The cannabinoid agonist WIN55212-2 decreases l-DOPA-induced PKA activation and dyskinetic behavior in 6-OHDA-treated rats

Alex Martinez; Teresa Macheda; Maria Grazia Morgese; Luigia Trabace; Andrea Giuffrida

doi:10.1016/j.neures.2011.12.006

The cannabinoid agonist WIN55212-2 decreases l-DOPA-induced PKA activation and dyskinetic behavior in 6-OHDA-treated rats

Alex Martinez, Teresa Macheda, Maria Grazia Morgese, Luigia Trabace, Andrea Giuffrida

Research output: Contribution to journal › Article › peer-review

46 Scopus citations

Abstract

Chronic Levodopa (l-DOPA), the gold standard therapy for Parkinson's disease (PD), causes disabling motor complications (dyskinesias) that are associated with changes in the activity of striatal protein kinase A (PKA) and cAMP-regulated phosphoprotein of 32kDa (DARPP-32). In this study, we showed that systemic administration of the cannabinoid agonist WIN55212-2 ameliorated l-DOPA-induced abnormal involuntary movements (AIMs) in the 6-OHDA rat model of PD and reversed l-DOPA-induced PKA hyperactivity via a CB ₁-mediated mechanism. This effect was accompanied by increased phosphorylation of DARPP-32 at threonine 34, which was partially blocked by CB ₁ antagonism. Striatal PKA activity was positively correlated with the severity of l-DOPA-induced axial and limb dyskinesias, suggesting a role for the cAMP/PKA signaling pathway in the expression of these motor disturbances.Our results indicate that activation of CB ₁ receptors, as well as reduction of striatal PKA hyperactivity, might be an effective strategy for the treatment of l-DOPA-induced dyskinesias.

Original language	English (US)
Pages (from-to)	236-242
Number of pages	7
Journal	Neuroscience Research
Volume	72
Issue number	3
DOIs	https://doi.org/10.1016/j.neures.2011.12.006
State	Published - Mar 2012
Externally published	Yes

Bibliographical note

Funding Information:
We thank Drs. Alexandre Seillier and Julien Matricon for the critical reading of the manuscript. This study was supported by the National Institute of Health , NS050401-07 (to A.G.) and 1F31NS073411-01 (to A.M.).

Keywords

C-AMP-regulated phosphoprotein 32
CB receptor
Cannabinoid
Dopamine
Dyskinesia
Parkinson's disease
Striatum

Publisher link

10.1016/j.neures.2011.12.006

Find It

Find It at U of M Libraries

Cite this

@article{28d894357708406b9e4c1d0624c5e82d,

title = "The cannabinoid agonist WIN55212-2 decreases l-DOPA-induced PKA activation and dyskinetic behavior in 6-OHDA-treated rats",

abstract = "Chronic Levodopa (l-DOPA), the gold standard therapy for Parkinson's disease (PD), causes disabling motor complications (dyskinesias) that are associated with changes in the activity of striatal protein kinase A (PKA) and cAMP-regulated phosphoprotein of 32kDa (DARPP-32). In this study, we showed that systemic administration of the cannabinoid agonist WIN55212-2 ameliorated l-DOPA-induced abnormal involuntary movements (AIMs) in the 6-OHDA rat model of PD and reversed l-DOPA-induced PKA hyperactivity via a CB 1-mediated mechanism. This effect was accompanied by increased phosphorylation of DARPP-32 at threonine 34, which was partially blocked by CB 1 antagonism. Striatal PKA activity was positively correlated with the severity of l-DOPA-induced axial and limb dyskinesias, suggesting a role for the cAMP/PKA signaling pathway in the expression of these motor disturbances.Our results indicate that activation of CB 1 receptors, as well as reduction of striatal PKA hyperactivity, might be an effective strategy for the treatment of l-DOPA-induced dyskinesias.",

keywords = "C-AMP-regulated phosphoprotein 32, CB receptor, Cannabinoid, Dopamine, Dyskinesia, Parkinson's disease, Striatum",

author = "Alex Martinez and Teresa Macheda and Morgese, {Maria Grazia} and Luigia Trabace and Andrea Giuffrida",

note = "Funding Information: We thank Drs. Alexandre Seillier and Julien Matricon for the critical reading of the manuscript. This study was supported by the National Institute of Health , NS050401-07 (to A.G.) and 1F31NS073411-01 (to A.M.).",

year = "2012",

month = mar,

doi = "10.1016/j.neures.2011.12.006",

language = "English (US)",

volume = "72",

pages = "236--242",

journal = "Neuroscience Research",

issn = "0168-0102",

publisher = "Elsevier Ireland Ltd",

number = "3",

}

TY - JOUR

T1 - The cannabinoid agonist WIN55212-2 decreases l-DOPA-induced PKA activation and dyskinetic behavior in 6-OHDA-treated rats

AU - Martinez, Alex

AU - Macheda, Teresa

AU - Morgese, Maria Grazia

AU - Trabace, Luigia

AU - Giuffrida, Andrea

N1 - Funding Information: We thank Drs. Alexandre Seillier and Julien Matricon for the critical reading of the manuscript. This study was supported by the National Institute of Health , NS050401-07 (to A.G.) and 1F31NS073411-01 (to A.M.).

PY - 2012/3

Y1 - 2012/3

N2 - Chronic Levodopa (l-DOPA), the gold standard therapy for Parkinson's disease (PD), causes disabling motor complications (dyskinesias) that are associated with changes in the activity of striatal protein kinase A (PKA) and cAMP-regulated phosphoprotein of 32kDa (DARPP-32). In this study, we showed that systemic administration of the cannabinoid agonist WIN55212-2 ameliorated l-DOPA-induced abnormal involuntary movements (AIMs) in the 6-OHDA rat model of PD and reversed l-DOPA-induced PKA hyperactivity via a CB 1-mediated mechanism. This effect was accompanied by increased phosphorylation of DARPP-32 at threonine 34, which was partially blocked by CB 1 antagonism. Striatal PKA activity was positively correlated with the severity of l-DOPA-induced axial and limb dyskinesias, suggesting a role for the cAMP/PKA signaling pathway in the expression of these motor disturbances.Our results indicate that activation of CB 1 receptors, as well as reduction of striatal PKA hyperactivity, might be an effective strategy for the treatment of l-DOPA-induced dyskinesias.

AB - Chronic Levodopa (l-DOPA), the gold standard therapy for Parkinson's disease (PD), causes disabling motor complications (dyskinesias) that are associated with changes in the activity of striatal protein kinase A (PKA) and cAMP-regulated phosphoprotein of 32kDa (DARPP-32). In this study, we showed that systemic administration of the cannabinoid agonist WIN55212-2 ameliorated l-DOPA-induced abnormal involuntary movements (AIMs) in the 6-OHDA rat model of PD and reversed l-DOPA-induced PKA hyperactivity via a CB 1-mediated mechanism. This effect was accompanied by increased phosphorylation of DARPP-32 at threonine 34, which was partially blocked by CB 1 antagonism. Striatal PKA activity was positively correlated with the severity of l-DOPA-induced axial and limb dyskinesias, suggesting a role for the cAMP/PKA signaling pathway in the expression of these motor disturbances.Our results indicate that activation of CB 1 receptors, as well as reduction of striatal PKA hyperactivity, might be an effective strategy for the treatment of l-DOPA-induced dyskinesias.

KW - C-AMP-regulated phosphoprotein 32

KW - CB receptor

KW - Cannabinoid

KW - Dopamine

KW - Dyskinesia

KW - Parkinson's disease

KW - Striatum

UR - http://www.scopus.com/inward/record.url?scp=84856516709&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84856516709&partnerID=8YFLogxK

U2 - 10.1016/j.neures.2011.12.006

DO - 10.1016/j.neures.2011.12.006

M3 - Article

C2 - 22192465

AN - SCOPUS:84856516709

SN - 0168-0102

VL - 72

SP - 236

EP - 242

JO - Neuroscience Research

JF - Neuroscience Research

IS - 3

ER -

The cannabinoid agonist WIN55212-2 decreases l-DOPA-induced PKA activation and dyskinetic behavior in 6-OHDA-treated rats

Abstract

Bibliographical note

Keywords

Publisher link

Find It

Other files and links

Fingerprint

Cite this