Spatiotemporal Pattern of Striatal ERK1/2 Phosphorylation in a Rat Model of L-DOPA–Induced Dyskinesia and the Role of Dopamine D1 Receptors

Westin, Jenny E.; Vercammen, Linda; Strome, Elissa M.; Konradi, Christine; Cenci, M. Angela

doi:10.1016/j.biopsych.2006.11.032

Cited by 247 publications

(231 citation statements)

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“…Pharmacological stimulation of D1 receptors causes an activation of ERK1/2 in DA-denervated striatal neurons (Gerfen et al, 2002) and this signaling event is implicated in the development of dyskinesia (Santini et al, 2007;Schuster et al, 2008;Westin et al, 2007). Activation of ERK1/2 also plays a central role in endothelial proliferation in different model systems (reviewed in Zachary and Gliki, 2001).…”

Section: Discussionmentioning

confidence: 99%

“…Experiment 3. Rats (n ¼ 40) were allocated to five treatment groups: (1) 'L-DOPA only' (10 mg/kg; n ¼ 8); (2) L-DOPA combined with the D1 receptor antagonist, SCH23390 ('SCH23390'; n ¼ 6) at the dose of 0.25 mg/kg (Taylor et al, 2005;Westin et al, 2007); (3 and 4) L-DOPA combined with the D2 antagonist, eticlopride at either 0.01 mg/kg ('eticlopride low', n ¼ 7) or 2 mg/kg ('eticlopride high'; n ¼ 7). The low dose and high dose were chosen in order not to interfere with normal motor activity (Bardo et al, 1999;Schindler and Carmona, 2002), or to reduce dyskinesia (Taylor et al, 2005), respectively.…”

Section: Experimental Design and Pharmacological Treatmentsmentioning

confidence: 99%

“…Rats with a 6-OHDA lesion were chronically treated with L-DOPA in combination with either the D1-like receptor antagonist, SCH23390 at an earlier characterized dose (0.25 mg/kg; Westin et al, 2007), or with the D2 antagonist, eticlopride at two doses ('eticlopride low', 0.01 mg/kg; 'eticlopride high', 2.0 mg/kg). An overall comparison of L-DOPA-induced AIM scores by repeatedmeasures ANOVA revealed highly significant differences between treatment groups and testing sessions (Figure 4a; p treatment o0.001, p time o0.001, and p interaction ¼ 0.008).…”

Section: Antagonism Of D1 But Not D2 Receptors Blocks Both Dyskinesiamentioning

confidence: 99%

“…The Ras-ERK1/2 signaling pathway is a critical mediator of L-DOPA-induced neuroplasticity and dyskinesia (Santini et al, 2007;Schuster et al, 2008;Westin et al, 2007). To address the possible involvement of this pathway in L-DOPA-induced angiogenesis, 6-OHDA-lesioned rats were treated with L-DOPA preceded by either the mitogenactivated protein kinase kinase (MEK) inhibitor, SL327 or its vehicle.…”

Section: Inhibition Of Erk1/2 Signaling Blocks L-dopa-induced Angiogementioning

confidence: 99%

“…Two doses of the inhibitor were used ('SL low', 100 mg/kg, and 'SL high', 300 mg/kg), which produced a partial or total blockade of L-DOPA-induced phospho-ERK1/2 expression in striatal neurons (see Supplementary Figure S4). For this study, we used a short regimen of L-DOPA treatment (3 days), which is sufficient to induce angiogenic activity (Westin et al, 2006) preceding the development of maximally severe AIMs (Westin et al, 2007; see also Figure 1a). An overall comparison of AIM scores revealed significant group differences over the 3-day treatment period (Figure 5a; p treatment ¼ 0.011, p time ¼ 0.093, and p interaction ¼ 0.136).…”

Section: Inhibition Of Erk1/2 Signaling Blocks L-dopa-induced Angiogementioning

confidence: 99%

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Differential Involvement of D1 and D2 Dopamine Receptors in L-DOPA-Induced Angiogenic Activity in a Rat Model of Parkinson's Disease

Lindgren

Ohlin

Cenci

2009

Neuropsychopharmacol

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Angiogenesis occurs in the brains of Parkinson's disease patients, but the effects of dopamine replacement therapy on this process have not been examined. Using rats with 6-hydroxydopamine lesions, we have compared angiogenic responses induced in the basal ganglia by chronic treatment with either L-DOPA, or bromocriptine, or a selective D1 receptor agonist (SKF38393). Moreover, we have asked whether L-DOPA-induced angiogenesis can be blocked by co-treatment with either a D1-or a D2 receptor antagonist (SCH23390 and eticlopride, respectively), or by an inhibitor of extracellular signal-regulated kinases 1 and 2 (ERK1/2) (SL327). L-DOPA, but not bromocriptine, induced dyskinesia, which was associated with endothelial proliferation, upregulation of immature endothelial markers (nestin) and downregulation of endothelial barrier antigen in the striatum and its output structures. At a dose inducing dyskinesia (1.5 mg/kg/day), SKF38393 elicited angiogenic changes similar to L-DOPA. Antagonism of D1-but not D2 class receptors completely suppressed both the development of dyskinesia and the upregulation of angiogenesis markers. In fact, L-DOPA-induced endothelial proliferation was markedly exacerbated by low-dose D2 antagonism (0.01 mg/kg eticlopride). Inhibition of ERK1/2 by SL327 attenuated L-DOPA-induced dyskinesia and completely inhibited all markers of angiogenesis. These results highlight the specific link between treatment-induced dyskinesias and microvascular remodeling in the dopamine-denervated brain. L-DOPA-induced angiogenesis requires stimulation of D1 receptors and activation of ERK1/2, whereas the stimulation of D2 receptors seems to oppose this response.

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Section: Discussionmentioning

confidence: 99%

Section: Experimental Design and Pharmacological Treatmentsmentioning

confidence: 99%

Section: Antagonism Of D1 But Not D2 Receptors Blocks Both Dyskinesiamentioning

confidence: 99%

Section: Inhibition Of Erk1/2 Signaling Blocks L-dopa-induced Angiogementioning

confidence: 99%

Section: Inhibition Of Erk1/2 Signaling Blocks L-dopa-induced Angiogementioning

confidence: 99%

See 3 more Smart Citations

Differential Involvement of D1 and D2 Dopamine Receptors in L-DOPA-Induced Angiogenic Activity in a Rat Model of Parkinson's Disease

Lindgren

Ohlin

Cenci

2009

Neuropsychopharmacol

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Differential involvement of Ras‐GRF1 and Ras‐GRF2 in L‐DOPA‐induced dyskinesia

Bido

Solari

Indrigo

et al. 2015

Ann Clin Transl Neurol

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ObjectiveRecent findings have shown that pharmacogenetic manipulations of the Ras-ERK pathway provide a therapeutic means to tackle l-3,4-dihydroxyphenylalanine (l-DOPA)-induced dyskinesia (LID). First, we investigated whether a prolonged l-DOPA treatment differentially affected ERK signaling in medium spiny neurons of the direct pathway (dMSNs) and in cholinergic aspiny interneurons (ChIs) and assessed the role of Ras-GRF1 in both subpopulations. Second, using viral-assisted technology, we probed Ras-GRF1 and Ras-GRF2 as potential targets in this pathway. We investigated how selective blockade of striatal Ras-GRF1 or Ras-GRF2 expression impacted on LID (induction, maintenance, and reversion) and its neurochemical correlates.MethodsWe used both Ras-GRF1 knockout mice and lentiviral vectors (LVs) delivering short-hairpin RNA sequences (shRNAs) to obtain striatum-specific gene knockdown of Ras-GRF1 and Ras-GRF2. The consequences of these genetic manipulations were evaluated in the 6-hydroxydopamine mouse model of Parkinson’s disease. Escalating doses of l-DOPA were administered and then behavioral analysis with immunohistochemical assays and in vivo microdialysis were performed.ResultsRas-GRF1 was found essential in controlling ERK signaling in dMSNs, but its ablation did not prevent ERK activation in ChIs. Moreover, striatal injection of LV-shRNA/Ras-GRF1 attenuated dyskinesia development and ERK-dependent signaling, whereas LV-shRNA/Ras-GRF2 was without effect, ruling out the involvement of Ras-GRF2 in LID expression. Accordingly, Ras-GRF1 but not Ras-GRF2 striatal gene-knockdown reduced l-DOPA-induced GABA and glutamate release in the substantia nigra pars reticulata, a neurochemical correlate of dyskinesia. Finally, inactivation of Ras-GRF1 provided a prolonged anti-dyskinetic effect for up to 7 weeks and significantly attenuated symptoms in animals with established LID.InterpretationOur results suggest that Ras-GRF1 is a promising target for LID therapy based on Ras-ERK signaling inhibition in the striatum.

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Maladaptive plasticity of serotonin axon terminals in levodopa‐induced dyskinesia

Rylander

Parent

O’Sullivan

et al. 2010

Annals of Neurology

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235

175

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This study provides the first evidence that L-dopa treatment induces sprouting of serotonin axon terminals, with an increased incidence of synaptic contacts, and a larger activity-dependent potentiation of dopamine release in the dopamine-denervated striatum. Treatment-induced plasticity of the serotonin innervation may therefore represent a previously unappreciated cause of altered dopamine dynamics. These results are important for understanding the mechanisms by which L-dopa pharmacotherapy predisposes to dyskinesia, and for defining biomarkers of motor complications in Parkinsons disease.

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Spatiotemporal Pattern of Striatal ERK1/2 Phosphorylation in a Rat Model of L-DOPA–Induced Dyskinesia and the Role of Dopamine D1 Receptors

Cited by 247 publications

References 55 publications

Differential Involvement of D1 and D2 Dopamine Receptors in L-DOPA-Induced Angiogenic Activity in a Rat Model of Parkinson's Disease

Differential Involvement of D1 and D2 Dopamine Receptors in L-DOPA-Induced Angiogenic Activity in a Rat Model of Parkinson's Disease

Differential involvement of Ras‐GRF1 and Ras‐GRF2 in L‐DOPA‐induced dyskinesia

Maladaptive plasticity of serotonin axon terminals in levodopa‐induced dyskinesia

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