Antidepressant-like activity and modulation of brain monoaminergic transmission by blockade of anandamide hydrolysis
Gabriella Gobbi, Francis Rodriguez Bambico, Regina A. Mangieri, Marco Bortolato, Patrizia Campolongo, Marcello Solinas, Tommaso Cassano, Maria Grazia Morgese, Guy Debonnel, Andrea Duranti, Andrea Tontini, Giorgio Tarzia, Marco Mor, Viviana Trezza, S. Goldberg, V. Cuomo, Daniele Piomelli
Proceedings of the National Academy of Sciences December 13, 2005 DOI: 10.1073/pnas.0509591102 via OpenAlex
Summary
AI-generated from the abstractInhibiting the enzyme fatty-acid amide hydrolase (FAAH) with URB597, which prevents the breakdown of the endocannabinoid anandamide, produces antidepressant-like effects in mice and rats. URB597 reduced immobility in the tail-suspension and forced-swim tests, and increased firing of serotonin and norepinephrine neurons in brain regions linked to mood. These effects required CB1 receptor activation and were accompanied by higher brain anandamide levels. Unlike direct THC-like drugs, URB597 showed no rewarding or abuse-related effects. The findings suggest FAAH inhibition as a potential target for antidepressant drugs without the psychotropic side effects of cannabis.
Study at a glance
| Characteristics | Preclinical study Peer reviewed |
|---|---|
| Population | Mice and rats |
| Intervention | URB597 |
| Keywords | Anandamide Endocannabinoid system Pharmacology Cannabinoid receptor Behavioural despair test |
| Citations | 675 |
| Key finding | URB597, a selective inhibitor of fatty-acid amide hydrolase, exerts antidepressant-like effects in behavioral tests without rewarding or THC-like effects. |
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, delta9-tetrahydrocannabinol, acts by binding to brain CB1 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 CB1 antagonist rimonabant, are accompanied by increased brain anandamide levels, and are maintained upon repeated URB597 administration. Unlike direct CB1 agonists, URB597 does not exert rewarding effects in the conditioned place preference test or produce generalization to the discriminative effects of delta9-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.