Antidepressant-Like Activity and Modulation of Brain Monoaminergic Transmission by Blockade of Anandamide Hydrolysis

• Published in: Proceedings of the National Academy of Sciences - PNAS 2005-12, Vol.102 (51), p.18620-18625
• Main Authors: G. Gobbi, F. R. Bambico, R. Mangieri, M. Bortolato, P. Campolongo, M. Solinasll, T. Cassano, M. G. Morgese, G. Debonnel, A. Duranti, Tontini, A., G. Tarzia, M. Mor, V. Trezza, S. R. Goldberg, V. Cuomo, Piomelli, D., McGaugh, James L.
• Format: Article
• Language: English
• Subjects: Amides; Animals; Antidepressants; Antidepressive Agents - pharmacology; Arachidonic Acids - metabolism; Behavior, Animal - drug effects; Benzamides - pharmacology; Biological Sciences; Brain - drug effects; Brain - metabolism; Cannabinoid Receptor Agonists; Cannabis; Carbamates - pharmacology; Depressive disorders; Dosage; Dronabinol - pharmacology; Endocannabinoids; Fatty acids; Hydrolysis - drug effects; Male; Mental depression; Mice; Mice, Inbred C57BL; Neurology; Neurons; Neurons - drug effects; Neurons - metabolism; Neurotransmitters; Norepinephrine - metabolism; Polyunsaturated Alkamides; Rats; Receptors; Receptors, Cannabinoid - metabolism; Serotonin - metabolism; Serotonin receptors; Vehicles
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.0509591102

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, $\Delta^9-tetrahydrocannabinol$, 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 $\Delta^9-tetrahydrocannabinol$ 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.