PT  - JOURNAL ARTICLE
AU  - Tom H Johnston
AU  - Philippe Huot
AU  - Susan H Fox
AU  - James D Wakefield
AU  - Kristine A Sykes
AU  - Wilmin P Bartolini
AU  - G Todd Milne
AU  - James P Pearson
AU  - Jonathan M Brotchie
TI  - Fatty acid amide hydrolase (FAAH) inhibition reduces L-DOPA-induced hyperactivity in the MPTP-lesioned non-human primate model of Parkinson's disease
AID  - 10.1124/jpet.110.169532
DP  - 2010 Jan 01
TA  - Journal of Pharmacology and Experimental Therapeutics
PG  - jpet.110.169532
4099  - http://jpet.aspetjournals.org/content/early/2010/10/21/jpet.110.169532.short
4100  - http://jpet.aspetjournals.org/content/early/2010/10/21/jpet.110.169532.full
AB  - Dopaminergic therapies remain the most efficacious symptomatic treatments for Parkinson's disease (PD) but are associated with motor complications, including dyskinesia, and non-motor complications, such as psychosis, impulse control disorders (ICD) and dopamine dysregulation syndrome (DDS). Non-dopaminergic neurotransmitter systems, including the endocannabinoid system, are likely critical to the development of these complications. The role of fatty acid amide hydrolase (FAAH) in mediating L-DOPA-induced behaviours was explored in the MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine)-lesioned marmoset model of PD. Pharmacodynamic and locomotor effects of the selective FAAH inhibitor URB597 were assessed via bioanalytical (LC-MS/MS) and behavioural observation approaches. URB597 (3, 10, 30, or 60 mg/kg, p.o.) increased plasma levels of the FAAH substrates N-arachidonoyl-ethanolamide (AEA, anandamide), N-oleoyl-ethanolamide (OEA), and N-palmitoyl-ethanolamide (PEA) by 10.3±;0.3, 7.8±0.2 and 1.8±0.1-fold (mean of URB597 groups ± SEM), respectively, cf. vehicle (all p<0.001) four hours after administration. Treatment with L-DOPA (20 mg/kg, s.c.) alleviated parkinsonism but elicited dyskinesia, psychosis-like-behaviours and hyperactivity, a potential correlate of ICD and DDS. During the period 2-4 h post-L-DOPA, corresponding to 4-6 hours after URB597 administration, URB597 reduced total L-DOPA-induced activity, as well as 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 anti-parkinsonian actions of L-DOPA, or L-DOPA-induced dyskinesia and psychosis. URB597 did not alter plasma L-DOPA levels and was without behavioural 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 anti-parkinsonian benefits of L-DOPA treatment.