Denervation and repeated l-DOPA induce a coordinate expression of the transcription factor NGFI-B in striatal projection pathways in hemi-parkinsonian rats

doi:10.1016/S0969-9961(03)00081-0

Neurobiology of Disease

Volume 14, Issue 1, October 2003, Pages 98-109

https://doi.org/10.1016/S0969-9961(03)00081-0 Get rights and content

Abstract

Repeated intermittent administration of l-DOPA in rats with a unilateral 6-hydroxydopamine (6-OHDA) lesion of the nigrostriatal pathway results in a progressive increase of contraversive circling behavior. In this study, we have investigated the effects of denervation and repeated l-DOPA administration on the expression of the nuclear receptor nerve growth factor inducible-B (NGFI-B) in striatal output pathways of unilaterally 6-OHDA-lesioned rats. The denervation process induced an increase of NGFI-B and enkephalin (ENK) mRNA levels and the increase of NGFI-B took place predominantly in ENK-containing cells. The percentage of cells colocalizing NGFI-B and dynorphin (DYN) was significantly reduced. Repeated l-DOPA treatment increased the striatal level of DYN mRNA but it further reduced the percentage of NGFI-B/DYN double-labeled cells. On the intact side, repeated l-DOPA treatment increased NGFI-B expression in both striatal subpopulations. Additional acute studies were performed in normal rats to determine the role of the denervation process in the coordinate expression of NGFI-B in striatal subpopulations. A combination of selective D₁ and D₂ agonists induced an important increase of striatal NGFI-B expression selectively in DYN-containing neurons. These results demonstrate that the denervation process causes a differential regulation of NGFI-B in the two striatal output pathways which is further exacerbated by l-DOPA treatment. These molecular changes in response to dopamine depletion and dopamine replacement therapy may contribute to the long-term effects of l-DOPA and to the development of behavioral sensitization.

Section snippets

Animals

Male Sprague–Dawley albino rats (Charles River, Montréal, Canada) weighing 225–250 g at the beginning of the experiment were used in this study. They were housed two per cage in a temperature-controlled environment maintained under a 12-h light/dark cycle with ad libitum access to food and water. Handling of the rats was performed in accordance with the Canadian Guide for the Care and Use of Laboratory animals and all procedures were approved by the Institutional Animal Care Committee of Laval

Increased rotational behavior induced by repeated l-DOPA administration

Unilaterally 6-OHDA-lesioned rats were injected twice a day for 10 days with l-DOPA and the rotational behavior was measured after the 1st, 4th, 8th, 10th, 12th, 16th, and 20th injections. Repeated treatment with l-DOPA produced a progressive increase of the rotational behavior (Fig. 1). The mean number of contralateral rotations increased from 190 ± 73 at the 1st injection to 615 ± 191 at the 20th injection (n = 5).

Striatal NGFI-B mRNA expression after denervation and repeated l-DOPA treatment

Unilateral removal of dopamine afferences induced an upregulation of NGFI-B

Discussion

The main objective of this study was to investigate the effects of denervation and repeated l-DOPA administration on the expression of the transcription factor NGFI-B and on its coordinate expression with striatal neuropeptides belonging to the direct and indirect striatal output pathways. The main finding of our study is the demonstration that the denervation process causes a differential regulation of NGFI-B in the two striatal output pathways and that this differential regulation is not

Acknowledgements

This work was supported by a grant from the Parkinson Society of Canada (to C.R. and D.L). D.L. is the recipient of a scholarship from Fonds de la Recherche en Santé du Québec. We thank Drs. Guy Drolet, Paul Bédard, and Francesca Cicchetti for their helpful discussions.

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The mechanisms underlying psychostimulant drug-induced sensitization include long-term cellular and molecular adaptations in dopaminergic circuits. Nur77, a member of the Nur family of transcription factors, is expressed in brain regions receiving dopamine inputs and plays a role in activity-induced synaptic modification. Here we evaluated changes in Nur77 mRNA levels in the medial prefrontal cortex (mPFC), dorsal striatum (Str) and nucleus accumbens (NAc) of rats receiving a repeated, sensitizing regimen of amphetamine (AMPH). Results were compared to two groups of controls – animals receiving repeated injections of saline (Rp-SAL) or with no treatment (CON). Two weeks after the last injection, the effect of an acute challenge dose of AMPH on Nur77 expression was evaluated using in-situ hybridization. Repeated AMPH treatment (Rp-AMPH) increased the levels of Nur77 mRNA in the mPFC, NAc core and shell regions. However, the effects of an acute injection of AMPH in each of the three groups of animals was distinct. Whereas an acute AMPH led to a significant increase of Nur77 in all brain regions of the CON animals, it had no significant effect in Rp-SAL animals. Interestingly, in acute AMPH-injected Rp-AMPH animals, Nur77 mRNA levels in the mPFC, Str and NAc regions were significantly lower compared to CON and Rp-SAL animals treated with acute AMPH. There was a positive correlation between AMPH -induced locomotor activity and Nur77 mRNA expression in CON animals; however, this relationship was absent in Rp-SAL and Rp-AMPH animals. The data suggest that Nur77 is a part of neuroadaptive changes caused by either mild stress of repeated injections as well as AMPH-sensitization and may play a role in abnormal behaviors induced by the drug.
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Citation Excerpt :
Then, rats were repeatedly treated with l-Dopa/benzerazide (6.25 mg/kg/10 mg/kg, i.p.) once a day for 21 consecutive days or as indicated. The circling behavior was measured as previously described (St-Hilaire et al., 2003). It was measured after the 1st, 5th, 10th, 15th, and 20th injections.
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.
BN82451 attenuates l-dopa-induced dyskinesia in 6-OHDA-lesioned rat model of Parkinson's disease
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The development of l-dopa-induced dyskinesia (LID) remains a major problem in the long-term treatment of Parkinson’s disease (PD). This study aimed to assess the effect of the multitargeting molecule BN82451 on LID and to measure striatal mRNA expression of several genes in a rat model of PD.
Rats were administered two unilateral injections of 6-OHDA in the striatum. After four weeks, the animals started a chronic daily treatment with increasing doses of l-dopa over a further four-week period. Over the course of l-dopa treatment, the rats developed abnormal involuntary movements (AIMs) classified as locomotive, axial, orolingual and forelimb dyskinesia.
In animals rendered dyskinetic by l-dopa, administration of BN82451 at doses ranging from 1 to 10 mg/kg p.o. attenuated the severity of fully-established AIMs in a dose-related manner. This anti-dyskinetic effect could be achieved with lower doses of BN82451 administered sub chronically vs. acute single treatment. The improvement of AIMs is not due to a reduction in the general motor activity of dyskinetic rats. BN82451 treatment significantly reversed the overexpression of c-Fos, FosB and Arc mRNA associated with the dyskinesiogenic action of l-dopa. A significant correlation between the degree of overexpression of c-Fos, FosB and Arc mRNA and the dyskinesiogenic action of l-dopa was observed. The data demonstrate that BN82451 effectively attenuates LID and the associated molecular alterations in an animal model of PD and may represent a treatment option for managing dyskinesia.
MEF-2 regulates activity-dependent spine loss in striatopallidal medium spiny neurons
2010, Molecular and Cellular Neuroscience
Striatal dopamine depletion profoundly reduces the density of spines and corticostriatal glutamatergic synapses formed on D₂ dopamine receptor expressing striatopallidal medium spiny neurons, leaving D₁ receptor expressing striatonigral medium spiny neurons relatively intact. Because D₂ dopamine receptors diminish the excitability of striatopallidal MSNs, the pruning of synapses could be a form of homeostatic plasticity aimed at restoring activity into a preferred range. To characterize the homeostatic mechanisms controlling synapse density in striatal medium spiny neurons, striatum from transgenic mice expressing a D₂ receptor reporter construct was co-cultured with wild-type cerebral cortex. Sustained depolarization of these co-cultures induced a profound pruning of glutamatergic synapses and spines in striatopallidal medium spiny neurons. This pruning was dependent upon Ca²⁺ entry through Cav1.2 L-type Ca²⁺ channels, activation of the Ca²⁺-dependent protein phosphatase calcineurin and up-regulation of myocyte enhancer factor 2 (MEF2) transcriptional activity. Depolarization and MEF2 up-regulation increased the expression of two genes linked to synaptic remodeling—Nur77 and Arc. Taken together, these studies establish a translational framework within which striatal adaptations linked to the symptoms of Parkinson's disease can be explored.
Effect of non-dopaminergic drug treatment on Levodopa induced dyskinesias in MPTP monkeys: Common implication of striatal neuropeptides
2010, Neuropharmacology
Dopamine denervation in Parkinson's disease and repeated Levodopa (L-DOPA) administration that induces dyskinesias are associated with an enhancement of basal ganglia neuropeptide transmission. Various adjunct non-dopaminergic treatments to Levodopa were shown to reduce and/or prevent dyskinesias. The aim of this study was to seek if non-dopaminergic drug treatments to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) lesioned monkeys combined with L-DOPA to prevent dyskinesia were associated with changes of striatal neuropeptides. Chronic treatment with Ro 61-8048 a kynurenine hydroxylase inhibitor, docosahexaenoic acid (DHA) a polyunsaturated fatty acid (omega-3), naltrexone an opioidergic antagonist and CI-1041 an N-methyl-d-aspartate (NMDA) glutamate receptor antagonist with L-DOPA prevented dyskinesias to various extents except naltrexone whereas all MPTP monkeys treated with L-DOPA alone developed dyskinesias. Striatal preproenkephalin (PPE), preprodynorphin (PPD) and preprotachykinin A (PPT-A) mRNA levels were measured by in situ hybridization. An increase of PPE and PPD mRNA levels was observed in anterior caudate nucleus of L-DOPA treated MPTP monkeys compared to controls and to Saline-treated MPTP monkeys whereas PPT-A mRNA levels were unchanged. Striatal PPE and PPD mRNA levels remained elevated in L-DOPA plus naltrexone-treated MPTP monkeys, while co-treatment with DHA, CI-1041 or Ro 61-8048 prevented their increase to various extents. Maximal dyskinesias scores of MPTP monkeys correlated significantly with striatal PPE and PPD mRNA levels but not with PPT-A mRNA levels. These results show that drugs displaying a wide range of pharmacological activities can modulate L-DOPA induced dyskinesias and this activity is correlated with striatal PPD and PPE mRNA levels suggesting a convergent mechanism.
Nur77 mRNA levels and L-Dopa-induced dyskinesias in MPTP monkeys treated with docosahexaenoic acid
2009, Neurobiology of Disease
Citation Excerpt :
Unilateral denervation induced by local injection of 6-hydroxydopamine (6-OHDA) in rats produces a complex regulation of Nur77 in the striatum (St-Hilaire et al., 2005, 2003). The expression of Nur77 transcripts is selectively up-regulated in enkephalin (ENK)-containing cells of the indirect striatal output pathway, whereas Nur77 expression is reduced in dynorphin (DYN)-positive cells of the direct output pathway in the denervated striatum (St-Hilaire et al., 2005, 2003). Interestingly, subsequent chronic L-DOPA treatment further reduced Nur77 expression in DYN-positive cells in specific striatal areas, whereas it strongly increased Nur77 mRNA levels in this same cell subpopulation in the non-denervated striatum (St-Hilaire et al., 2005, 2003).
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.

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Regular articleDenervation and repeated l-DOPA induce a coordinate expression of the transcription factor NGFI-B in striatal projection pathways in hemi-parkinsonian rats

Abstract

Section snippets

Animals

Increased rotational behavior induced by repeated l-DOPA administration

Striatal NGFI-B mRNA expression after denervation and repeated l-DOPA treatment

Discussion

Acknowledgements

Neurobiol. Dis.

Brain Res.

Trends Neurosci.

Mol. Brain Res.

Trends Neurosci.

Neuroscience

Mol. Brain Res.

Neuroscience

Neuropharmacology

Eur. J. Pharmacol.

Biochem. Biophys. Res. Commun.

Neuroscience

Neuroscience

J Biol. Chem.

Mol. Brain Res.

cAMP response element-binding protein is required for dopamine-dependent gene expression in the intact but not the dopamine-denervated striatum

J. Neurosci.

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.

Regular article
Denervation and repeated l-DOPA induce a coordinate expression of the transcription factor NGFI-B in striatal projection pathways in hemi-parkinsonian rats