title: 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.affiliation: Department of Pharmacology, University of Texas Health Science Center, 7703 Floyd Curl Drive, San Antonio, TX 78229, USA.
authors.forename: Alex
authors.initials: A
authors.lastname: Martinez
authors.forename: Teresa
authors.initials: T
authors.lastname: Macheda
authors.forename: Maria Grazia
authors.initials: MG
authors.lastname: Morgese
authors.forename: Luigia
authors.initials: L
authors.lastname: Trabace
authors.forename: Andrea
authors.initials: A
authors.lastname: Giuffrida
mesh_terms: D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D048588:Benzoxazines / Q000494:pharmacology*; D002186:Cannabinoids / Q000494:pharmacology*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism*; D015259:Dopamine Agents / Q000494:pharmacology*; D051937:Dopamine and cAMP-Regulated Phosphoprotein 32 / Q000378:metabolism; D004409:Dyskinesia, Drug-Induced / Q000378:metabolism*; D007980:Levodopa / Q000494:pharmacology*; D008297:Male; D009025:Morpholines / Q000494:pharmacology*; D009043:Motor Activity / Q000187:drug effects; D009281:Naphthalenes / Q000494:pharmacology*; D016627:Oxidopamine; D010302:Parkinson Disease, Secondary / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar
chemical_list: D048588:Benzoxazines; D002186:Cannabinoids; D015259:Dopamine Agents; D051937:Dopamine and cAMP-Regulated Phosphoprotein 32; D009025:Morpholines; D009281:Naphthalenes; D007980:Levodopa; C070417:(3R)-((2,3-dihydro-5-methyl-3-((4-morpholinyl)methyl)pyrrolo-(1,2,3-de)-1,4-benzoxazin-6-yl)(1-naphthalenyl))methanone; D016627:Oxidopamine; D017868:Cyclic AMP-Dependent Protein Kinases