In addition to guiding GxE research, neuroscience can be used to disentangle the neural mechanisms through which genetic variation and the environment promote individual differences in behavior (Caspi & Moffitt, 2006). Cross-species research on the effects of stress on the eCB system as well as pharmacologic eCB manipulation suggest that individual differences in amygdala function, and in particular its diminished response to repeated threat-related stimuli (i.e., habituation), may play a key role in mediating associations between the eCB system, stress exposure, and behavior (Ramikie & Patel, 2012). First, stress-induced endocannabinoid changes (e.g., reduced AEA, increased 2-AG) within the basolateral amygdala (BLA) facilitate HPA axis activation and increase anxiety (Rademacher et al., 2008). Moreover, chronic early life stress results in sustained eCB differences within the BLA that may provide a lasting environmental signature conferring vulnerability to cannabis dependence symptoms (Lee & Hill, 2013; Sciolino et al., 2010). Second, THC and CB1 agonist administration reduce subjective anxiety, blunt threat-related amygdala function, and facilitate fear extinction (Gruber, Rogowska, & Yurgelun-Todd, 2009; Phan et al., 2008; Rabinak et al., 2013). Importantly, knockout and pharmacologic
