The fatty acid amide hydrolase inhibitor URB 597: interactions with anandamide in rhesus monkeys
Article first published online: 28 AUG 2011
© 2011 The Authors. British Journal of Pharmacology © 2011 The British Pharmacological Society
British Journal of Pharmacology
Volume 164, Issue 2b, pages 655–666, September 2011
How to Cite
Stewart, J. L. and McMahon, L. R. (2011), The fatty acid amide hydrolase inhibitor URB 597: interactions with anandamide in rhesus monkeys. British Journal of Pharmacology, 164: 655–666. doi: 10.1111/j.1476-5381.2011.01388.x
- Issue published online: 28 AUG 2011
- Article first published online: 28 AUG 2011
- Accepted manuscript online: 30 MAR 2011 07:49AM EST
- Received; 28 December 2010; Revised; 7 March 2011; Accepted; 10 March 2011
- drug discrimination;
- rhesus monkey;
- URB 597
BACKGROUND AND PURPOSE The fatty acid amide hydrolase inhibitor URB 597 increases brain anandamide levels, suggesting that URB 597 could enhance the behavioural effects of anandamide. The goal of the current study was to examine and characterize the in vivo pharmacology of URB 597 alone and in combination with anandamide and Δ9-tetrahydrocannabinol (Δ9-THC) in two drug discrimination assays in rhesus monkeys.
EXPERIMENTAL APPROACH The effects of URB 597 alone and in combination with anandamide were investigated in one group of monkeys (n= 4) that discriminated Δ9-THC (0.1 mg·kg−1 i.v.) from vehicle, and in another group (n= 5) receiving chronic Δ9-THC (1 mg·kg−112 h−1 s.c.) that discriminated the cannabinoid antagonist rimonabant (1 mg·kg−1 i.v.).
KEY RESULTS Intravenous anandamide fully substituted for, and had infra-additive effects with, Δ9-THC. URB 597 (up to 3.2 mg·kg−1 i.v.) did not substitute for or modify the effects of Δ9-THC but markedly increased the potency (32-fold) and duration of action of anandamide. The rimonabant discriminative stimulus in Δ9-THC-treated monkeys (i.e. Δ9-THC withdrawal) was attenuated by both Δ9-THC (at doses larger than 1 mg·kg−1 per 12 h) and anandamide but not by URB 597 (3.2 mg·kg−1). URB 597 did not increase the potency of anandamide to attenuate the rimonabant-discriminative stimulus.
CONCLUSIONS AND IMPLICATIONS URB 597 enhanced the behavioural effects of anandamide but not other CB1 agonists. However, URB 597 did not significantly enhance the attenuation of Δ9-THC withdrawal induced by anandamide. Collectively, these data suggest that endogenous anandamide in primate brain does not readily mimic the behavioural effects of exogenously administered anandamide.