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 32 kDa (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.

• Authors: Alex Martinez, Teresa Macheda, Maria Grazia Morgese, Luigia Trabace, Andrea Giuffrida
• Journal: Neuroscience research (Neurosci Res) Vol. 72 Issue 3 Pg. 236-42 (Mar 2012) ISSN: 1872-8111 [Electronic] Ireland
• PMID: 22192465 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
• Copyright: Copyright © 2011 Elsevier Ireland Ltd and the Japan Neuroscience Society. All rights reserved.

Chemical References

• Benzoxazines
• Cannabinoids
• Dopamine Agents
• Dopamine and cAMP-Regulated Phosphoprotein 32
• Morpholines
• Naphthalenes
• Levodopa
• (3R)-((2,3-dihydro-5-methyl-3-((4-morpholinyl)methyl)pyrrolo-(1,2,3-de)-1,4-benzoxazin-6-yl)(1-naphthalenyl))methanone
• Oxidopamine
• Cyclic AMP-Dependent Protein Kinases

Topics

• Animals
• Behavior, Animal (drug effects)
• Benzoxazines (pharmacology)
• Cannabinoids (pharmacology)
• Cyclic AMP-Dependent Protein Kinases (metabolism)
• Dopamine Agents (pharmacology)
• Dopamine and cAMP-Regulated Phosphoprotein 32 (metabolism)
• Dyskinesia, Drug-Induced (metabolism)
• Levodopa (pharmacology)
• Male
• Morpholines (pharmacology)
• Motor Activity (drug effects)
• Naphthalenes (pharmacology)
• Oxidopamine
• Parkinson Disease, Secondary (metabolism)
• Phosphorylation (drug effects)
• Rats
• Rats, Wistar