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Modulation of anxiety through blockade of anandamide hydrolysis

Abstract

The psychoactive constituent of cannabis, Δ9-tetrahydrocannabinol, produces in humans subjective responses mediated by CB1 cannabinoid receptors, indicating that endogenous cannabinoids may contribute to the control of emotion. But the variable effects of Δ9-tetrahydrocannabinol obscure the interpretation of these results and limit the therapeutic potential of direct cannabinoid agonists. An alternative approach may be to develop drugs that amplify the effects of endogenous cannabinoids by preventing their inactivation. Here we describe a class of potent, selective and systemically active inhibitors of fatty acid amide hydrolase, the enzyme responsible for the degradation of the endogenous cannabinoid anandamide. Like clinically used anti-anxiety drugs, in rats the inhibitors exhibit benzodiazepine-like properties in the elevated zero-maze test and suppress isolation-induced vocalizations. These effects are accompanied by augmented brain levels of anandamide and are prevented by CB1 receptor blockade. Our results indicate that anandamide participates in the modulation of emotional states and point to fatty acid amide hydrolase inhibition as an innovative approach to anti-anxiety therapy.

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Figure 1: The FAAH inhibitors URB532 and URB597 block [3H]anandamide degradation in intact brain neurons.
Figure 2: In vivo inhibition of FAAH activity by URB532 and URB597.
Figure 3: Anti-nociceptive actions of URB532 and URB597.
Figure 4: Anxiolytic-like actions of URB532 and URB597.

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Acknowledgements

We thank A. Giuffrida and M. Solbrig for critical reading of the manuscript; B. Ferrer and F. Rodríguez de Fonseca for help with initial experiments; and J. Yoo and C. Park for technical assistance. The assistance of the Centro Interfacoltà Misure (CIM) and the Centro di Calcolo at the University of Parma is gratefully acknowledged. This research was supported by grants from the National Institute on Drug Abuse (to D.P.) and from MIUR, CNR and Universities of Parma and Urbino. D.P. is a Staglin Music Festival Investigator of the National Alliance for Research on Schizophrenia and Depression.

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Correspondence to Daniele Piomelli.

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A patent has been filed, with A.D., A.T., M.M., G.T. and D.P. listed as inventors, the value of which may be affected by the publication of this work.

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Kathuria, S., Gaetani, S., Fegley, D. et al. Modulation of anxiety through blockade of anandamide hydrolysis. Nat Med 9, 76–81 (2003). https://doi.org/10.1038/nm803

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