Stimulation of Cannabinoid Receptors Reduces Levodopa-induced Dyskinesia in the MPTP-lesioned Nonhuman Primate Model of Parkinson's Disease

Long-term treatment with levodopa in Parkinson's disease results in the development of motor fluctuations, including reduced duration of antiparkinsonian action and involuntary movements, i.e., levodopa-induced dyskinesia. Cannabinoid receptors are concentrated in the basal ganglia, and stimulation of cannabinoid receptors can increase gamma-aminobutyric acid transmission in the lateral segment of globus pallidus and reduce glutamate release in the striatum. We thus tested the hypothesis that the cannabinoid receptor agonist nabilone (0.01, 0.03, and 0.10 mg/kg) would alleviate levodopa-induced dyskinesia in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine hydrochloride (MPTP) -lesioned marmoset model of Parkinson's disease. Coadministration of nabilone (0.1 mg/kg) with levodopa was associated with significantly less total dyskinesia (dyskinesia score, 12; range, 6-17; primate dyskinesia rating scale) than levodopa alone (22; range, 14-23; P < 0.05). This effect was more marked during the onset period (0-20 minutes post levodopa). There was no reduction in the antiparkinsonian action of levodopa. Furthermore, the intermediate dose of nabilone used (0.03 mg/kg) increased the duration of antiparkinsonian action of levodopa by 76%. Thus, cannabinoid receptor agonists may be useful in the treatment of motor complications in Parkinson's disease.