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This Article Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Giuffrida, A. Articles by Morgese, M. G. PubMed Articles by Giuffrida, A. Articles by Morgese, M. G.

Direct and indirect cannabinoid agonists reduce L-dopa-induced-dyskinesias via CB1- and TRPV1-mediated mechanisms

Pharmacology, University of Texas Health Science Center, 7703 Floyd Curl Drive, San Antonio, TX, 78229

ABSTRACT

L-dopa is the most effective treatment for Parkinson’s disease (PD). Although L-dopa improves PD symptoms in the initial stages of the disease, its long-term use causes disabling side effects (dyskinesias) consisting of abnormal involuntary movements (AIMs). Recent studies point to endocannabinoid system as an important modulator of dopamine transmission in the basal ganglia and activation of cannabinoid receptors is emerging as a promising therapy to alleviate L-dopa-induced dyskinesias.

6-OHDA-lesioned rats chronically treated (12 days) with L-dopa (6mg/kg, plus carbidopa, 12 mg/kg, i.p.) develop increasingly severe axial, limb, locomotor and orofacial AIMs. Administration of the cannabinoid agonist WIN 55,212-2 (WIN, 1mg/kg, i.p.) significantly attenuated L-Dopa-induced AIMs. The antidiskynetic effect of WIN was reversed by the CB1 antagonist AM251 (1mg/kg, i.p), and was not due to a generalized motor suppression, as the dose used had no effect on behavioral measures of catalepsy and locomotor activity. Systemic administration of URB597 (0.3mg/kg, i.p.), a potent FAAH inhibitor, had no effect on AIMs scoring although it significantly elevated anandamide throughout the basal ganglia of lesioned rats. Unlike WIN, anandamide can activate TRPV1 receptors, which have been implicated in the regulation of basal ganglia functions. Interestingly, subchronic co-administration of URB597 and capsazepine (10mg/kg), a selective TRPV1 antagonist, significantly decreased all L-dopa-induced AIMs subtypes, whereas capsazepine had no effect when administered alone. Our data suggest that CB1 and TRPV1 receptors play opposite roles in levodopa-induced dyskinesias.

Supported by NIH - NS 050401 (A.G.).

This Article Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Giuffrida, A. Articles by Morgese, M. G. PubMed Articles by Giuffrida, A. Articles by Morgese, M. G.