Time course of striatal ΔFosB‐like immunoreactivity and prodynorphin mRNA levels after discontinuation of chronic dopaminomimetic treatment

Andersson, Malin; Westin, Jenny E.; Cenci, M. Angela

doi:10.1046/j.1460-9568.2003.02469.x

Cited by 74 publications

(54 citation statements)

References 21 publications

(32 reference statements)

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“…Our laboratory and others have noted FosB expression in the denervated striatum of dyskinetic animals (2,3,20,24). DA-and cAMP-regulated phosphoprotein of 32 kDa (DARPP-32) is also involved in DA-stimulated signal transduction and DARPP-32 knockout mice have significantly attenuated LID (4).…”

Section: Resultsmentioning

confidence: 99%

Enhanced striatal cholinergic neuronal activity mediatesl-DOPA–induced dyskinesia in parkinsonian mice

Ding¹,

Won²,

Britt

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

172

192

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Treatment of Parkinson disease (PD) with L-3,4-dihydroxyphenylalanine (L-DOPA) dramatically relieves associated motor deficits, but L-DOPA-induced dyskinesias (LID) limit the therapeutic benefit over time. Previous investigations have noted changes in striatal medium spiny neurons, including abnormal activation of extracellular signal-regulated kinase1/2 (ERK). Using two PD models, the traditional 6-hydroxydopamine toxic lesion and a genetic model with nigrostriatal dopaminergic deficits, we found that acute dopamine challenge induces ERK activation in medium spiny neurons in denervated striatum. After repeated L-DOPA treatment, however, ERK activation diminishes in medium spiny neurons and increases in striatal cholinergic interneurons. ERK activation leads to enhanced basal firing rate and stronger excitatory responses to dopamine in striatal cholinergic neurons. Pharmacological blockers of ERK activation inhibit L-DOPA-induced changes in ERK phosphorylation, neuronal excitability, and the behavioral manifestation of LID. In addition, a muscarinic receptor antagonist reduces LID. These data indicate that increased dopamine sensitivity of striatal cholinergic neurons contributes to the expression of LID, which suggests novel therapeutic targets for LID.antagonist D opaminergic drugs are effective treatments for the motor symptoms of Parkinson disease (PD), but long-term therapy is limited by disabling abnormal involuntary movements, referred to as L-DOPA-induced dyskinesias (LID) (1). Thus, understanding the molecular and cellular mechanisms underlying LID will help identify more effective treatments for PD, and may also help elucidate the role of dopamine (DA) signaling in motor control.Several biochemical markers of LID have been studied in striatum using animal models. FosB/δFosB expression show a long-term temporal correlation with LID development in DA denervation PD models (2). The increased FosB expression persists over days or weeks and may contribute to the development of LID, but does not correlate with the L-DOPA-induced episodes of dyskinesia that follow each dose. To mediate expression of LID directly, cell signals should grow stronger with repeated L-DOPA treatment and show temporal correlation with acute dopaminergic stimulation. Acute administration of L-DOPA or dopamine agonists activates ERK1/2 by phosphorylation in striatal neurons of DA-denervated animals (3-7). In animals with unilateral 6-hydroxydopamine (6-OHDA) lesions, coadministration of inhibitors of ERK1/2 phosphorylation during repeated L-DOPA treatments reduce LID development (4,8). Studies on these molecular changes have focused on the predominant cell type in the striatum, medium spiny neurons (MSN). In addition, although the unilateral 6-OHDA lesion has been the standard model for the PD phenotype, and particularly for LID, the abrupt nature of the lesion and extreme depletion of dopaminergic afferents has posed limitations in behavioral and biochemical studies.In this study, we used both a unilateral 6-OHDA lesion model and a g...

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Section: Resultsmentioning

confidence: 99%

Enhanced striatal cholinergic neuronal activity mediatesl-DOPA–induced dyskinesia in parkinsonian mice

Ding¹,

Won²,

Britt

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

172

192

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“…⌬FosB is induced to high levels in a region-specific manner in brain after chronic, but not acute, exposure to a variety of psychoactive stimuli, including stress, certain lesions, antipsychotic and antidepressant drugs, drugs of abuse, and natural rewards (Hope et al, 1994b;Hiroi and Graybiel, 1996;Moratalla et al, 1996;Bing et al, 1997;Mandelzys et al, 1997;Kelz et al, 1999;Werme et al, 2002;Andersson et al, 2003;Colby et al, 2003;Peakman et al, 2003;Perrotti et al, 2004;Zachariou et al, 2006).…”

Section: Introductionmentioning

confidence: 99%

Regulation of ΔFosB Stability by Phosphorylation

Ulery¹,

Rudenko²,

Nestler³

2006

J. Neurosci.

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The transcription factor ⌬FosB (also referred to as FosB2 or FosB[short form]) is an important mediator of the long-term plasticity induced in brain by chronic exposure to several types of psychoactive stimuli, including drugs of abuse, stress, and electroconvulsive seizures. A distinct feature of ⌬FosB is that, once induced, it persists in brain for relatively long periods of time in the absence of further stimulation. The mechanisms underlying this apparent stability, however, have remained unknown. Here, we demonstrate that ⌬FosB is a relatively stable transcription factor, with a half-life of ϳ10 h in cell culture. Furthermore, we show that ⌬FosB is a phosphoprotein in brain and that phosphorylation of a highly conserved serine residue (Ser27) in ⌬FosB protects it from proteasomal degradation. We provide several lines of evidence suggesting that this phosphorylation is mediated by casein kinase 2. These findings constitute the first evidence that ⌬FosB is phosphorylated and demonstrate that phosphorylation contributes to its stability, which is at the core of its ability to mediate long-lasting adaptations in brain.

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“…As a marker of short-term molecular changes induced by L-DOPA, we examined the striatal phosphorylation of extracellular signal-regulated kinase (ERK) 1/2 and mitogen-and stress-activated kinase (MSK)-1, which is transiently induced by L-DOPA after each dose administration in both acute and chronic treatment regimens (Westin et al, 2007). As a marker of long-lasting molecular changes, we examined the up-regulation of prodynorphin (PDyn) mRNA in the striatum, which remains elevated during at least 16 days after discontinuation of chronic L-DOPA treatment (Andersson et al, 2003).…”

mentioning

confidence: 99%

Pharmacological Modulation of Glutamate Transmission in a Rat Model of l-DOPA-Induced Dyskinesia: Effects on Motor Behavior and Striatal Nuclear Signaling

Rylander

Recchia²,

Mela³

et al. 2009

J Pharmacol Exp Ther

158

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L-DOPA-induced dyskinesia (LID) in Parkinson's disease has been linked to altered dopamine and glutamate transmission within the basal ganglia. In the present study, we compared compounds targeting specific subtypes of glutamate receptors or calcium channels for their ability to attenuate LID and the associated activation of striatal nuclear signaling and gene expression in the rat. Rats with 6-hydroxydopamine lesions were treated acutely or chronically with L-DOPA in combination with the following selective compounds: antagonists of group I metabotropic glutamate receptors (mGluR), (2-methyl-1,3-thiazol-4-yl) ethynylpyridine (MTEP) for mGluR5 and (3-ethyl-2-methyl-quinolin-6-yl)-(4-methoxy-cyclohexyl)-methanone methane sulfonate (EMQMCM) for mGluR1; an agonist of group II mGluR, 1R,4R,5S,6R-2-oxa-4-aminobicyclo[3.; and an L-type calcium channel antagonist, 4-(4-benzofurazanyl)-1,-4-dihydro-2,6-dimethyl-3,5-pyridinedicarboxylic acid methyl 1-methylethyl ester (isradipine). Dyskinesia and rotarod performance were monitored during chronic drug treatment. The striatal expression of phospho-extracellular signal-regulated kinase (ERK) 1/2 and mitogen-and stress-activated kinase (MSK)-1, or prodynorphin mRNA was examined after acute or chronic treatment, respectively. In the acute treatment studies, only MTEP and EMQMCM significantly attenuated L-DOPA-induced phospho-ERK1/2 and/or phospho-MSK-1 expression, with MTEP being the most effective (70 -80% reduction). In the chronic experiment, only MTEP significantly attenuated dyskinesia without adverse motor effects, whereas EMQMCM and LY379268 inhibited the L-DOPA-induced improvement in rotarod performance. The NR2B antagonist had positive antiakinetic effects but did not reduce dyskinesia. Only MTEP blocked the up-regulation of prodynorphin mRNA induced by L-DOPA. Among the pharmacological treatments examined, MTEP was most effective in inhibiting LID and the associated molecular alterations. Antagonism of mGluR5 seems to be a promising strategy to reduce dyskinesia in Parkinson's disease.

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Time course of striatal ΔFosB‐like immunoreactivity and prodynorphin mRNA levels after discontinuation of chronic dopaminomimetic treatment

Cited by 74 publications

References 21 publications

Enhanced striatal cholinergic neuronal activity mediatesl-DOPA–induced dyskinesia in parkinsonian mice

Enhanced striatal cholinergic neuronal activity mediatesl-DOPA–induced dyskinesia in parkinsonian mice

Regulation of ΔFosB Stability by Phosphorylation

Pharmacological Modulation of Glutamate Transmission in a Rat Model of l-DOPA-Induced Dyskinesia: Effects on Motor Behavior and Striatal Nuclear Signaling

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