Abstract
Recent studies have demonstrated anxiolytic potential of pharmacological endocannabinoid (eCB) augmentation approaches in a variety of preclinical models. Pharmacological inhibition of endocannabinoid-degrading enzymes, such as fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL), elicit promising anxiolytic effects in rodent models with limited adverse behavioral effects, however, the efficacy of dual FAAH/MAGL inhibition has not been investigated. In the present study, we compared the effects of FAAH (PF-3845), MAGL (JZL184) and dual FAAH/MAGL (JZL195) inhibitors on (1) anxiety-like behaviors under non-stressed and stressed conditions, (2) locomotor activity and body temperature, (3) lipid levels in the brain and (4) cognitive functions. Behavioral analysis showed that PF-3845 or JZL184, but not JZL195, was able to prevent restraint stress-induced anxiety in the light–dark box assay when administered before stress exposure. Moreover, JZL195 treatment was not able to reverse foot shock-induced anxiety-like behavior in the elevated zero maze or light–dark box. JZL195, but not PF-3845 or JZL184, decreased body temperature and increased anxiety-like behavior in the open-field test. Overall, JZL195 did not show anxiolytic efficacy and the effects of JZL184 were more robust than that of PF-3845 in the models examined. These results showed that increasing either endogenous AEA or 2-AG separately produces anti-anxiety effects under stressful conditions but the same effects are not obtained from simultaneously increasing both AEA and 2-AG.
Highlights
Mood and anxiety disorders are chronic, disabling conditions that impose enormous cost both on individuals and society[1]
Inhibition, prevents novelty-induced anxiety-like behavior in the novelty-induced hypophagia (NIH) assay we examined the effects of PF-3845 (0.1 and 1 mg kg–1), JZL184 (5, 10, 15 mg kg–1) or JZL195 (5, 10, 15 mg kg–1) on novelty-induced anxiety-like behaviors by using the NIH assay, which is highly sensitive to stress and eCB manipulations[30]
The main findings of this study are that (1) restraint stress-induced anxiety-like behavior can be prevented by either acute selective fatty acid amide hydrolase (FAAH) or monoacylglycerol lipase (MAGL), but not by dual FAAH/MAGL, inhibition, (2) acute MAGL inhibition decreases novelty-induced anxiety and can reverse foot shock-induced anxiety-like behavior, (3) dual FAAH/ MAGL, but not FAAH or MAGL, inhibition decreases body temperature and increases anxiety-like behavior and (4) none of the inhibitors impaired cognitive functions at doses relevant for anxiety-like behavior
Summary
Mood and anxiety disorders are chronic, disabling conditions that impose enormous cost both on individuals and society[1]. Current clinical treatments for anxiety and mood disorders are primarily based on augmenting monoaminergic transmission[2]. Current treatment approaches are often only partially effective and are often associated with adverse effects[3]. The search for novel pharmacological treatments for these conditions is driven. The endocannabinoid (eCB) system has gained attention in recent years as a potential target for novel anxiolytics[6,7]. A number of preclinical studies support the role of the eCB system as a modulator of anxiety-related behaviors, depressive-like behaviors and extinction of fear memories[9,10,11].
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