l-DOPA-induced dyskinesia in hemiparkinsonian rats is associated with up-regulation of adenylyl cyclase type V/VI and increased GABA release in the substantia nigra reticulata

Rangel‐Barajas, Claudia; Silva, Isaac; Lopéz-Santiago, Luz María; Aceves, Jorge; Erlij, David; Florán, Benjamí­n

doi:10.1016/j.nbd.2010.08.018

Cited by 86 publications

(99 citation statements)

References 36 publications

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“…We replicated in mice the upregulation of G␣ olf protein observed in the dorsal striatum of hemiparkinsonian rats and PD patients (Hervé et al, 1993;Marcotte et al, 1994;Penit-Soria et al, 1997;Corvol et al, 2004;Rangel-Barajas et al, 2011). Previous data suggested that this upregulation was posttranscriptional (Hervé et al, 1993) and resulted from a lack of usage of the receptor (Hervé et al, 2001).…”

Section: G␣ Olf Upregulation In Dyskinetic Micesupporting

confidence: 67%

“…Therefore, our results, as those in patients (Corvol et al, 2004), suggest the existence of a dysregulation responsible for the "abnormal" persistence of high levels of G␣ olf and associated with the occurrence of dyskinesia. It should be noted that no persistent increase in G␣ olf was reported in dyskinetic L-DOPA-treated rats (Rangel-Barajas et al, 2011). We do not know whether this discrepancy results from differences between species or experimental protocols, yet the persistence of G␣ olf increase in treated PD patients (see above) suggests that results in mice are relevant for the human disease.…”

Section: G␣ Olf Upregulation In Dyskinetic Micementioning

confidence: 92%

“…Although its precise mechanisms are still unknown, a parallel can be made with the highly related G␣s whose degradation increases after its activation in cultured cells (Levis and Bourne, 1992). In support of this hypothesis, treatment of lesioned rats with L-DOPA or a D 1 R agonist normalized G␣ olf levels (Corvol et al, 2004;Rangel-Barajas et al, 2011). However, G␣ olf increase was observed in the putamen of PD patients who had received a prolonged L-DOPA treatment (Corvol et al, 2004).…”

Section: G␣ Olf Upregulation In Dyskinetic Micementioning

confidence: 98%

“…In MSNs, D 1 Rs and adenosine A 2A receptors (A 2A Rs) are coupled to adenylyl-cyclase through a heterotrimeric G-protein comprising G␣ olf , G␤2, and G␥7 subunits (Drinnan et al, 1991;Hervé et al, 1993;Kull et al, 2000;Zhuang et al, 2000;Corvol et al, 2001;Schwindinger et al, 2003Schwindinger et al, , 2010. Levels of G␣ olf increase in DAdenervated striatum of rats and PD patients (Hervé et al, 1993;Marcotte et al, 1994;Penit-Soria et al, 1997;Corvol et al, 2004;Rangel-Barajas et al, 2011). Because G␣ olf levels are a limiting factor for receptor signaling (Corvol et al, , 2007, G␣ olf upregulation is a plausible but untested mechanism for the D 1 R hypersensitivity in LID-developing animals.…”

Section: Introductionmentioning

confidence: 99%

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Gα_olfMutation Allows Parsing the Role of cAMP-Dependent and Extracellular Signal-Regulated Kinase-Dependent Signaling in l-3,4-Dihydroxyphenylalanine-Induced Dyskinesia

Alcacer¹,

Santini²,

Valjent³

et al. 2012

J. Neurosci.

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LID, and their relationship are not known. In striatal neurons, D 1 R activates adenylyl-cyclase through G␣ olf , a protein upregulated after lesion of DA neurons in rats and in patients. We report here that increased G␣ olf levels in hemiparkinsonian mice are correlated with LID after chronic L-DOPA treatment. To determine the role of this upregulation, we performed unilateral lesion in mice lacking one allele of the Gnal gene coding for G␣ olf (Gnal ϩ/Ϫ ). Despite an increase in the lesioned striatum, G␣ olf levels remained below those of unlesioned wild-type mice. In Gnal ϩ/Ϫ mice, the lesion-induced L-DOPA stimulation of cAMP/PKA-mediated phosphorylation of GluA1 Ser845 and DARPP-32 (32 kDa DA-and cAMP-regulated phosphoprotein) Thr34 was dramatically reduced, whereas ERK activation was preserved. LID occurrence was similar in Gnal ϩ/ϩ and Gnal ϩ/Ϫ mice after a 10-d L-DOPA (20 mg/kg) treatment. Thus, in lesioned animals, G␣ olf upregulation is critical for the activation by L-DOPA of D 1 R-stimulated cAMP/PKA but not ERK signaling. Although the cAMP/PKA pathway appears to be required for LID development, our results indicate that its activation is unlikely to be the main source of LID. In contrast, the persistence of L-DOPAinduced ERK activation in Gnal ϩ/Ϫ mice supports its causal role in LID development.

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Section: G␣ Olf Upregulation In Dyskinetic Micesupporting

confidence: 67%

Section: G␣ Olf Upregulation In Dyskinetic Micementioning

confidence: 92%

Section: G␣ Olf Upregulation In Dyskinetic Micementioning

confidence: 98%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Gα_olfMutation Allows Parsing the Role of cAMP-Dependent and Extracellular Signal-Regulated Kinase-Dependent Signaling in l-3,4-Dihydroxyphenylalanine-Induced Dyskinesia

Alcacer¹,

Santini²,

Valjent³

et al. 2012

J. Neurosci.

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show abstract

“…Indeed, long-term changes in gene expression, intracellular signaling pathways, neuronal plasticity, and morphology have all been linked to the expression of LIDs (Santini et al, 2009;Cenci and Konradi, 2010;Feyder et al, 2011;Huot et al, 2011;Rangel-Barajas et al, 2011;Zhang et al, 2013b). Moreover, these changes may occur via numerous neurotransmitter systems, such as the dopaminergic, glutamatergic, serotonergic, and others, which are all implicated in the development and maintenance of LIDs (Carta and Bezard, 2011;Huot et al, 2011;Blandini and Armentero, 2012;Duty, 2012;Rylander, 2012;Huot et al, 2013).…”

Section: Discussionmentioning

confidence: 99%

The α7 Nicotinic Receptor Agonist ABT-107 Decreases l-Dopa–Induced Dyskinesias in Parkinsonian Monkeys

Zhang¹,

McGregor²,

Decker³

et al. 2014

J Pharmacol Exp Ther

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Previous studies in Parkinsonian rats and monkeys have shown that b2-selective nicotinic acetylcholine receptor (nAChR) agonists reduce L-Dopa-induced dyskinesias (LIDs), a serious complication of L-Dopa therapy for Parkinson's disease. Since rodent studies also suggested an involvement of a7 nAChRs in LIDs, we tested the effect of the potent, selective a7 agonist . MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine)-lesioned monkeys were gavaged with L-Dopa/carbidopa (10 and 2.5 mg/kg, respectively) twice daily, which resulted in stable LIDs. A dose-response study (0.03-1.0 mg/kg) showed that oral ABT-107 decreased LIDs by 40-60%. LIDs returned to control levels only after a 6-week ABT-107 washout, suggesting that long-term molecular changes were involved. Subsequent readministration of ABT-107 decreased LIDs by 50-60%, indicating that tolerance did not develop. ABT-107 had no effect on Parkinsonism or cognitive performance. We next tested ABT-107 together with the b2 agonist ABT-894 [(3-(5,6-dichloro-pyridin-3-yl)-1(S),5 (S)-3,6-diazabicyclo [3.2.0]heptane], previously shown to reduce LIDs in Parkinsonian monkeys. In one study, the monkeys were first given oral ABT-894 (0.01 mg/kg), which maximally decreased LIDs by 50-60%; they were then also treated with 0.1 mg/kg ABT-107, a dose that maximally reduced LIDs. The effect of combined treatment on LIDs was similar to that with either drug alone. Comparable results were observed in a group of monkeys first treated with ABT-107 and then also given ABT-894. Thus, a7 and b2 nAChR-selective drugs may function via a final common mechanism to reduce LIDs. The present results suggest that drugs targeting either a7 or b2 nAChRs may be useful as antidyskinetic agents in Parkinson's disease.

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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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l-DOPA-induced dyskinesia in hemiparkinsonian rats is associated with up-regulation of adenylyl cyclase type V/VI and increased GABA release in the substantia nigra reticulata

Cited by 86 publications

References 36 publications

Gα_olfMutation Allows Parsing the Role of cAMP-Dependent and Extracellular Signal-Regulated Kinase-Dependent Signaling in l-3,4-Dihydroxyphenylalanine-Induced Dyskinesia

Gα_olfMutation Allows Parsing the Role of cAMP-Dependent and Extracellular Signal-Regulated Kinase-Dependent Signaling in l-3,4-Dihydroxyphenylalanine-Induced Dyskinesia

The α7 Nicotinic Receptor Agonist ABT-107 Decreases l-Dopa–Induced Dyskinesias in Parkinsonian Monkeys

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

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l-DOPA-induced dyskinesia in hemiparkinsonian rats is associated with up-regulation of adenylyl cyclase type V/VI and increased GABA release in the substantia nigra reticulata

Cited by 86 publications

References 36 publications

GαolfMutation Allows Parsing the Role of cAMP-Dependent and Extracellular Signal-Regulated Kinase-Dependent Signaling in l-3,4-Dihydroxyphenylalanine-Induced Dyskinesia

GαolfMutation Allows Parsing the Role of cAMP-Dependent and Extracellular Signal-Regulated Kinase-Dependent Signaling in l-3,4-Dihydroxyphenylalanine-Induced Dyskinesia

The α7 Nicotinic Receptor Agonist ABT-107 Decreases l-Dopa–Induced Dyskinesias in Parkinsonian Monkeys

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

Contact Info

Product

Resources

About

Gα_olfMutation Allows Parsing the Role of cAMP-Dependent and Extracellular Signal-Regulated Kinase-Dependent Signaling in l-3,4-Dihydroxyphenylalanine-Induced Dyskinesia

Gα_olfMutation Allows Parsing the Role of cAMP-Dependent and Extracellular Signal-Regulated Kinase-Dependent Signaling in l-3,4-Dihydroxyphenylalanine-Induced Dyskinesia