Phenotypic assessment of THC discriminative stimulus properties in fatty acid amide hydrolase knockout and wildtype mice.
D Matthew Walentiny, Robert E Vann, Jenny L Wiley
Neuropharmacology June 2015 DOI: 10.1016/j.neuropharm.2015.02.004 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Drug discrimination study in transgenic mice Peer reviewed |
|---|---|
| Population | FAAH knockout and wildtype mice |
| Interventions | Δ(9)-tetrahydrocannabinol (THC) anandamide O-1812 rimonabant JZL184 JZL195 |
| Dose | THC 5.6 mg/kg |
| Topics | Cannabis |
| Keywords | 2-arachidonoylglycerol Anandamide Drug discrimination Rimonabant Δ9-tetrahydrocannabinol |
| Key points | THC produced similar discriminative stimulus effects in FAAH knockout and wildtype mice, but anandamide fully substituted for THC only in knockouts, and the anandamide analog O-1812 was more potent in knockouts. MAGL inhibition with JZL184 fully substituted in knockouts and nearly fully in wildtypes. The authors suggest elevated baseline anandamide does not alter THC's subjective effects, but FAAH knockout mice are more sensitive to THC-like effects of pharmacologically increased anandamide and MAGL inhibition. |
Abstract
A number of studies have examined the ability of the endogenous cannabinoid anandamide to elicit Δ(9)-tetrahydrocannabinol (THC)-like subjective effects, as modeled through the THC discrimination paradigm. In the present study, we compared transgenic mice lacking fatty acid amide hydrolase (FAAH), the enzyme primarily responsible for anandamide catabolism, to wildtype counterparts in a THC discrimination procedure. THC (5.6 mg/kg) served as a discriminative stimulus in both genotypes, with similar THC dose-response curves between groups. Anandamide fully substituted for THC in FAAH knockout, but not wildtype, mice. Conversely, the metabolically stable anandamide analog O-1812 fully substituted in both groups, but was more potent in knockouts. The CB1 receptor antagonist rimonabant dose-dependently attenuated THC generalization in both groups and anandamide substitution in FAAH knockouts. Pharmacological inhibition of monoacylglycerol lipase (MAGL), the primary catabolic enzyme for the endocannabinoid 2-arachidonoylglycerol (2-AG), with JZL184 resulted in full substitution for THC in FAAH knockout mice and nearly full substitution in wildtypes. Quantification of brain endocannabinoid levels revealed expected elevations in anandamide in FAAH knockout mice compared to wildtypes and equipotent dose-dependent elevations in 2-AG following JZL184 administration. Dual inhibition of FAAH and MAGL with JZL195 resulted in roughly equipotent increases in THC-appropriate responding in both groups. While the notable similarity in THC's discriminative stimulus effects across genotype suggests that the increased baseline brain anandamide levels (as seen in FAAH knockout mice) do not alter THC's subjective effects, FAAH knockout mice are more sensitive to the THC-like effects of pharmacologically induced increases in anandamide and MAGL inhibition (e.g., JZL184).
Comparable studies
Other preclinical and animal studies on cannabis, most cited first.
Citations in the library
Cited by 3
- Discriminative Stimulus Properties of Phytocannabinoids, Endocannabinoids, and Synthetic Cannabinoids. Current Topics in Behavioral Neurosciences 2018
- Discriminative Stimulus Properties of the Endocannabinoid Catabolic Enzyme Inhibitor SA-57 in Mice. Journal of Pharmacology and Experimental Therapeutics August 2016
- Just add water: cannabinoid discrimination in a water T-maze with FAAH(-/-) and FAAH(+/+) mice. Behavioural Pharmacology August 2016
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