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.
Marcello Solinas, Gianluigi Tanda, Zuzana Justinova, Carrie E Wertheim, Sevil Yasar, Daniele Piomelli, Subramanian K Vadivel, Alexandros Makriyannis, Steven R Goldberg
Journal of Pharmacology and Experimental Therapeutics April 2007 DOI: 10.1124/jpet.106.114124 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Experimental study (drug-discrimination and in vivo microdialysis in rats) Peer reviewed |
|---|---|
| Population | Rats |
| Interventions | Anandamide Methanandamide (AM-356) URB-597 AM-404 UCM-707 Rimonabant Capsazepine |
| Dose | 10 mg/kg anandamide; 3 mg/kg anandamide after URB-597 |
| Topics | Cannabis |
| Key findings | The FAAH inhibitor URB-597 dramatically potentiated THC-like discriminative effects of anandamide, with 3 mg/kg anandamide completely substituting for the THC training dose, and also enhanced anandamide-induced dopamine increases in the accumbens shell. These effects were blocked by rimonabant but not capsazepine. Transport inhibitors AM-404 and UCM-707 did not potentiate anandamide's effects, indicating FAAH inhibition is more effective than transport inhibition. |
Abstract
Anandamide is an endogenous ligand for brain cannabinoid CB(1) receptors, but its behavioral effects are difficult to measure due to rapid inactivation. Here we used a drug-discrimination procedure to test the hypothesis that anandamide, given i.v. or i.p., would produce discriminative effects like those of delta-9-tetrahydrocannabinol (THC) in rats when its metabolic inactivation was inhibited. We also used an in vivo microdialysis procedure to investigate the effects of anandamide, given i.v. or i.p., on dopamine levels in the nucleus accumbens shell in rats. When injected i.v., methanandamide (AM-356), a metabolically stable anandamide analog, produced clear dose-related THC-like discriminative effects, but anandamide produced THC-like discriminative effects only at a high 10-mg/kg dose that almost eliminated lever-press responding. Cyclohexyl carbamic acid 3'-carbamoyl-biphenyl-3-yl ester (URB-597), an inhibitor of fatty acid amide hydrolase (FAAH), the main enzyme responsible for metabolic inactivation of anandamide, produced no THC-like discriminative effects alone but dramatically potentiated discriminative effects of anandamide, with 3 mg/kg anandamide completely substituting for the THC training dose. URB-597 also potentiated the ability of anandamide to increase dopamine levels in the accumbens shell. The THC-like discriminative-stimulus effects of anandamide after URB-597 and methanandamide were blocked by the CB1 receptor antagonist rimonabant, but not the vanilloid VR1 receptor antagonist capsazepine. Surprisingly, the anandamide transport inhibitors N-(4-hydroxyphenyl)-eicosa-5,8,11,14-tetraenamide (AM-404) and N-(3-furylmethyl)eicosa-5,8,11,14-tetraenamide (UCM-707) did not potentiate THC-like discriminative effects of anandamide or its dopamine-elevating effects. Thus, anandamide has THC-like discriminative and neurochemical effects that are enhanced after treatment with a FAAH inhibitor but not after treatment with transport inhibitors, suggesting brain area specificity for FAAH versus transport/FAAH inactivation of anandamide.
Comparable studies
Other preclinical and animal studies on cannabis, most cited first.
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- Discriminative Stimulus Properties of Phytocannabinoids, Endocannabinoids, and Synthetic Cannabinoids. Current Topics in Behavioral Neurosciences 2018
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and 17 more in the library
Cites 5
- Antidepressant-like activity and modulation of brain monoaminergic transmission by blockade of anandamide hydrolysis Proceedings of the National Academy of Sciences December 13, 2005
- (R)-methanandamide and Delta 9-THC as discriminative stimuli in rats: tests with the cannabinoid antagonist SR-141716 and the endogenous ligand anandamide. Psychopharmacology August 2001
- Supersensitivity to anandamide and enhanced endogenous cannabinoid signaling in mice lacking fatty acid amide hydrolase. Proceedings of the National Academy of Sciences of the United States of America July 31, 2001
- Cannabis: discrimination of "internal bliss"? Pharmacology, Biochemistry, and Behavior October 1999
- (R)-methanandamide, but not anandamide, substitutes for delta 9-THC in a drug-discrimination procedure. Experimental and Clinical Psychopharmacology August 1997