FAAH−/− Mice Display Differential Tolerance, Dependence, and Cannabinoid Receptor Adaptation After Δ9-Tetrahydrocannabinol and Anandamide Administration

Abstract Repeated administration of Δ9-tetrahydrocannabinol (THC), the primary psychoactive constituent of Cannabis sativa, induces profound tolerance that correlates with desensitization and downregulation of CB1 cannabinoid receptors in the CNS. However, the consequences of repeated administration of the endocannabinoid N-arachidonoyl ethanolamine (anandamide, AEA) on cannabinoid receptor regulation are unclear because of its rapid metabolism by fatty acid amide hydrolase (FAAH). FAAH−/− mice dosed subchronically with equi-active maximally effective doses of AEA or THC displayed greater rightward shifts in THC dose–effect curves