Abstract
The stress response is an evolutionarily conserved mechanism to both allow an organism to cope with a threat and to restore homeostasis following exposure to a stressor. With respect to this response, preclinical research demonstrates that the endogenous cannabinoid (ECB) system constrains the hypothalamic-pituitary-adrenal axis and plays a major role in the habituation to stressors. Specifically, anandamide tonically constrains activation of stress responsive circuits in the brain under basal conditions; however, exposure to stress or glucocorticoids initiates a cascade of events whereby corticotropin-releasing hormone (CRH) rapidly reduces anandamide metabolism through CRHR1-mediated activation of fatty acid amide hydrolase (FAAH) in the basolateral amygdala (BLA), which ultimately facilitates activation of the neuroendocrine axis and emotional response to stress. On the other hand, 2-arachidonoylglycerol (2-AG) provides on-demand synaptic modulation and promotes short-term adaptation to stress via glucocorticoid receptor-dependent mobilization in the hypothalamus and extrahypothalamic inhibitory feedback centers such as the medial prefrontal cortex (mPFC) and hippocampus. Additionally, 2-AG is recruited in the BLA to facilitate habituation to chronic homotypic stress, thus facilitating long-term adaptation as well. Accordingly, impairments in ECB signaling within the hypothalamus, BLA, mPFC, and/or hippocampus may confer maladaptive neuroendocrine and behavioral responses to stress, thereby contributing to the emergence of stress-related disorders such as anxiety, depression, and substance abuse. Moreover, sexual dimorphism and genetic differences in the ECB system may contribute to individual differences in stress coping strategies, which can have profound ramifications for susceptibility and resilience to stress-related mental disorders. This chapter will review the growing preclinical and clinical evidence demonstrating that the ECB system may be a promising therapeutic target for a host of human affective disorders.
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Berger, A.L., Henricks, A.M., Hill, M.N., McLaughlin, R.J. (2017). Endocannabinoids, Stress, and Negative Affect. In: Melis, M. (eds) Endocannabinoids and Lipid Mediators in Brain Functions. Springer, Cham. https://doi.org/10.1007/978-3-319-57371-7_3
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