Modulation of anxiety through blockade of anandamide hydrolysis.
The psychoactive constituent of cannabis, Delta(9)-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 Delta(9)-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.
Kathuria
Satish
S
Department of Pharmacology, University of California, Irvine, California, USA.
Gaetani
Silvana
S
Fegley
Darren
D
Valiño
Fernando
F
Duranti
Andrea
A
Tontini
Andrea
A
Mor
Marco
M
Tarzia
Giorgio
G
La Rana
Giovanna
G
Calignano
Antonio
A
Giustino
Arcangela
A
Tattoli
Maria
M
Palmery
Maura
M
Cuomo
Vincenzo
V
Piomelli
Daniele
D
D000581:Amidohydrolases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000818:Animals; D014151:Anti-Anxiety Agents / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology / Q000627:therapeutic use; D001007:Anxiety / Q000188:drug therapy / Q000378:metabolism*; D001095:Arachidonic Acids / Q000378:metabolism* / Q000627:therapeutic use; D001522:Behavior, Animal / Q000187:drug effects / Q000502:physiology; D002186:Cannabinoids / Q000037:antagonists & inhibitors / Q000378:metabolism* / Q000627:therapeutic use; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D063388:Endocannabinoids; D006801:Humans; D015394:Molecular Structure; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D010880:Piperidines / Q000494:pharmacology; D053284:Polyunsaturated Alkamides; D011720:Pyrazoles / Q000494:pharmacology; D011869:Radioligand Assay; D051381:Rats; D017208:Rats, Wistar; D043882:Receptors, Cannabinoid; D011955:Receptors, Drug / Q000378:metabolism; D000077285:Rimonabant; D014828:Vocalization, Animal; D000099252:Fatty Acid Amide Hydrolases
D000581:Amidohydrolases; D014151:Anti-Anxiety Agents; D001095:Arachidonic Acids; D002186:Cannabinoids; D063388:Endocannabinoids; D010880:Piperidines; D053284:Polyunsaturated Alkamides; D011720:Pyrazoles; D043882:Receptors, Cannabinoid; D011955:Receptors, Drug; D000077285:Rimonabant; D000099252:Fatty Acid Amide Hydrolases; C078814:anandamide; C107594:N-(4-hydroxyphenyl)arachidonylamide