Simultaneous Inhibition of Fatty Acid Amide Hydrolase and Monoacylglycerol Lipase Shares Discriminative Stimulus Effects with Δ⁹-Tetrahydrocannabinol in Mice

Abstract

Monoacylglycerol lipase (MAGL) and fatty acid amide hydrolase (FAAH) inhibitors exert preclinical effects indicative of therapeutic potential (i.e., analgesia). However, the extent to which MAGL and FAAH inhibitors produce unwanted effects remains unclear. Here, FAAH and MAGL inhibition was examined separately and together in a D 9-tetrahydrocannabinol (D 9 -THC; 5.6 mg/kg i.p.) discrimination assay predictive of subjective effects associated with cannabis use, and the relative contribution of N-arachidonoyl ethanolamine (AEA) and 2-arachidonoylglycerol (2-AG) in the prefrontal cortex, hippocampus, and caudate putamen to those effects was examined. -THC was also produced by a combination of JZL184 and PF-3845, but not by a combination of JZL184 and URB597 (i.e., 52% maximum). Cannabinoid receptor type 1 antagonist rimonabant attenuated the discriminative stimulus effects of D 9 -THC, SA-57, JZL195, and the combined effects of JZL184 and PF-3845. Full substitution for the D 9 -THC discriminative stimulus occurred only when both 2-AG and AEA were significantly elevated, and the patterns of increased endocannabinoid content were similar among brain regions. Overall, these results suggest that increasing both endogenous 2-AG and AEA produces qualitatively unique effects (i.e., the subjective effects of cannabis) that are not obtained from increasing either 2-AG or AEA separately.

Discriminative Stimulus Properties of the Endocannabinoid Catabolic Enzyme Inhibitor SA-57 in Mice

“…Consistent with previous studies reporting that SA-57 or the dual FAAH-MAGL inhibitor JZL195 substitute for the THC discriminative stimulus (Long et al, 2009b;Hruba et al, 2015;Walentiny et al, 2015), we found that SA-57 (10 mg/kg) fully substituted for the discriminative stimulus effects of the potent cannabinoid receptor agonist CP55,940 in C57BL/6J mice and the endogenous cannabinoid AEA (6 mg/kg) in FAAH (2/2) mice. The potency of SA-57 in producing a discriminative …”

“…Similarly, the MAGL inhibitor JZL184 elevates endogenous 2-AG brain levels and produces antinociception, but it only partially substitutes for THC (Long et al, 2009a,b;Wiley et al, 2014;Walentiny et al, 2015). Conversely, the dual FAAH-MAGL inhibitor JZL195 fully substitutes for THC, elicits a constellation of cannabimimetic effects (Long et al, 2009b;Wise et al, 2012;Hruba et al, 2015), and produces an increased magnitude of antinociceptive effects compared with single enzyme inhibition (Long et al, 2009b;Ghosh et al, 2015). Similarly, the dual FAAH-MAGL inhibitor SA-57 fully substitutes for THC in wild-type mice .…”

Full Fatty Acid Amide Hydrolase Inhibition Combined with Partial Monoacylglycerol Lipase Inhibition: Augmented and Sustained Antinociceptive Effects with Reduced Cannabimimetic Side Effects in Mice

“…Although 4 mg/kg JZL184 plus PF-3845 completely reversed carrageenan-induced allodynia, significant cataleptic, hypothermic, and locomotor depressant effects emerged only after 100 mg/kg JZL184 in combination of PF-3845. Similarly, whereas we found that 4 mg/kg JZL184 plus PF-3845 did not substitute for THC in the drug-discrimination assay, the combination of 10 mg/kg PF-3845 and 40 mg/kg JZL184 partially substituted and 120 mg/kg JZL184 fully substituted for THC (Hruba et al, 2015); however, the different vehicles used in the drug-discrimination experiment (i.e., 1:1:18 mixture of propylene glycol, Tween-80, and saline) compared with the other experiments (i.e., 1:1:18 mixture of ethanol, alkamuls-620, and saline) limit direct comparison. Nonetheless, observations that the dose of JZL184 in combination with PF-3845 that elicited significant antiallodynic effects in CCI and carrageenan assays was 25-fold lower than the dose required to produce significant cataleptic, hypothermic, and motor depressive effects represent a reasonable separation between antiallodynic effects and cannabimimetic side effects.…”

“…However, dual blockade of these enzymes can also elicit cannabimimetic side effects, including catalepsy, hypomotility, deficits in learning and memory, and THC-like interoceptive cues (Long et al, 2009d;Anderson et al, 2014;Ignatowska-Jankowska et al, 2014;Wiley et al, 2014;Hruba et al, 2015;Walentiny et al, 2015). Moreover, prolonged and complete MAGL inactivation results in tolerance accompanied with CB 1 receptor downregulation and desensitization (Chanda et al, 2010;Schlosburg et al, 2010;Schlosburg et al, 2014).…”

Effects of fatty acid amide hydrolase (FAAH) inhibitors on working memory in rats

“…dose of AM3506 fully inhibited FAAH and increased anandamide in rat brain, but did not increase 2-AG; higher doses were not tested in rats, but a 3 mg/kg dose produced a moderate (-39%) inhibition of MGL in mice. One reason that selectivity is important is that treatment with a dual inhibitor of FAAH and MGL or with a selective FAAH inhibitor combined with a selective MGL inhibitor can produce THC-like effects in drug discrimination (Hruba et al 2015) and short-term memory tests (Wise et al 2012). Interestingly, Hruba et al (2015) found that combined treatment with the FAAH inhibitor PF3845 plus the MGL inhibitor JZL184 produced THC-like discriminative effects in mice, but combined treatment with the FAAH inhibitor URB597 plus JZL184 did not.…”