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.
Fox
Susan H
SH
Manchester Movement Disorder Laboratory, Division of Neuroscience, School of Biological Sciences, University of Manchester, Oxford Road, Manchester, United Kingdom. shfox@hotmail.com
Henry
Brian
B
Hill
Michael
M
Crossman
Alan
A
Brotchie
Jonathan
J
D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D000818:Animals; D000978:Antiparkinson Agents / Q000633:toxicity*; D001545:Benserazide / Q000633:toxicity*; D002144:Callithrix; D003342:Corpus Striatum / Q000187:drug effects / Q000503:physiopathology; D004305:Dose-Response Relationship, Drug; D013759:Dronabinol / Q000031:analogs & derivatives* / Q000494:pharmacology*; D004338:Drug Combinations; D004359:Drug Therapy, Combination; D004409:Dyskinesia, Drug-Induced / Q000503:physiopathology*; D005260:Female; D005917:Globus Pallidus / Q000187:drug effects / Q000503:physiopathology; D007980:Levodopa / Q000633:toxicity*; D008297:Male; D009048:Motor Skills / Q000187:drug effects; D020734:Parkinsonian Disorders / Q000503:physiopathology*; D043882:Receptors, Cannabinoid; D011955:Receptors, Drug / Q000187:drug effects* / Q000502:physiology; D005680:gamma-Aminobutyric Acid / Q000378:metabolism
D000978:Antiparkinson Agents; D004338:Drug Combinations; D043882:Receptors, Cannabinoid; D011955:Receptors, Drug; C005177:benserazide, levodopa drug combination; C011941:nabilone; D007980:Levodopa; D005680:gamma-Aminobutyric Acid; D001545:Benserazide; D013759:Dronabinol; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine