RT Journal Article SR Electronic T1 Fatty Acid Amide Hydrolase (FAAH) Inhibition Reduces l-3,4-Dihydroxyphenylalanine-Induced Hyperactivity in the 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine-Lesioned Non-Human Primate Model of Parkinson's Disease JF Journal of Pharmacology and Experimental Therapeutics JO J Pharmacol Exp Ther FD American Society for Pharmacology and Experimental Therapeutics SP 423 OP 430 DO 10.1124/jpet.110.169532 VO 336 IS 2 A1 Tom H. Johnston A1 Philippe Huot A1 Susan H. Fox A1 James D. Wakefield A1 Kristine A. Sykes A1 Wilmin P. Bartolini A1 G. Todd Milne A1 James P. Pearson A1 Jonathan M. Brotchie YR 2011 UL http://jpet.aspetjournals.org/content/336/2/423.abstract AB Dopaminergic therapies remain the most efficacious symptomatic treatments for Parkinson's disease (PD) but are associated with motor complications, including dyskinesia, and nonmotor complications, such as psychosis, impulse control disorders (ICD), and dopamine dysregulation syndrome (DDS). Nondopaminergic neurotransmitter systems, including the endocannabinoid system, are probably critical to the development of these complications. The role of fatty acid amide hydrolase (FAAH) in mediating l-3,4-dihydroxyphenylalanine (l-DOPA)-induced behaviors was explored in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-lesioned marmoset model of PD. Pharmacodynamic and locomotor effects of the selective FAAH inhibitor [3-(3-carbamoylphenyl)phenyl] N-cyclohexylcarbamate (URB597) were assessed via bioanalytical (liquid chromatography-tandem mass spectrometry) and behavioral observation approaches. URB597 (3, 10, 30, or 60 mg/kg p.o.) increased plasma levels of the FAAH substrates N-arachidonoyl ethanolamide (anandamide), N-oleoyl ethanolamide, and N-palmitoyl ethanolamide by 10.3 ± 0.3-, 7.8 ± 0.2-, and 1.8 ± 0.1-fold (mean of URB597 groups ± S.E.M.), respectively, compared with vehicle (all p < 0.001) 4 h after administration. Treatment with l-DOPA (20 mg/kg s.c.) alleviated parkinsonism but elicited dyskinesia, psychosis-like-behaviors and hyperactivity, a potential correlate of ICD and DDS. During the 2 to 4 h after l-DOPA, corresponding to 4 to 6 h after URB597 administration, URB597 reduced total l-DOPA-induced activity and the magnitude of hyperactivity by 32 and 52%, respectively, to levels equivalent to those seen in normal animals. Treatment with URB597 (10 mg/kg p.o.) did not modify the antiparkinsonian actions of l-DOPA or l-DOPA-induced dyskinesia and psychosis. URB597 did not alter plasma l-DOPA levels and was without behavioral effects when administered alone. Inhibition of FAAH may represent a novel approach to reducing l-DOPA-induced side effects, such as ICD and DDS, while maintaining the antiparkinsonian benefits of l-DOPA treatment.