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 (endoca nnabinoids) have been identified within the brain. The high density of CB1 cannabinoid receptors within the basal ganglia suggests a potential role fo r endocannabinoids in the control of voluntary movement and in basal gangli a-related movement disorders such as Parkinson's disease. However, whether endocannabinoids play a role in regulating motor behavior in health and dis ease is unknown. Here we report the presence in two regions of the basal ga nglia, the g-lobus pallidus and substantia nigra, of the endocannabinoids 2 -arachidonoylglycerol (2AG) and anandamide. The levels of the latter compou nd are similar to threefold higher than those previously reported in any ot her brain region. In the reserpine-treated rat, an animal model of Parkinso n's disease, suppression of locomotion is accompanied by a sevenfold increa se in the levels of the 2AG in the globus pallidus, but not in the other fi ve brain regions analyzed. Stimulation of locomotion in the reserpine-treat ed rat by either of the two selective agonists of D2 and D1 dopamine recept ors, 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 i n the reduction of both anandamide and 2AG levels in the g-lobus pallidus. Finally, full restoration of locomotion in the reserpine-treated rat is obt ained by coadministration of quinpirole and the selective antagonist of the cannabinoid CB1 receptor subtype, SR141716A. These findings indicate a lin k between endocannabinoid signaling in the globus pallidus and symptoms of Parkinson's disease in the reserpine-treated rat, and suggest that modulati on of the endocannabinoid signaling system might prove useful in treating t his or other basal ganglia-related movement disorders.