Enhancement of endocannabinoid signaling with JZL184, an inhibitor of the 2-arachidonoylglycerol hydrolyzing enzyme monoacylglycerol lipase, produces anxiolytic effects under conditions of high environmental aversiveness in rats

Abstract

Dysregulation in signaling of the endocannabinoid 2-arachidonoylglycerol (2-AG) is implicated in hyperresponsiveness to stress. We hypothesized that blockade of monoacylglycerol lipase (MGL), the primary enzyme responsible for 2-AG deactivation in vivo, would produce context-dependent anxiolytic effects in rats. Environmental aversiveness was manipulated by varying illumination of an elevated plus maze. Percentage open arm time and numbers of open and closed arm entries were measured in rats receiving a single intraperitoneal (i.p.) injection of either vehicle, the MGL inhibitor JZL184 (1–8 mg/kg), the benzodiazepine diazepam (1 mg/kg), the cannabinoid CB1 receptor antagonist rimonabant (1 mg/kg), or JZL184 (8 mg/kg) coadministered with rimonabant (1 mg/kg). JZL184 (8 mg/kg) produced anxiolytic-like effects (i.e. increased percentage open arm time and number of open arm entries) under high, but not low, levels of environmental aversiveness. Diazepam produced anxiolytic effects in either context. Rimonabant blocked the anxiolytic-like effects of JZL184, consistent with mediation by CB1. Anxiolytic effects of JZL184 were preserved following chronic (8 mg/kg per day × 6 days) administration. Chronic and acute JZL184 treatment similarly enhanced behavioral sensitivity to an exogenous cannabinoid (WIN55,212-2; 2.5 mg/kg i.p.) 24 or 72 h following the terminal injection, suggesting a pervasive effect of MGL inhibition on the endocannabinoid system. We attribute our results to alterations in emotion rather than locomotor activity as JZL184 did not alter the number of closed arm entries in the plus maze or produce motor ataxia in the bar test. Our results demonstrate that JZL184 has beneficial, context-dependent effects on anxiety in rats, presumably via inhibition of MGL-mediated hydrolysis of 2-AG. These data warrant further testing of MGL inhibitors to elucidate the functional role of 2-AG in controlling anxiety and stress responsiveness. Our data further implicate a role for 2-AG in the regulation of emotion and validate MGL as a therapeutic target.

Therapeutic Potential of Inhibitors of Endocannabinoid Degradation for the Treatment of Stress-Related Hyperalgesia in an Animal Model of Chronic Pain

“…In CUS mice, eCB signaling enhancing drugs induced remarkable effects. Indeed, URB597 administration was effective in decreasing the mechanical hyperalgesia and the anxiety-like behavior induced by CUS in mice even in more challenging anxiety tests (EPM), whereas JZL184, consistent with previous reports (Sciolino et al, 2011;Sumislawski et al, 2011), was not. Interestingly, simultaneous inhibition of FAAH and MAGL (combo), known to induce analgesia in mice (Long et al, 2009b), did not elicit further alleviation of the CUSinduced anxiety and hyperalgesia as compared with individual drug administration.…”

“…The ECS has important roles in both psychiatric disorders (Lutz, 2009;Hill and Patel, 2013) and pain states (Kinsey et al, 2009Piomelli et al, 2006;Piomelli and Sasso, 2014). The anxiolytic and analgesic properties of inhibitors of FAAH and MAGL have been extensively described (Kathuria et al, 2003;Jhaveri et al, 2006;Rossi et al, 2010;Sciolino et al, 2011;Ghosh et al, 2013;Kinsey et al, 2013). Therefore, targeting the ECS may represent a therapeutic strategy, particularly for the treatment of chronic pain associated with emotional imbalance.…”

Endocannabinoid Modulation of Predator Stress-Induced Long-Term Anxiety in Rats

“…These findings complement a growing body of evidence suggesting a role for 2-AG in the Endocannabinoid modulation of long-term anxiety J Lim et al modulation of emotional responses to stress (Evanson et al, 2010;Hill et al, 2011;Sciolino et al, 2011;Sutt et al, 2008). For example, studies have shown that cat odor exposure causes rapid changes in the expression of enzymes involved in the biosynthesis and degradation of 2-AG in various rat brain regions, including amygdala and periaqueductal gray area, immediately after odor exposure (Sutt et al, 2008).…”

“…decreased MGL activity (JZL184 effect, F 1,20 = 23.58 Po0.0001; Figure 2a) and increased 2-AG levels (JZL184 effect, F 1,20 = 11.46, P = 0.0029; Figure 2b) in the brain, irrespective of whether the rats were exposed to saline or TMT. As previously reported for other models of anxiety (Sciolino et al, 2011), treatment with the MGL inhibitor resulted in a reduction in anxiety-like behavior. Administration of JZL184 (16 mg/kg, i.p.)…”

“…Indeed, FAAH inhibitors are currently under investigation as potential treatment for anxiety disorders and secondary prevention for PTSD (Finn, 2010). In addition to anandamide, changes in 2-AG have also been implicated in the regulation of stress-induced responses (Evanson et al, 2010;Hill et al, 2011;Sciolino et al, 2011;Sutt et al, 2008). However, a systematic investigation of the longterm impact of trauma-induced stress on 2-AG-mediated signaling is still lacking.…”