The Endocannabinoid, 2-arachidonoylglycerol, Regulates Resilience to Stress-induced Anxiety

Abstract

Nearly 30% of the global burden of nonfatal disease is due to affective disorders. Stress is a potent risk factor for affective disorders including major depression and posttraumatic stress disorder. The neurobiological mechanisms by which stress influences psychopathology are poorly understood, however, it is clear that stress does not affect every individual equally. Understanding the mechanisms conferring resilience to adverse consequences of stress could have broad implications for the treatment of affective disorders. Endogenous cannabinoid (eCb) signaling is implicated in modulating affective behavior, but the role of the most abundant eCb, 2-arachidonoylglycerol (2-AG), has not been adequately investigated. We hypothesize that 2-AG signaling is a critical regulator of basal and stress-induced affective responses. In support of this, herein we demonstrate a necessity for 2-AG in regulating basal anxiety. We then develop a novel model of stress-resilience and show that 2-AG signaling is critical for resilience to stress-induced anxiety. Germline depletion of brain 2-AG produces a striking anxiety-like phenotype and acute, systemic 2-AG depletion increases susceptibility to stress-induced anxiety-like phenotypes in previously resilient mice. Conversely, acute, systemic 2-AG augmentation enhances resilience in previously susceptible mice. Human imaging studies strongly suggest an association between affective disorders and hyperactivity of the amygdala, a well-established regulator of responses to aversive stimuli. Additionally, rodent studies indicate that stress exposure increases excitatory drive to the basolateral amygdala (BLA). eCbs are implicated in regulating the effects of stress and inhibit glutamate inputs to the BLA. We hypothesize that the anxiogenic effects of global 2-AG depletion are due to impaired BLA eCb signaling. Using our model of stress-resilience, we show that amygdala-specific 2-AG depletion impairs adaptation to repeated stress and that stress-resilience is associated with increased BLA 2-AG signaling. These data demonstrate that BLA 2-AG signaling promotes resilience to stress. Altogether these data strongly support the suggestion that eCb deficiency could promote susceptibility to affective disorders and pharmacological enhancement of 2-AG signaling could be an effective treatment for stress-related affective dysfunction.