Genetic Inactivation of Dopamine D1 but Not D2 Receptors Inhibits L-DOPA–Induced Dyskinesia and Histone Activation

Darmopil, Sanja; Martín, Ana Belén Barragán; Diego, Irene Ruiz de; Ares, Sara; Moratalla, Rosario

doi:10.1016/j.biopsych.2009.04.025

Cited by 235 publications

(277 citation statements)

References 53 publications

Supporting

Mentioning

256

Contrasting

Unclassified

Order By: Relevance

“…Direct D1R stimulation in the denervated striatum of PD animals activates ERK by phosphorylation (5,35,36). Our data show that L-DOPA-induced ERK activation shifts from being predominantly in MSN to cholinergic interneurons concomitant with behavioral LID expression in both unilateral 6-OHDA lesion and the Pitx3 ak/ak model.…”

Section: Discussionmentioning

confidence: 61%

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

View full text Add to dashboard Cite

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...

show abstract

Section: Discussionmentioning

confidence: 61%

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

View full text Add to dashboard Cite

show abstract

“…We set up this protocol to detect subtle differences between genotypes in the sensitivity to L-dopa that may have been masked by the use of higher drug doses (20,21). Daily scoring of AIMs revealed a gradual development of dyskinesia in both genotypes.…”

Section: Resultsmentioning

confidence: 99%

Inhibition of Ras-guanine nucleotide-releasing factor 1 (Ras-GRF1) signaling in the striatum reverts motor symptoms associated with l -dopa–induced dyskinesia

Fasano

Bézard

D'Antoni

et al. 2010

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

142

154

View full text Add to dashboard Cite

L-dopa-induced dyskinesia (LID) is a common debilitating complication of dopamine replacement therapy in Parkinson's disease. Recent evidence suggests that LID may be linked causally to a hyperactivation of the Ras-ERK signaling cascade in the basal ganglia. We set out to determine whether specific targeting of Ras-guanine nucleotide-releasing factor 1 (Ras-GRF1), a brain-specific activator of the Ras-ERK pathway, may provide a therapy for LID. On the rodent abnormal involuntary movements scale, Ras-GRF1-deficient mice were significantly resistant to the development of dyskinesia during chronic L-dopa treatment. Furthermore, in a nonhuman primate model of LID, lentiviral vectors expressing dominant negative forms of Ras-GRF1 caused a dramatic reversion of dyskinesia severity leaving intact the therapeutic effect of Ldopa. These data reveal the central role of Ras-GRF1 in governing striatal adaptations to dopamine replacement therapy and validate a viable treatment for LID based on intracellular signaling modulation. P arkinson's disease (PD) is a neurodegenerative disorder characterized by a loss of dopaminergic neurons in the substantia nigra pars compacta (SNc) causing dopamine depletion in the striatum, the main input nucleus of the basal ganglia. Dopamine replacement therapy with L-dopa remains the most effective treatment for PD, but its use is associated with motor fluctuations and abnormal involuntary movements (AIMs), termed "L-dopa-induced dyskinesia" (LID), which are doselimiting and potentially disabling (1-3).A key objective for the future treatment of PD is to avoid dyskinesia altogether, but doing so will require an understanding of the molecular mechanisms that are involved. LID is attributed to a sequence of events, largely occurring in the striatum, that include pulsatile stimulation of dopamine D1 receptors, downstream changes in proteins and genes, dendritic alterations, and functional abnormalities in nondopaminergic transmitter systems, all of which concur to modify neuronal firing patterns in the basal ganglia-thalamocortical networks (1-4). Once symptoms have appeared, LID can be triggered easily by a single dose of L-dopa even after several weeks of treatment washout (4). Regulation of striatal gene expression is the likely mechanism underlying neuronal plasticity in LID. The ERK signaling cascade is a key regulator of striatal plasticity and an interesting candidate for drug targeting (5-8). Stimulation of dopamine and glutamate receptors on striatal neurons can switch on the small GTPases of the Ras family, which in turn activate the Raf/Mek/ Erk protein kinase cascade (5-8). Sustained activation of these biochemical pathways leads to synaptic rearrangements requiring de novo gene expression and protein synthesis. Importantly, in neurotoxic models of PD, such as the unilaterally 6-hydroxydopamine (6-OHDA)-lesioned rodent and the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated nonhuman primate (NHP), a supersensitivity of striatal D1 receptors leads to ERK hyperactivation in ...

show abstract

“…Finally, our data suggest that the effect of D1/D5 receptors on the priming effect in the DG may be mediated directly through the regulation of HDAC. Genetic inactivation of dopamine D1 but not D2 receptors inhibits histone acetylation (Darmopil et al 2009). When a D1 receptor agonist is given together with the HDAC inhibitor, the combination enhances cocaine-induced locomotor response and conditioned place preference (Schroeder et al 2008).…”

Section: Discussionmentioning

confidence: 99%

D1/D5 receptors and histone deacetylation mediate the Gateway Effect of LTP in hippocampal dentate gyrus

et al. 2014

View full text Add to dashboard Cite

The dentate gyrus (DG) of the hippocampus is critical for spatial memory and is also thought to be involved in the formation of drug-related associative memory. Here, we attempt to test an aspect of the Gateway Hypothesis, by studying the effect of consecutive exposure to nicotine and cocaine on long-term synaptic potentiation (LTP) in the DG. We find that a single injection of cocaine does not alter LTP. However, pretreatment with nicotine followed by a single injection of cocaine causes a substantial enhancement of LTP. This priming effect of nicotine is unidirectional: There is no enhancement of LTP if cocaine is administrated prior to nicotine. The facilitation induced by nicotine and cocaine can be blocked by oral administration of the dopamine D1/D5 receptor antagonist (SKF 83566) and enhanced by the D1/D5 agonist (SKF 38393). Application of the histone deacetylation inhibitor suberoylanilide hydroxamic acid (SAHA) simulates the priming effect of nicotine on cocaine. By contrast, the priming effect of nicotine on cocaine is blocked in genetically modified mice that are haploinsufficient for the CREB-binding protein (CBP) and possess only one functional CBP allele and therefore exhibit a reduction in histone acetylation. These results demonstrate that the DG of the hippocampus is an important brain region contributing to the priming effect of nicotine on cocaine. Moreover, both activation of dopamine-D1 receptor/ PKA signaling pathway and histone deacetylation/CBP mediated transcription are required for the nicotine priming effect in the DG.

show abstract

Genetic Inactivation of Dopamine D1 but Not D2 Receptors Inhibits L-DOPA–Induced Dyskinesia and Histone Activation

Cited by 235 publications

References 53 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

Inhibition of Ras-guanine nucleotide-releasing factor 1 (Ras-GRF1) signaling in the striatum reverts motor symptoms associated with l -dopa–induced dyskinesia

D1/D5 receptors and histone deacetylation mediate the Gateway Effect of LTP in hippocampal dentate gyrus

Contact Info

Product

Resources

About