Fatty Acid Amide Hydrolase Inhibition Heightens Anandamide Signaling Without Producing Reinforcing Effects in Primates

doi:10.1016/j.biopsych.2008.08.008

Biological Psychiatry

Volume 64, Issue 11, 1 December 2008, Pages 930-937

https://doi.org/10.1016/j.biopsych.2008.08.008 Get rights and content

Background

CB₁ cannabinoid receptors in the brain are known to participate in the regulation of reward-based behaviors. However, the contribution of each of the endocannabinoid transmitters, anandamide and 2-arachidonoylglycerol (2-AG), to these behaviors remains undefined. To address this question, we assessed the effects of URB597, a selective anandamide deactivation inhibitor, as a reinforcer of drug-seeking and drug-taking behavior in squirrel monkeys.

Methods

We investigated the reinforcing effects of the fatty acid amide hydrolase (FAAH) inhibitor URB597 in monkeys trained to intravenously self-administer Δ⁹-tetrahydrocannabinol (THC), anandamide, or cocaine and quantified brain endocannabinoid levels using liquid chromatography/mass spectrometry. We measured brain FAAH activity using an ex vivo enzyme assay.

Results

URB597 (.3 mg/kg, intravenous) blocked FAAH activity and increased anandamide levels throughout the monkey brain. This effect was accompanied by a marked compensatory decrease in 2-AG levels. Monkeys did not self-administer URB597, and the drug did not promote reinstatement of extinguished drug-seeking behavior previously maintained by THC, anandamide, or cocaine. Pretreatment with URB597 did not modify self-administration of THC or cocaine, even though, as expected, it significantly potentiated anandamide self-administration.

Conclusions

In the monkey brain, the FAAH inhibitor URB597 increases anandamide levels while causing a compensatory down-regulation in 2-AG levels. These effects are accompanied by a striking lack of reinforcing properties, which distinguishes URB597 from direct-acting cannabinoid agonists such as THC. Our results reveal an unexpected functional heterogeneity within the endocannabinoid signaling system and suggest that FAAH inhibitors might be used therapeutically without risk of abuse or triggering of relapse to drug abuse.

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

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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••].
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Priority CommunicationFatty Acid Amide Hydrolase Inhibition Heightens Anandamide Signaling Without Producing Reinforcing Effects in Primates

Background

Methods

Results

Conclusions

Section snippets

Subjects

Effects of URB597 on FAAH Activity and Brain Endocannabinoid Levels

Discussion

Pharmacol Biochem Behav

J Biol Chem

Chem Biol

Neuropharmacology

J Lipid Res

Biol Psychiatry

Eur J Pharmacol

Oral nabilone capsules in the treatment of chemotherapy-induced nausea and vomiting and pain

Expert Opin Investig Drugs

Analgesic effect of the synthetic cannabinoid CT-3 on chronic neuropathic pain: A randomized controlled trial

JAMA

Cannabis in painful HIV-associated sensory neuropathy: A randomized placebo-controlled trial

Neurology

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

Priority Communication
Fatty Acid Amide Hydrolase Inhibition Heightens Anandamide Signaling Without Producing Reinforcing Effects in Primates