One important question is whether there are conditions under which physiologically released AEA and 2-AG exert actions over distinct synapses in the amygdala, especially since some types of stress appear to differentially regulate these two ligands (see above). For example, do AEA and 2-AG regulate retrograde signaling at different synapses based on chemical characteristics, i.e. AEA modulating glutamate release while 2-AG modulates GABA release? Alternatively, is differential signaling spatially regulated, with perisomatic synapses being regulated by one ligand regardless of the neurotransmitter being affected, while distal dendritic synapses being regulated by the other or both? Additionally, determining whether there are pathological conditions under which this type of regulation is perturbed could facilitate rational development of eCB-based treatment for these conditions.
