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Neuropharmacology. 2015 Jun;93:237-42. doi: 10.1016/j.neuropharm.2015.02.004. Epub 2015 Feb 16.

Phenotypic assessment of THC discriminative stimulus properties in fatty acid amide hydrolase knockout and wildtype mice.

Author information

1
Department of Pharmacology and Toxicology, Virginia Commonwealth University, Richmond, VA, USA. Electronic address: walentinydm@vcu.edu.
2
Department of Pharmacology and Toxicology, Virginia Commonwealth University, Richmond, VA, USA.
3
Department of Pharmacology and Toxicology, Virginia Commonwealth University, Richmond, VA, USA; Research Triangle Institute, Research Triangle Park, NC, USA.

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).

KEYWORDS:

2-arachidonoylglycerol; Anandamide; Drug discrimination; Fatty acid amide hydrolase; Rimonabant; Δ(9)-Tetrahydrocannabinol

PMID:
25698527
PMCID:
PMC4387086
DOI:
10.1016/j.neuropharm.2015.02.004
[Indexed for MEDLINE]
Free PMC Article

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