Central anandamide deficiency predicts stress-induced anxiety: behavioral reversal through endocannabinoid augmentation

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.