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 journalArticlepeer-review

37 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 languageEnglish (US)
Pages (from-to)236-242
Number of pages7
JournalNeuroscience Research
Volume72
Issue number3
DOIs
StatePublished - Mar 2012

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

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