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.
Key Words
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References
- Oral nabilone capsules in the treatment of chemotherapy-induced nausea and vomiting and pain.Expert Opin Investig Drugs. 2008; 17: 85-95
- Analgesic effect of the synthetic cannabinoid CT-3 on chronic neuropathic pain: A randomized controlled trial.JAMA. 2003; 290: 1757-1762
- Cannabis in painful HIV-associated sensory neuropathy: A randomized placebo-controlled trial.Neurology. 2007; 68: 515-521
- Randomized, controlled trial of cannabis-based medicine in central pain in multiple sclerosis.Neurology. 2005; 65: 812-819
- Meta-analysis of cannabis based treatments for neuropathic and multiple sclerosis-related pain.Curr Med Res Opin. 2007; 23: 17-24
- Cannabinoids reduce symptoms of Tourette's syndrome.Expert Opin Pharmacother. 2003; 4: 1717-1725
- Self-administration of cannabinoids by experimental animals and human marijuana smokers.Pharmacol Biochem Behav. 2005; 81: 285-299
- Cannabinoids: Reward, dependence, and underlying neurochemical mechanisms—a review of recent preclinical data.Psychopharmacology (Berl). 2003; 169: 115-134
- The endocannabinoid system in brain reward processes.Br J Pharmacol. 2008; 154: 369-383
- The molecular logic of endocannabinoid signalling.Nat Rev Neurosci. 2003; 4: 873-884
- Molecular characterization of an enzyme that degrades neuromodulatory fatty-acid amides.Nature. 1996; 384: 83-87
- Anandamide amidohydrolase activity in rat brain microsomes.J Biol Chem. 1995; 270: 6030-6035
- Brain monoglyceride lipase participating in endocannabinoid inactivation.Proc Natl Acad Sci U S A. 2002; 99: 10819-10824
- A comprehensive profile of brain enzymes that hydrolyze the endocannabinoid 2-arachidonoylglycerol.Chem Biol. 2007; 14: 1347-1356
- 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. 2004; 47: 4998-5008
- Design, synthesis, and structure-activity relationships of alkylcarbamic acid aryl esters, a new class of fatty acid amide hydrolase inhibitors.J Med Chem. 2003; 46: 2352-2360
- Modulation of anxiety through blockade of anandamide hydrolysis.Nat Med. 2003; 9: 76-81
- Antidepressant-like activity and modulation of brain monoaminergic transmission by blockade of anandamide hydrolysis.Proc Natl Acad Sci U S A. 2005; 102: 18620-18625
- The endogenous cannabinoid anandamide has effects on motivation and anxiety that are revealed by fatty acid amide hydrolase (FAAH) inhibition.Neuropharmacology. 2008; 54: 129-140
- Actions of the FAAH inhibitor URB597 in neuropathic and inflammatory chronic pain models.Br J Pharmacol. 2006; 147: 281-288
- The fatty acid amide hydrolase inhibitor URB597 (cyclohexylcarbamic acid 3'-carbamoylbiphenyl-3-yl ester) reduces neuropathic pain after oral administration in mice.J Pharmacol Exp Ther. 2007; 322: 236-242
- Self-administration of Delta(9)-tetrahydrocannabinol (THC) by drug naive squirrel monkeys.Psychopharmacology (Berl). 2003; 169: 135-140
- The opioid antagonist naltrexone reduces the reinforcing effects of Delta 9 tetrahydrocannabinol (THC) in squirrel monkeys.Psychopharmacology (Berl). 2004; 173: 186-194
- The endogenous cannabinoid anandamide and its synthetic analog R(+)-methanandamide are intravenously self-administered by squirrel monkeys.J Neurosci. 2005; 25: 5645-5650
- Blockade of THC-seeking behavior and relapse in monkeys by the cannabinoid CB(1)-receptor antagonist rimonabant [published online ahead of print February 27].Neuropsychopharmacology. 2008; (doi: 10.1038/npp.2008.21)
- Self-administration behavior is maintained by the psychoactive ingredient of marijuana in squirrel monkeys.Nat Neurosci. 2000; 3: 1073-1074
- Comparable behavior maintained under fixed-ratio and second-order schedules of food presentation, cocaine injection or d-amphetamine injection in the squirrel monkey.J Pharmacol Exp Ther. 1973; 186: 18-30
- A Stereotaxic Atlas of the Brain of the Squirrel Monkey (Saimiri sciureus).University of Wisconsin Press, Madison1963
- Characterization of the fatty acid amide hydrolase inhibitor cyclohexyl carbamic acid 3'-carbamoyl-biphenyl-3-yl ester (URB597): Effects on anandamide and oleoylethanolamide deactivation.J Pharmacol Exp Ther. 2005; 313: 352-358
- Identification of biosynthetic precursors for the endocannabinoid anandamide in the rat brain.J Lipid Res. 2008; 49: 48-57
- Oleylethanolamide regulates feeding and body weight through activation of the nuclear receptor PPAR-alpha.Nature. 2003; 425: 90-93
- Antidepressant-like activity of the fatty acid amide hydrolase inhibitor URB597 in a rat model of chronic mild stress.Biol Psychiatry. 2007; 62: 1103-1110
- Endocannabinoids acting at cannabinoid-1 receptors regulate cardiovascular function in hypertension.Circulation. 2004; 110: 1996-2002
- Mechanisms of endocannabinoid inactivation: Biochemistry and pharmacology.J Pharmacol Exp Ther. 2001; 298: 7-14
- The endogenous cannabinoid anandamide produces delta-9-tetrahydrocannabinol-like discriminative and neurochemical effects that are enhanced by inhibition of fatty acid amide hydrolase but not by inhibition of anandamide transport.J Pharmacol Exp Ther. 2007; 321: 370-380
- Anandamide administration alone and after inhibition of fatty acid amide hydrolase (FAAH) increases dopamine levels in the nucleus accumbens shell in rats.J Neurochem. 2006; 98: 408-419
- Anandamide inhibits metabolism and physiological actions of 2-arachidonoylglycerol in the striatum.Nat Neurosci. 2008; 11 (V): 152-159
- Relationship between minimum reinforcing doses and injection speed in cocaine and pentobarbital self-administration in crab-eating monkeys.Pharmacol Biochem Behav. 1987; 28: 407-410
- Relationship between injection duration, transporter occupancy and reinforcing strength of cocaine.Eur J Pharmacol. 2004; 486: 251-257
- Reinforcing effect as a function of infusion speed in intravenous self-administration of nicotine in rhesus monkeys.Nihon Shinkei Seishin Yakurigaku Zasshi. 1995; 15: 53-59
- Fixed-interval schedule of cocaine reinforcement: Effect of dose and infusion duration.J Exp Anal Behav. 1973; 20: 119-129
- Effects of delivery rate and non-contingent infusion of cocaine on cocaine self-administration in rhesus monkeys.Psychopharmacology (Berl). 1998; 137: 253-258
Article info
Publication history
Published online: September 25, 2008
Accepted:
August 4,
2008
Received in revised form:
July 8,
2008
Received:
May 8,
2008
Identification
Copyright
© 2008 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.
