Endocannabinoid contribution to Δ9-tetrahydrocannabinol discrimination in rodents.
Jenny L Wiley, D Matthew Walentiny, M Jerry Wright, Patrick M. Beardsley, James J Burston, Justin L. Poklis, Aron H Lichtman, Robert E Vann
European Journal of Pharmacology August 15, 2014 DOI: 10.1016/j.ejphar.2014.05.013 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Preclinical behavioral pharmacology study (drug discrimination) Peer reviewed |
|---|---|
| Population | Adult male mice and rats |
| Interventions | Anandamide 2-arachidonoyl glycerol (2-AG) URB597 N-arachidonyl maleimide (NAM) PF3845 JZL184 THC |
| Dose | THC 5.6 mg/kg (mice) and 3 mg/kg (rats); PF3845 10 mg/kg |
| Topics | Cannabis |
| Keywords | 2-arachidonoylglycerol Anandamide Jzl184 Pf3845 Urb597 Δ9-tetrahydrocannabinol |
| Key points | Exogenous anandamide or 2-AG alone did not substitute for THC in drug-discrimination tests, but inhibiting their breakdown enzymes produced THC-like responding: PF3845 (10 mg/kg) enhanced anandamide substitution in mice, JZL184 increased brain 2-AG and produced THC-like responding, and combined URB597 plus JZL184 approached full substitution in rats. The authors suggest that raising both endocannabinoids together is most effective at eliciting THC-like discriminative stimulus effects. |
Abstract
The mechanism through which marijuana produces its psychoactive effects is Δ(9)-tetrahydrocannabinol (THC)-induced activation of cannabinoid CB1 receptors. These receptors are normally activated by endogenous lipids, including anandamide and 2-arachidonoyl glycerol (2-AG). A logical "first step" in determination of the role of these endocannabinoids in THC׳s psychoactive effects is to investigate the degree to which pharmacologically induced increases in anandamide and/or 2-AG concentrations through exogenous administration and/or systemic administration of inhibitors of their metabolism, fatty acid amide hydrolase (FAAH) or monoacylglycerol lipase (MAGL), respectively, share THC׳s discriminative stimulus effects. To this end, adult male mice and rats were trained to discriminate THC (5.6 and 3mg/kg, respectively). In Experiment 1, exogenous administration of anandamide or 2-AG did not substitute for THC in mice nor was substitution enhanced by co-administration of the FAAH or MAGL inhibitors, URB597 and N-arachidonyl maleimide (NAM), respectively. Significant decreases in responding may have prevented assessment of adequate endocannabinoid doses. In mice trained at higher baseline response rates (Experiment 2), the FAAH inhibitor PF3845 (10mg/kg) enhanced anandamide substitution for THC without producing effects of its own. The MAGL inhibitor JZL184 increased brain levels of 2-AG in vitro and in vivo, increased THC-like responding without co-administration of 2-AG. In rats, neither URB597 nor JZL184 engendered significant THC-appropriate responding, but co-administration of these two enzyme inhibitors approached full substitution. The present results highlight the complex interplay between anandamide and 2-AG and suggest that endogenous increases of both endocannabinoids are most effective in elicitation of THC-like discriminative stimulus effects.
Comparable studies
Other preclinical and animal studies on cannabis, most cited first.
Citations in the library
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- Sex and Gender Differences in the Effects of Novel Psychoactive Substances. Brain Sciences September 3, 2020
- Regulation of neural connectivity and oscillations by cannabinoids: A review. Neuroscience & Biobehavioral Reviews September 7, 2026
- Discriminative Stimulus Properties of Phytocannabinoids, Endocannabinoids, and Synthetic Cannabinoids. Current Topics in Behavioral Neurosciences 2018
- Inhibition of the endocannabinoid-regulating enzyme monoacylglycerol lipase elicits a CB1 receptor-mediated discriminative stimulus in mice. Neuropharmacology October 2017
- Comparison of the discriminative stimulus and response rate effects of Δ9-tetrahydrocannabinol and synthetic cannabinoids in female and male rats. Drug and Alcohol Dependence March 1, 2017
and 3 more in the library
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and 6 more in the library