A role for endocannabinoids in the generation of parkinsonism and levodopa-induced dyskinesia in MPTP-lesioned non-human primate models of Parkinson's disease.
Endocannabinoids and cannabinoid CB1 receptors play a role in the control of movement by modulating GABA, glutamate, and other neurotransmitters throughout the basal ganglia. Roles for abnormalities in endocannabinoid signaling in Parkinson's disease (PD) and the major side effect of current treatments, levodopa-induced dyskinesia (LID), have been suggested by rodent studies. Here we show that signaling by endocannabinoids contributes to the pathophysiology of parkinsonism and LID in MPTP-lesioned, non-human primate models of Parkinson's disease. In MPTP-lesioned marmosets previously treated with levodopa to establish LID, attenuation of CB1 signaling by systemic administration of rimonabant (1 and 3 mg/kg) had anti-parkinsonian actions, equivalent to a 71% increase in motor activity at 3 mg/kg. Rimonabant did not elicit dyskinesia. Co-administration of levodopa (8 mg/kg) and rimonabant (1 and 3 mg/kg) resulted in significantly less dyskinesia than levodopa alone, without significantly affecting the anti-parkinsonian action of levodopa. These data suggest that enhanced endocannabinoid signaling may be involved in the pathophysiology of both parkinsonism and LID. To define potential mechanisms by which such a role might be mediated, we determined the levels of the endocannabinoids anandamide and 2-arachidonyl glycerol (2-AG) throughout the basal ganglia in normal and three groups of MPTP-lesioned cynomolgus monkeys (untreated; acutely treated with L-DOPA, non-dyskinetic; long-term treated, with levodopa-induced dyskinesia). In the untreated, MPTP-lesioned primate, parkinsonism was associated with increases in both 2-AG (+88%) and anandamide (+49%) in the striatum, and of 2-AG (+97%) in the substantia nigra, changes that are consistent with the previously suggested role for endocannabinoids in mechanisms attempting to compensate for loss of dopamine in untreated parkinsonism. Increased levels of anandamide (+34%) in the external globus pallidus of MPTP-lesioned animals were normalized by levodopa treatment and may contribute to the generation of parkinsonian symptoms. However, no clear alteration in endocannabinoid levels could be correlated with the expression of LID. These data highlight the potential roles played by endocannabinoids and CB1 in PD and LID and suggest the need for further research to pursue the multiple therapeutic opportunities for manipulating this system in movement disorders.
van der Stelt
Mario
M
Endocannabinoid Research Group, Istituto di Chimica Biomolecolare, Consiglio Nazionale delle Ricerche, Pozzuoli, NA, Italy.
Fox
Susan H
SH
Hill
Michael
M
Crossman
Alan R
AR
Petrosino
Stefania
S
Di Marzo
Vincenzo
V
Brotchie
Jonathan M
JM
D000818:Animals; D001095:Arachidonic Acids / Q000032:analysis; D002144:Callithrix; D063385:Cannabinoid Receptor Modulators / Q000032:analysis / Q000502:physiology*; D004409:Dyskinesia, Drug-Induced / Q000209:etiology*; D063388:Endocannabinoids; D005260:Female; D005989:Glycerides / Q000032:analysis; D007980:Levodopa / Q000633:toxicity*; D020267:MPTP Poisoning / Q000188:drug therapy / Q000209:etiology*; D008297:Male; D010880:Piperidines / Q000627:therapeutic use; D053284:Polyunsaturated Alkamides; D011720:Pyrazoles / Q000627:therapeutic use; D043884:Receptor, Cannabinoid, CB1 / Q000819:agonists / Q000502:physiology; D000077285:Rimonabant; D005680:gamma-Aminobutyric Acid / Q000378:metabolism
D001095:Arachidonic Acids; D063385:Cannabinoid Receptor Modulators; D063388:Endocannabinoids; D005989:Glycerides; D010880:Piperidines; D053284:Polyunsaturated Alkamides; D011720:Pyrazoles; D043884:Receptor, Cannabinoid, CB1; D007980:Levodopa; D005680:gamma-Aminobutyric Acid; C094503:glyceryl 2-arachidonate; D000077285:Rimonabant; C078814:anandamide