,3,5-hexatriene. DAT changes positively correlated with changes of membrane microviscosity in rat and monkey brain regions investigated and with membrane cholesterol contents. Similar findings were observed with desmosterol but to a lower extent than with cholesterol. These results show an important effect of cholesterol on the DAT associated with microviscosity changes that should be considered in drug therapies.

Genetic disruption of the nuclear receptor Nur77 (Nr4a1) in rat reduces dopamine cell loss and l-Dopa-induced dyskinesia in experimental Parkinson's disease.

Parkinson's disease (PD) is an idiopathic progressive neurodegenerative disorder characterized by the loss of midbrain dopamine neurons. Levodopa (l-dopa) is the main pharmacological approach to relieve PD motor symptoms. However, chronic treatment with l-Dopa is inevitably associated with the generation of abnormal involuntary movements (l-Dopa-induced dyskinesia). We have previously shown that Nr4a1 (Nur77), a transcription factor of the nuclear receptor family, is closely associated with dopamine neurotransmission in the mature brain. However, the role of Nr4a1 in the etiology of PD and its treatment remain elusive. We report here that the neurotoxin 6-hydroxydopamine in rat lead to a rapid up-regulation of Nr4a1 in the substantia nigra. Genetic disruption of Nr4a1 in rat reduced neurotoxin-induced dopamine cell loss and l-Dopa-induced dyskinesia, whereas virally-driven striatal overexpression of Nr4a1 enhanced or partially restored involuntary movements induced by chronic l-Dopa in wild type and Nr4a1-deficient rats, respectively. Collectively, these results suggest that Nr4a1 is involved in dopamine cell loss and l-Dopa-induced dyskinesia in experimental PD.

Opioids and motor complications in Parkinson's disease.

The long-term treatment of Parkinson's disease with L-dopa is often associated with the appearance of involuntary movements called L-dopa-induced dyskinesias. These debilitating side-effects are thought to result from an aberrant form of plasticity triggered by a combination of factors related to dopamine denervation and repeated L-dopa administration. In animal models of Parkinson's disease, dopamine denervation and repeated L-dopa administration are associated with an enhancement of opioid transmission in the basal ganglia. The exact role of this increased opioid activity is still under debate. It has been proposed that some of the changes in opioid transmission are directly involved in the genesis of L-dopa-induced dyskinesias. In this article, we suggest that changes in opioid transmission in the basal ganglia in response to denervation and repeated L-dopa therapy are, instead, part of compensatory mechanisms to prevent motor complications. Initially, these compensatory mechanisms might be sufficient to attenuate the parkinsonian syndrome and delay the appearance of involuntary movements. But with the progression of the disease and repeated exposure to L-dopa, these mechanisms eventually fail. These new insights could contribute to better understanding of the motor complications in Parkinson's disease and lead to the development or improvement of pharmacological strategies to prevent or reduce L-dopa-induced dyskinesias.

Nur77 gene knockout alters dopamine neuron biochemical activity and dopamine turnover.

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.

Neuroprotective effects of cystamine in aged parkinsonian mice.

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.

Naltrexone in the short-term decreases antiparkinsonian response to l-Dopa and in the long-term increases dyskinesias in drug-naïve parkinsonian monkeys.

Nigrostriatal dopaminergic denervation and levodopa therapy in animal models and in parkinsonian patients are associated with an enhanced opioid transmission in the striatum. The functional role of this increase has always been a subject of debate. In this study two groups of drug-naïve macaque monkeys with MPTP-induced parkinsonism were treated daily, during four weeks, with l-Dopa alone or l-Dopa plus naltrexone, a non-selective opioid receptor antagonist. The improvement of parkinsonism in all animals treated with l-Dopa alone was clearly displayed from the first day of treatment. By contrast, naltrexone co-treatment blocked the antiparkinsonian action of l-Dopa for 7-14 days. As soon as the therapeutical action of l-Dopa appeared in naltrexone-treated monkeys, the magnitude and duration of the antiparkinsonian response were similar in both groups. Furthermore, in animals treated with l-Dopa plus naltrexone the beginning of the therapeutical effect of l-Dopa was accompanied by the appearance of dyskinesias. In this group, the severity of dyskinesias during the third and fourth weeks of treatment was significantly higher than the group treated with l-Dopa alone. The results of the present study demonstrate that in de novo MPTP parkinsonian monkeys antagonizing the action of opioid receptors worsens the motor response to l-Dopa.