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Phenotypic assessment of THC discriminative stimulus properties in fatty acid amide hydrolase knockout and wildtype mice.
Neuropharmacology. 2015 Jun; 93:237-42.N

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).

Authors+Show Affiliations

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

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural

Language

eng

PubMed ID

25698527

Citation

Walentiny, D Matthew, et al. "Phenotypic Assessment of THC Discriminative Stimulus Properties in Fatty Acid Amide Hydrolase Knockout and Wildtype Mice." Neuropharmacology, vol. 93, 2015, pp. 237-42.
Walentiny DM, Vann RE, Wiley JL. Phenotypic assessment of THC discriminative stimulus properties in fatty acid amide hydrolase knockout and wildtype mice. Neuropharmacology. 2015;93:237-42.
Walentiny, D. M., Vann, R. E., & Wiley, J. L. (2015). Phenotypic assessment of THC discriminative stimulus properties in fatty acid amide hydrolase knockout and wildtype mice. Neuropharmacology, 93, 237-42. https://doi.org/10.1016/j.neuropharm.2015.02.004
Walentiny DM, Vann RE, Wiley JL. Phenotypic Assessment of THC Discriminative Stimulus Properties in Fatty Acid Amide Hydrolase Knockout and Wildtype Mice. Neuropharmacology. 2015;93:237-42. PubMed PMID: 25698527.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Phenotypic assessment of THC discriminative stimulus properties in fatty acid amide hydrolase knockout and wildtype mice. AU - Walentiny,D Matthew, AU - Vann,Robert E, AU - Wiley,Jenny L, Y1 - 2015/02/16/ PY - 2014/08/20/received PY - 2014/12/05/revised PY - 2015/02/01/accepted PY - 2015/2/21/entrez PY - 2015/2/24/pubmed PY - 2016/1/2/medline KW - 2-arachidonoylglycerol KW - Anandamide KW - Drug discrimination KW - Fatty acid amide hydrolase KW - Rimonabant KW - Δ(9)-Tetrahydrocannabinol SP - 237 EP - 42 JF - Neuropharmacology JO - Neuropharmacology VL - 93 N2 - 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). SN - 1873-7064 UR - https://www.unboundmedicine.com/medline/citation/25698527/Phenotypic_assessment_of_THC_discriminative_stimulus_properties_in_fatty_acid_amide_hydrolase_knockout_and_wildtype_mice_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0028-3908(15)00050-7 DB - PRIME DP - Unbound Medicine ER -