The long-term use of
levodopa (
L-DOPA) in
Parkinson's disease (PD) results in the development of abnormal
involuntary movements called
L-DOPA-induced
dyskinesias. Increasing evidences suggest that the
endocannabinoid system may play a role in the modulation of
dyskinesias. In this work, we assessed the antidyskinetic effect of the
endocannabinoid analog
oleoylethanolamide (OEA), an agonist of PPARĪ± and antagonist of TRPV1 receptors. We used a hemiparkinsonian model of PD in mice with
6-OHDA striatal lesion. The chronic
L-DOPA treatment developed intense axial, forelimb and orolingual dyskinetic symptoms, as well as contralateral rotations. Treatment with OEA reduced all these symptoms without reducing motor activity or the therapeutic motor effects of
L-DOPA. Moreover, the OEA-induced reduction in dyskinetic behavior correlated with a reduction in molecular correlates of
dyskinesia. OEA reduced FosB striatal overexpression and phosphoacetylation of
histone 3, both molecular markers of
L-DOPA-induced
dyskinesias. We found that OEA antidyskinetic properties were mediated by
TRPV1 receptor, as pretreatment with
capsaicin, a TRPV1 agonist, blocked OEA antidyskinetic actions, as well as the reduction in FosB- and pAcH3-overexpression induced by
L-DOPA. This study supports the hypothesis that the
endocannabinoid system plays an important role in the development and expression of
dyskinesias and might be an effective target for the treatment of
L-DOPA-induced
dyskinesias. Importantly, there was no development of tolerance to OEA in any of the parameters we examined, which has important implications for the therapeutic potential of drugs targeting the
endocannabinoid system.