Abstract
Rationale
Since the discovery of endogenous cannabinoid signaling, the number of studies exploring its role in health and disease has increased exponentially. Fatty acid amide hydrolase (FAAH), the enzyme responsible for degradation of the endocannabinoid anandamide, has emerged as a promising target for anxiety-related disorders. FAAH inhibitors (e.g., URB597) increase brain levels of anandamide and induce anxiolytic-like effects in rodents. Recent findings, however, questioned the efficacy of URB597 as an anxiolytic.
Objectives
We tested here the hypothesis that conflicting findings are due to variations in the stressfulness of experimental conditions employed in various studies.
Results
We found that URB597 (0.1–0.3 mg/kg) did not produce anxiolytic effects when the aversiveness of testing procedures was minimized by handling rats daily before experimentation, by habituating them to the experimental room, or by employing low illumination during testing. In contrast, URB597 had robust anxiolytic effects when the aversiveness of the testing environment was increased by eliminating habituation to the experimental room or by employing bright lighting conditions. Unlike URB597, the benzodiazepine chlordiazepoxide (5 mg/kg) had anxiolytic effects under all testing conditions. The anxiolytic effects of URB597 were abolished by the cannabinoid CB1-receptor antagonist AM251, showing that they were mediated by CB1 receptors. Close inspection of experimental conditions employed in earlier reports suggests that conflicting findings with URB597 can be explained by different testing conditions, such as those manipulated in the present study.
Conclusions
Our findings show that FAAH inhibition does not affect anxiety under mildly stressful circumstances but protects against the anxiogenic effects of aversive stimuli.
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Acknowledgments
This study was supported in part by the Intramural Research Program of the National Institute on Drug Abuse, National Institutes of Health, Department of Health and Human Services, Baltimore, MD, USA and OTKA (Hungarian Scientific Research Fund) grant No. K72621 to J. Haller. The authors thank Sachin Patel for help provided during preparation of the manuscript. Both funding institutions sponsor basic research. No income was obtained from commercial sponsors. The authors have full control of all primary data and they agree to allow the journal to review their data if requested.
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Haller, J., Barna, I., Barsvari, B. et al. Interactions between environmental aversiveness and the anxiolytic effects of enhanced cannabinoid signaling by FAAH inhibition in rats. Psychopharmacology 204, 607–616 (2009). https://doi.org/10.1007/s00213-009-1494-7
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DOI: https://doi.org/10.1007/s00213-009-1494-7