title: Central anandamide deficiency predicts stress-induced anxiety: behavioral reversal through endocannabinoid augmentation.
abstract: Stress is a major risk factor for the development of mood and anxiety disorders; elucidation of novel approaches to mitigate the deleterious effects of stress could have broad clinical applications. Pharmacological augmentation of central endogenous cannabinoid (eCB) signaling may be an effective therapeutic strategy to mitigate the adverse behavioral and physiological consequences of stress. Here we show that acute foot-shock stress induces a transient anxiety state measured 24 h later using the light-dark box assay and novelty-induced hypophagia test. Acute pharmacological inhibition of the anandamide-degrading enzyme, fatty acid amide hydrolase (FAAH), reverses the stress-induced anxiety state in a cannabinoid receptor-dependent manner. FAAH inhibition does not significantly affect anxiety-like behaviors in non-stressed mice. Moreover, whole brain anandamide levels are reduced 24 h after acute foot-shock stress and are negatively correlated with anxiety-like behavioral measures in the light-dark box test. These data indicate that central anandamide levels predict acute stress-induced anxiety, and that reversal of stress-induced anandamide deficiency is a key mechanism subserving the therapeutic effects of FAAH inhibition. These studies provide further support that eCB-augmentation is a viable pharmacological strategy for the treatment of stress-related neuropsychiatric disorders.
authors.affiliation: 1] Department of Psychiatry, Vanderbilt University School of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA [2] Vanderbilt Brain Institute, Vanderbilt University Medical Center, Nashville, TN, USA.
authors.forename: R J
authors.initials: RJ
authors.lastname: Bluett
authors.affiliation: 1] Department of Psychiatry, Vanderbilt University School of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA [2] Vanderbilt Brain Institute, Vanderbilt University Medical Center, Nashville, TN, USA.
authors.forename: J C
authors.initials: JC
authors.lastname: Gamble-George
authors.affiliation: A.B. Hancock Jr. Memorial Laboratory for Cancer Research, Departments of Biochemistry, Chemistry, and Pharmacology, Vanderbilt Institute of Chemical Biology, Center in Molecular Toxicology, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA.
authors.forename: D J
authors.initials: DJ
authors.lastname: Hermanson
authors.affiliation: Department of Psychiatry, Vanderbilt University School of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA.
authors.forename: N D
authors.initials: ND
authors.lastname: Hartley
authors.affiliation: A.B. Hancock Jr. Memorial Laboratory for Cancer Research, Departments of Biochemistry, Chemistry, and Pharmacology, Vanderbilt Institute of Chemical Biology, Center in Molecular Toxicology, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA.
authors.forename: L J
authors.initials: LJ
authors.lastname: Marnett
authors.affiliation: 1] Department of Psychiatry, Vanderbilt University School of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA [2] Vanderbilt Brain Institute, Vanderbilt University Medical Center, Nashville, TN, USA [3] Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA.
authors.forename: S
authors.initials: S
authors.lastname: Patel
mesh_terms: D000581:Amidohydrolases / Q000037:antagonists & inhibitors*; D000818:Animals; D001007:Anxiety / Q000209:etiology / Q000378:metabolism*; D001095:Arachidonic Acids / Q000172:deficiency / Q000378:metabolism*; D001522:Behavior, Animal / Q000187:drug effects / Q000502:physiology*; D004195:Disease Models, Animal; D063388:Endocannabinoids / Q000172:deficiency / Q000378:metabolism*; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D053284:Polyunsaturated Alkamides / Q000378:metabolism*; D013315:Stress, Psychological / Q000150:complications / Q000378:metabolism*; D000099252:Fatty Acid Amide Hydrolases
chemical_list: D000581:Amidohydrolases; D001095:Arachidonic Acids; D063388:Endocannabinoids; D053284:Polyunsaturated Alkamides; D000099252:Fatty Acid Amide Hydrolases; C078814:anandamide