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Chronic stress causes a variety of physiological and behavioral alterations, including social impairments, altered endocrine function, and an increased risk for psychiatric disorders. Thereby, social stress is one of the most effective stressful stimuli among mammals and considered to be one of the major risk factors for the onset and progression of neuropsychiatric diseases. For analyzing the effects of social stress in mice, the resident/intruder paradigm of social defeat is a widely used model. Although the chronic social defeat stress model has been extensively studied, little is known about the effects of repeated or chronic social defeat stress on the endocannabinoid system (ECS). The present study aimed to understand the effects of chronic social stress on anxiety behavior and the levels of endocannabinoids (ECs) and two N-acylethanolamines (NAEs) in different brain regions of mice. Materials and Methods: Two-month-old, male C57Bl/6J mice were exposed to chronic psychosocial stress for 3 weeks. The effects of stress on anxiety behavior were measured using the light-dark box and hole board test. The EC levels of 2-arachidonoyl glycerol (2-AG) and anandamide (N-arachidonoylethanolamine [AEA]), as well as the levels of two NAEs (oleoylethanolamide [OEA] and palmitoylethanolamide), were analyzed by liquid chromatography-tandem mass spectrometry in the hippocampus, cerebellum, and cortex. Results: In comparison with control mice ( n =12), mice exposed to social defeat stress ( n =11) showed increased anxiety behaviors in the light-dark box and hole board test and gained significantly more weight during the experimental period. Additionally, chronic social stress induced differential alterations in the brain levels of 2-AG and AEA. More precisely, 2-AG levels were higher in the cortex and cerebellum, whereas reduced AEA levels were found in the hippocampus. Furthermore, we observed lower OEA levels in the hippocampus. Conclusion: The current study confirms that the ECS plays an essential role in stress responses, whereby its modulation seems to be brain region dependent.

Chronic Psychosocial Stress Causes Increased Anxiety-Like Behavior and Alters Endocannabinoid Levels in the Brain of C57Bl/6J Mice