Determining the adaptations in eCB synaptic signaling that occur after in vivo treatment with eCB modulating ligands with anxiolytic/antidepressant actions are important experiments that could shed light on fundamental aspects of the pathology of anxiety and depressive disorders. Some initial studies have suggested that chronic MGL inhibition with JZL184 treatment (which increases 2-AG levels and has anxiolytic effects in animal models) down-regulates CB1 receptor function after chronic treatment and, thus, impairs eCB retrograde signaling in some brain regions (Schlosburg et al., 2010). Therefore, if pathological conditions exist where eCB signaling is deleteriously enhanced, chronic, high-dose JZL184 administration may provide therapeutic benefits by “tuning down” eCB signaling in brain regions with high 2-AG turnover. In contrast, if pathological conditions can be identified where eCB signaling is reduced, low-doses of eCB degradation inhibitors could be beneficial by enhancing or prolonging eCB-mediated synaptic signaling in brain regions with eCB deficits. This hypothesis suggests that determining the relationship between tissue content of eCBs and retrograde signaling capacity is a critical question, as is determining the relationship between eCB signaling at different synapses in the
