Enhanced levels of endogenous cannabinoids in the globus pallidus are associated with a reduction in movement in an animal model of Parkinson's disease.
In recent years, cannabinoid receptors and their endogenous ligands (endocannabinoids) have been identified within the brain. The high density of CB1 cannabinoid receptors within the basal ganglia suggests a potential role for endocannabinoids in the control of voluntary movement and in basal ganglia-related movement disorders such as Parkinson's disease. However, whether endocannabinoids play a role in regulating motor behavior in health and disease is unknown. Here we report the presence in two regions of the basal ganglia, the globus pallidus and substantia nigra, of the endocannabinoids 2-arachidonoylglycerol (2AG) and anandamide. The levels of the latter compound are approximately threefold higher than those previously reported in any other brain region. In the reserpine-treated rat, an animal model of Parkinson's disease, suppression of locomotion is accompanied by a sevenfold increase in the levels of the 2AG in the globus pallidus, but not in the other five brain regions analyzed. Stimulation of locomotion in the reserpine-treated rat by either of the two selective agonists of D2 and D1 dopamine receptors, quinpirole and R-(+/-)-3-allyl-6-chloro-7, 8-dihydroxy-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrobromide (Cl-APB), respectively, results in the reduction of both anandamide and 2AG levels in the globus pallidus. Finally, full restoration of locomotion in the reserpine-treated rat is obtained by coadministration of quinpirole and the selective antagonist of the cannabinoid CB1 receptor subtype, SR141716A. These findings indicate a link between endocannabinoid signaling in the globus pallidus and symptoms of Parkinson's disease in the reserpine-treated rat, and suggest that modulation of the endocannabinoid signaling system might prove useful in treating this or other basal ganglia-related movement disorders.
Di Marzo
V
V
School of Biological Sciences, University of Manchester, United Kingdom. vdimarzo@icmib.na.cnr.it
Hill
M P
MP
Bisogno
T
T
Crossman
A R
AR
Brotchie
J M
JM
D000818:Animals; D001095:Arachidonic Acids / Q000378:metabolism; D001552:Benzazepines / Q000494:pharmacology; D063385:Cannabinoid Receptor Modulators; D002186:Cannabinoids / Q000378:metabolism*; D018491:Dopamine Agonists / Q000494:pharmacology; D063388:Endocannabinoids; D005917:Globus Pallidus / Q000378:metabolism*; D005989:Glycerides / Q000378:metabolism; D006801:Humans; D008297:Male; D009043:Motor Activity / Q000502:physiology*; D020734:Parkinsonian Disorders / Q000378:metabolism* / Q000503:physiopathology*; D010880:Piperidines / Q000494:pharmacology; D053284:Polyunsaturated Alkamides; D011720:Pyrazoles / Q000494:pharmacology; D019257:Quinpirole / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D043882:Receptors, Cannabinoid; D011955:Receptors, Drug / Q000037:antagonists & inhibitors; D012110:Reserpine / Q000633:toxicity; D000077285:Rimonabant; D013378:Substantia Nigra / Q000378:metabolism; D014018:Tissue Distribution
D001095:Arachidonic Acids; D001552:Benzazepines; D063385:Cannabinoid Receptor Modulators; D002186:Cannabinoids; D018491:Dopamine Agonists; D063388:Endocannabinoids; D005989:Glycerides; D010880:Piperidines; D053284:Polyunsaturated Alkamides; D011720:Pyrazoles; D043882:Receptors, Cannabinoid; D011955:Receptors, Drug; D019257:Quinpirole; C071262:SK&F 82958; D012110:Reserpine; C094503:glyceryl 2-arachidonate; D000077285:Rimonabant; C078814:anandamide