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 (CB 1 Rs) and assessed the behavioral and neuroendocrine effects of intra-LHb CB 1 R 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 CB 1 Rs can bias coping strategies in rats with a history of chronic stress. Results Electron microscopy studies revealed CB 1 R 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 CB 1 R 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 CB 1 R 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.