Priority CommunicationFatty Acid Amide Hydrolase Inhibition Heightens Anandamide Signaling Without Producing Reinforcing Effects in Primates
Section snippets
Subjects
Twenty-three adult male squirrel monkeys (Saimiri sciureus) weighing .9 to 1.1 kg were housed in individual cages in a temperature- and humidity-controlled room with unrestricted access to water. Monkeys were fed (2 hours after the session) a daily ration consisting of five biscuits of high-protein monkey diet (Lab Diet 5045, PMI Nutrition International, Richmond, Indiana) and two pieces of Banana Softies (Bio-Serv, Frenchtown, New Jersey) that maintained their body weights at a constant level
Effects of URB597 on FAAH Activity and Brain Endocannabinoid Levels
Systemic administration of URB597 (.3 mg/kg, intravenous, IV) resulted in a marked inhibition of FAAH activity in all brain areas examined [Figure 1; midbrain: F(1,6) = 56.88, p < .001; putamen: F(1,6) = 126.93, p < .001; nucleus accumbens: F(1,6) = 8.52, p = .027; prefrontal cortex: F(1,6) = 53.04, p < .001; thalamus: F(1,6) = 153.84, p < .001; amygdala: F(1,5) = 162.93, p < .001; hippocampus: F(1,6) = 107.27, p < .001]. As previously observed in rodents (17, 29), FAAH inhibition was
Discussion
We found that the selective FAAH inhibitor URB597 suppresses FAAH activity and increases anandamide levels in regions of the squirrel monkey brain that participate in motivational, cognitive, and emotional functions. This effect is accompanied by a marked decrease in the levels of 2-AG, a major endocannabinoid substance in the brain, even though URB597 does not affect activities of 2-AG-metabolizing enzymes such as MGL and DGL. We further observed that URB597 does not display overt reinforcing
References (42)
- et al.
Self-administration of cannabinoids by experimental animals and human marijuana smokers
Pharmacol Biochem Behav
(2005) - et al.
Anandamide amidohydrolase activity in rat brain microsomesIdentification and partial characterization
J Biol Chem
(1995) - et al.
A comprehensive profile of brain enzymes that hydrolyze the endocannabinoid 2-arachidonoylglycerol
Chem Biol
(2007) - et al.
The endogenous cannabinoid anandamide has effects on motivation and anxiety that are revealed by fatty acid amide hydrolase (FAAH) inhibition
Neuropharmacology
(2008) - et al.
Identification of biosynthetic precursors for the endocannabinoid anandamide in the rat brain
J Lipid Res
(2008) - et al.
Antidepressant-like activity of the fatty acid amide hydrolase inhibitor URB597 in a rat model of chronic mild stress
Biol Psychiatry
(2007) - et al.
Relationship between injection duration, transporter occupancy and reinforcing strength of cocaine
Eur J Pharmacol
(2004) Oral nabilone capsules in the treatment of chemotherapy-induced nausea and vomiting and pain
Expert Opin Investig Drugs
(2008)- et al.
Analgesic effect of the synthetic cannabinoid CT-3 on chronic neuropathic pain: A randomized controlled trial
JAMA
(2003) - et al.
Cannabis in painful HIV-associated sensory neuropathy: A randomized placebo-controlled trial
Neurology
(2007)
Randomized, controlled trial of cannabis-based medicine in central pain in multiple sclerosis
Neurology
Meta-analysis of cannabis based treatments for neuropathic and multiple sclerosis-related pain
Curr Med Res Opin
Cannabinoids reduce symptoms of Tourette's syndrome
Expert Opin Pharmacother
Cannabinoids: Reward, dependence, and underlying neurochemical mechanisms—a review of recent preclinical data
Psychopharmacology (Berl)
The endocannabinoid system in brain reward processes
Br J Pharmacol
The molecular logic of endocannabinoid signalling
Nat Rev Neurosci
Molecular characterization of an enzyme that degrades neuromodulatory fatty-acid amides
Nature
Brain monoglyceride lipase participating in endocannabinoid inactivation
Proc Natl Acad Sci U S A
Cyclohexylcarbamic acid 3'- or 4'-substituted biphenyl-3-yl esters as fatty acid amide hydrolase inhibitors: Synthesis, quantitative structure-activity relationships, and molecular modeling studies
J Med Chem
Design, synthesis, and structure-activity relationships of alkylcarbamic acid aryl esters, a new class of fatty acid amide hydrolase inhibitors
J Med Chem
Modulation of anxiety through blockade of anandamide hydrolysis
Nat Med
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2021, Current Opinion in PharmacologyCitation Excerpt :Paradoxically, FAAH inhibition opposes to rimonabant effects, and yet similar anti-abuse effects are achieved. This is probably due to submaximal agonist potency of AEA acting as a partial agonist of CB1R and competing with 2-AG [52]. Alternatively, the therapeutic potential of elevated AEA tone may reside in its ability to bind to other targets, such as PPARα/γ, TRPV1 channels and CB2R, or in the modification of other FAAH substrates [26••].