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

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 CB1-mediated mechanism. This effect was accompanied by increased phosphorylation of DARPP-32 at threonine 34, which was partially blocked by CB1 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 CB1 receptors, as well as reduction of striatal PKA hyperactivity, might be an effective strategy for the treatment of l-DOPA-induced dyskinesias.

► Activation of cannabinoid CB1 receptors ameliorates l-DOPA-induced dyskinetic behavior in rats.
► Cannabinoid agonism reduces the cAMP/PKA pathway hyperactivity associated with dyskinesia.
► Cannabinoid drugs are promising therapeutics for the treatment of Parkinson's disease.