Antidepressant-like activity and modulation of brain monoaminergic transmission by blockade of anandamide hydrolysis

TLDR

Cannabis may alleviate depression, but its psychotropic properties limit therapeutic use, suggesting that enhancing endogenous cannabinoid signaling by blocking anandamide degradation could be a viable alternative. The study aimed to determine whether URB597, a selective fatty‑acid amide hydrolase inhibitor, produces antidepressant‑like effects in rodents. URB597 selectively inhibits FAAH, thereby increasing anandamide levels, and was tested in the mouse tail‑suspension and rat forced‑swim paradigms. URB597 elevated serotonergic and noradrenergic firing, raised brain anandamide, and elicited antidepressant‑like behavior without rewarding effects; these actions were blocked by the CB1 antagonist rimonabant, supporting anandamide’s role in mood regulation and identifying FAAH as a novel antidepressant target.

Abstract

Although anecdotal reports suggest that cannabis may be used to alleviate symptoms of depression, the psychotropic effects and abuse liability of this drug prevent its therapeutic application. The active constituent of cannabis, Δ 9 -tetrahydrocannabinol, acts by binding to brain CB 1 cannabinoid receptors, but an alternative approach might be to develop agents that amplify the actions of endogenous cannabinoids by blocking their deactivation. Here, we show that URB597, a selective inhibitor of the enzyme fatty-acid amide hydrolase, which catalyzes the intracellular hydrolysis of the endocannabinoid anandamide, exerts potent antidepressant-like effects in the mouse tail-suspension test and the rat forced-swim test. Moreover, URB597 increases firing activity of serotonergic neurons in the dorsal raphe nucleus and noradrenergic neurons in the nucleus locus ceruleus. These actions are prevented by the CB 1 antagonist rimonabant, are accompanied by increased brain anandamide levels, and are maintained upon repeated URB597 administration. Unlike direct CB 1 agonists, URB597 does not exert rewarding effects in the conditioned place preference test or produce generalization to the discriminative effects of Δ 9 -tetrahydrocannabinol in rats. The findings support a role for anandamide in mood regulation and point to fatty-acid amide hydrolase as a previously uncharacterized target for antidepressant drugs.