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NEUROPHARMACOLOGY

Blockade of Cannabinoid Type 1 Receptors Augments the Antiparkinsonian Action of Levodopa without Affecting Dyskinesias in 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine-Treated Rhesus Monkeys

Department of Neurology, Emory University, Atlanta, Georgia (X.C., L.L., S.F., S.M.P.), Department of Neurology, University of Pittsburgh, Pittsburgh, Pennsylvania (J.T.G.); and Neuroscience Biology (J.R.H., P.A.I., F.S.M.) and CVMD Chemistry (D.A.G.), Pfizer Global Research & Development, Groton, Connecticut

Drugs acting at cannabinoid type 1 receptors (CB1) have modulatory effects on glutamate and GABA neurotransmission in basal ganglia; thus, they potentially affect motor behavior in the parkinsonian setting. Preclinical trials with diverse cannabinoid agents have shown varied results, and the precise effects of blocking cannabinoid CB1 receptors remain uncertain. We tested behavioral effects of the selective antagonist 1-[7-(2-chlorophenyl)-8-(4-chlorophenyl)-2-methylpyrazolo[1,5-a]-[1,3,5]triazin-4-yl]-3-ethylaminoazetidine-3-carboxylic acid amide benzenesulfonate (CE) as monotherapy and in combination with L-DOPA in treatment-naive and L-DOPA-primed 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated rhesus monkeys with moderate and severe parkinsonism. Motor disability and L-DOPA-induced dyskinesias were scored with a standardized scale after subcutaneous drug administration, and plasma levels of L-DOPA were determined by high-performance liquid chromatography/electrochemical detection. CE doses ranged from 0.03 to 1 mg/kg, and L-DOPA methyl ester doses were selected as optimal and suboptimal doses (maximal and 50% of maximal responses, respectively). CE had no intrinsic effects on motor behavior regardless of the degree of parkinsonism (moderate or severe groups) or previous drug exposure ("de novo" or after L-DOPA priming). Initial CE administration did not affect development of L-DOPA antiparkinsonian responses. In coadministration trials, CE, in a dose-dependent manner, increased responses to L-DOPA (suboptimal doses). These effects were seen in both moderate and severely parkinsonian monkeys as a 30% increase of, predominantly, response duration with no effects on L-DOPA pharmacokinetics. CE did not modify levodopa-induced dyskinesias. These results suggest that selective cannabinoid CB1 antagonists may enhance the antiparkinsonian action of dopaminomimetics and possibly facilitate the use of lower doses, thereby reducing side effects.

Address correspondence to: Dr. Stella M. Papa, Department of Neurology, Emory University, 6000 WMRB, 101 Woodruff Circle, Atlanta, GA 30322. E-mail: spapa{at}emory.edu