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. 2014 Jul 8;4(7):e408.
doi: 10.1038/tp.2014.53.

Central Anandamide Deficiency Predicts Stress-Induced Anxiety: Behavioral Reversal Through Endocannabinoid Augmentation

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Free PMC article

Central Anandamide Deficiency Predicts Stress-Induced Anxiety: Behavioral Reversal Through Endocannabinoid Augmentation

R J Bluett et al. Transl Psychiatry. .
Free PMC article

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.

Figures

Figure 1
Figure 1
PF-3845 treatment reduces anxiety-like behaviors in the light–dark box and NIH assay. PF-3845 (maroon bars) reverses stress-induced anxiety in the light–dark box as compared with vehicle treatment (white bars) as measured by (a) distance traveled in the light zone as a percent of total distance traveled, (b) time in the light zone and (c) total number of light-zone entries. (d) PF-3845 also reverses the stress-induced increase in latency to first drink in the NIH assay (e) without affecting total food consumption (f). (g) Pharmacological blockade of CB1 receptors via rimonabant treatment (R, white bars) prevents PF-3845 (maroon bars) from reversing stress effects on latency in the NIH assay. (h) PF-3845 does not significantly alter consumption in the NIH assay with rimonabant co-treatment. *P<0.05, **P<0.01, ***P<0.001 significantly different from vehicle. NIH, novelty-induced hypophagia.
Figure 2
Figure 2
Stress reduces whole brain AEA levels while PF-3845 treatment increases AEA and OEA. Whole brain (a) AEA, (b) OEA and (c) 2-AG levels from mice immediately after completion of the light–dark box test (24 h after acute foot-shock stress and 2 h after drug treatment) demonstrate that stress decreases AEA and PF-3845 increases AEA and OEA, whereas neither stress nor PF-3845 treatment affects 2-AG. *P<0.05, ††††P<0.001 significantly different from corresponding vehicle control. AEA, N-arachidonylethanolamine; 2-AG, 2-arachidonoylglycerol; OEA, oleoylethananolamide.
Figure 3
Figure 3
Whole brain decreases in AEA correlate with increased anxiety in the light–dark box test. Linear regression analyses reveal significant correlations between whole brain AEA levels in control and stressed mice and (a) light-zone entries, (c) light-zone distance traveled as a percent of total distance traveled, (e) light-zone time and (g) total distance traveled. After PF-3845 treatment, however, the same measures no longer correlate with AEA levels (b, d, f and h), suggesting a saturation of AEA effects on anxiety at supraphysiological levels. Linear regression (solid line) with 95% confidence intervals (dashed lines) shown in figures. AEA, N-arachidonylethanolamine.

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References

    1. Caspi A, Sugden K, Moffitt TE, Taylor A, Craig IW, Harrington H, et al. Influence of life stress on depression: moderation by a polymorphism in the 5-HTT gene. Science. 2003;301:386–389. - PubMed
    1. Hunter RG, McEwen BS. Stress and anxiety across the lifespan: structural plasticity and epigenetic regulation. Epigenomics. 2013;5:177–194. - PubMed
    1. Griebel G, Holmes A. 50 years of hurdles and hope in anxiolytic drug discovery. Nat Rev Drug Discov. 2013;12:667–687. - PMC - PubMed
    1. Gamble-George JC, Conger JR, Hartley ND, Gupta P, Sumislawski JJ, Patel S. Dissociable effects of CB1 receptor blockade on anxiety-like and consummatory behaviors in the novelty-induced hypophagia test in mice. Psychopharmacology. 2013;228:401–409. - PMC - PubMed
    1. Hermanson DJ, Hartley ND, Gamble-George J, Brown N, Shonesy BC, Kingsley PJ, et al. Substrate-selective COX-2 inhibition decreases anxiety via endocannabinoid activation. Nat Neurosci. 2013;16:1291–1298. - PMC - PubMed

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