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

Abstract

Whereas the inhibition of fatty acid amide hydrolase (FAAH) or monoacylglycerol lipase (MAGL), the respective major hydrolytic enzymes of N-arachidonoyl ethanolamine (AEA) and 2-arachidonoylglycerol (2-AG), elicits no or partial substitution for D 9-tetrahydrocannabinol (THC) in drug-discrimination procedures, combined inhibition of both enzymes fully substitutes for THC, as well as produces a constellation of cannabimimetic effects. The present study tested whether C57BL/6J mice would learn to discriminate the dual FAAH-MAGL inhibitor SA-57 (4-[2-(4-chlorophenyl)ethyl]-1-piperidinecarboxylic acid 2-(methylamino)-2-oxoethyl ester) from vehicle in the drugdiscrimination paradigm. In initial experiments, 10 mg/kg SA-57 fully substituted for CP55,940 ((-)-cis-3-[2-hydroxy-4-(1,1-dimethylheptyl)phenyl]-trans-4-(3-hydroxypropyl)cyclohexanol), a high-efficacy CB 1 receptor agonist in C57BL/6J mice and for AEA in FAAH (2/2) mice. Most (i.e., 23 of 24) subjects achieved criteria for discriminating SA-57 (10 mg/kg) from vehicle within biphenyl]-3-yl ester) did not substitute for SA-57, PF-3845 produced a 2-fold leftward shift in the MJN110 substitution doseresponse curve. In addition, the CB 1 receptor antagonist rimonabant blocked the generalization of SA-57, as well as substitution of CP55,940, JZL195, MJN110, and JZL184. These findings suggest that MAGL inhibition plays a major role in the CB 1 receptor-mediated SA-57 training dose, which is further augmented by FAAH inhibition.

Inhibition of the endocannabinoid-regulating enzyme monoacylglycerol lipase elicits a CB1 receptor-mediated discriminative stimulus in mice

“…The findings that CB 1 receptor antagonists block the subjective effects of THC (Järbe et al, 2001; McMahon, 2009; Wiley et al, 1995b) as well as the potent cannabinoid receptor agonist CP55,940 (Owens et al, 2016; Wiley et al, 1995a) establish a receptor mechanism for the discriminative stimulus produced by the naturally occurring and synthetic cannabinoids. Given the challenges associated with investigating the rewarding properties of THC and other cannabinoids in traditional preclinical behavioral assays of abuse liability, the drug discrimination paradigm offers utility to investigate psychoactive properties of this class of drugs (Tanda, 2016).…”

“…Pharmacological inhibitors of FAAH and MAGL that elevate brain levels of endogenous cannabinoids serve as useful investigative tools to reveal the pharmacological properties of endocannabinoids. Notably, FAAH inhibitors do not substitute for the THC discriminative stimulus (Gobbi et al, 2005; Owens et al, 2016; Solinas et al, 2007; Wiley et al, 2014), but increases substitution of exogenously administered AEA (Solinas et al, 2007; Stewart and McMahon, 2011; Vann et al, 2012; Wiley et al, 2014). Moreover, FAAH (−/−) mice learn to discriminate AEA from vehicle, an effect that was blocked by the CB 1 receptor antagonist rimonabant (Walentiny et al, 2011).…”

“…Moreover, mice learn to discriminate SA-57 from vehicle, and rimonabant blocks this discriminative stimulus, implicating CB 1 receptor involvement (Owens et al, 2016). CP55,940, as well as the MAGL inhibitors MJN110 and JZL184 fully substitute for SA-57 (Owens et al, 2016). Thus, in the present study we examined whether mice would learn to discriminate a MAGL inhibitor from vehicle.…”

“…We selected MJN110 as the training drug because of its high potency and increased selectivity compared with other MAGL inhibitors such as JZL184 (Niphakis et al, 2013). We chose 2.5 mg/kg MJN110 as the training dose because this dose fully substitutes for SA-57 2 h following administration without decreasing response rates (Owens et al, 2016). Rimonabant was used to test whether CB 1 receptors mediate the discriminative stimulus effects of MJN110.…”

“…Additionally, as MAGL plays a rate-limiting role in the production of arachidonic acid and its metabolites such as the prostaglandins (Nomura et al, 2011), we tested the COX-2 inhibitor valdecoxib for MJN110 substitution. Finally, we tested two noncannabinoid psychoactive drugs, nicotine (de Moura and McMahon, 2017; Shannon and Herling, 1983) and diazepam (Ator and Griffiths, 1989), the latter of which partially substitutes for the discriminative stimuli of THC (Wiley, 1999) and of SA-57 (Owens et al, 2016). …”