Initial studies into the role of cannabinoid signaling in the CeA by Onaivi and coworkers described an anxiogenic effect of THC (100 and 150 μg per injection) bilaterally administered into the CeA of mice using the elevated plus-maze test (Onaivi et al., 1995). However, a more recent study demonstrated that the CB1 agonist ACPA (1.25 and 5 ng/rat) caused an anxiolytic effect in rats when administered directly into the CeA using this same assay (Zarrindast et al., 2008). The differences in these studies could be related to the well-known bi-phasic effects of cannabinoids on anxiety, with low doses producing anxiolytic effects, while higher doses produce anxiogenic effects, since the former study used doses of THC significantly higher than doses of ACPA used in the latter. Interestingly, intra-CeA blockade of the CB1 receptor, using AM251, caused a decrease in exploratory activity without changing any anxiety measures (Zarrindast et al., 2008). In addition to these studies on unconditioned fear, the expression of conditioned fear is also modulated by eCB signaling in the CeA. Specifically, post-training infusion of the CB1 antagonist SR141716 into
