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The Lateral Habenula Directs Coping Styles Under Conditions of Stress via Recruitment of the Endocannabinoid System

      Abstract

      Background

      The ability to effectively cope with stress is a critical determinant of disease susceptibility. The lateral habenula (LHb) and the endocannabinoid (ECB) system have independently been shown to be involved in the selection of stress coping strategies, yet the role of ECB signaling in the LHb remains unknown.

      Methods

      Using a battery of complementary techniques in rats, we examined the localization of type-1 cannabinoid receptors (CB1Rs) and assessed the behavioral and neuroendocrine effects of intra-LHb CB1R manipulations. We further tested the extent to which the ECB system in the LHb is impacted following chronic unpredictable stress or social defeat stress, and whether manipulation of LHb CB1Rs can bias coping strategies in rats with a history of chronic stress.

      Results

      Electron microscopy studies revealed CB1R expression on presynaptic axon terminals, postsynaptic membranes, mitochondria, and glial processes in the rat LHb. In vivo microdialysis experiments indicated that acute stress increased the amount of 2-arachidonoylglycerol in the LHb, while intra-LHb CB1R blockade increased basal corticosterone, augmented proactive coping strategies, and reduced anxiety-like behavior. Basal LHb 2-arachidonoylglycerol content was similarly elevated in rats that were subjected to chronic unpredictable stress or social defeat stress and positively correlated with adrenal weight. Finally, intra-LHb CB1R blockade increased proactive behaviors in response to a novel conspecific, increasing approach behaviors irrespective of stress history and decreasing the latency to be attacked during an agonistic encounter.

      Conclusions

      Alterations in LHb ECB signaling may be relevant for development of stress-related pathologies in which LHb dysfunction and stress-coping impairments are hallmark symptoms.

      Keywords

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      Linked Article

      • Endocannabinoid Signaling in the Habenula Regulates Adaptive Responses to Stress
        Biological PsychiatryVol. 84Issue 8
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          Stress is a normal part of everyday life. However, when stressors accumulate and stress is experienced for extended periods of time, it eventually becomes necessary to adapt to this chronic state in order to maintain physiological and behavioral homeostasis. The endocannabinoid (ECB) system, which includes the neuronal type-1 cannabinoid receptor (CB1R) and the endogenous CB1R agonists 2-arachidonoylglycerol (2-AG) and N-arachidonylethanolamide, plays an important role in adaptions to stressful situations, particularly during periods of prolonged exposure to stress.
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