Potential Therapeutic Value of a Novel FAAH Inhibitor for the Treatment of Anxiety

Abstract

Anxiety disorders are among the most prevalent psychiatric diseases with high personal costs and a remarkable socio-economic burden. However, current treatment of anxiety is far from satisfactory. Novel pharmacological targets have emerged in the recent years, and attention has focused on the endocannabinoid (eCB) system, given the increasing evidence that supports its central role in emotion, coping with stress and anxiety. In the management of anxiety disorders, drug development strategies have left apart the direct activation of type-1 cannabinoid receptors to indirectly enhance eCB signalling through the inhibition of eCB deactivation, that is, the inhibition of the fatty acid amide hydrolase (FAAH) enzyme. In the present study, we provide evidence for the anxiolytic-like properties of a novel, potent and selective reversible inhibitor of FAAH, ST4070, orally administered to rodents. ST4070 (3 to 30 mg/kg per os) administered to CD1 male mice induced an increase of time spent in the exploration of the open arms of the elevated-plus maze. A partial reduction of anxiety-related behaviour by ST4070 was also obtained in Wistar male rats, which moderately intensified the time spent in the illuminated compartment of the light-dark box. ST4070 clearly inhibited FAAH activity and augmented the levels of two of its substrates, N-arachidonoylethanolamine (anandamide) and N-palmitoylethanolamine, in anxiety-relevant brain regions. Altogether, ST4070 offers a promising anxiolytic-like profile in preclinical studies, although further studies are warranted to clearly demonstrate its efficacy in the clinic management of anxiety disorders.

Fig 1. ST4070 effects in mice exposed to the elevated plus maze.

Data are expressed as mean ± SEM. Animals were orally administered ST4070 (3, 10 or 30 mg/kg, 60 min before testing) or diazepam (Dzp, 1 mg/kg, i.p. 30 min before testing), and were challenged in the elevated plus-maze for 5 min (n = 12 per experimental group). One-way ANOVA followed by Tukey post-hoc comparisons, * p < 0.05 vs. vehicle.

Fig 2. ST4070 effects in rats exposed to the light-dark box.

Data are expressed as mean ± SEM. Rats were orally administered ST4070 (10 or 30 mg/kg, 60 min before testing), and were challenged in the LD box for 10 min (n = 16–18 per experimental group). One-way ANOVA followed by Tukey post-hoc comparisons, # p = 0.07 vs. vehicle.

Fig 3. ST4070 effects on brain endocannabinoid content.

Data are expressed as mean ± SEM. Rats were orally administered ST4070 (10 or 30 mg/kg, 60 min before testing), and were challenged in the LD box for 10 min. Immediately after testing, animals were sacrificed and brain regions rapidly dissected. Levels of anandamide (AEA), 2-arachidonoylglycerol (2-AG) and N-palmitoylethanolamine (PEA) were measured in specific brain regions (frontal cortex, striatum and hippocampus) (n = 8 per experimental group). One-way ANOVA a followed by Tukey post-hoc comparisons, * p = 0.05 vs. vehicle; # p = 0.06 vs. vehicle.