ECBs are fatty acid amides and monoacylglyerols functioning as neuromodulator lipids that exhibit rapid (within seconds) on-demand biosynthesis in response to neuronal activation, and are subsequently degraded by specialized catabolic enzymes. There are two known receptors binding ECBs with high affinity – CB1R is the most densely expressed in the brain and is present at high levels in corticolimbic regions mediating anxiety, including the medial prefrontal cortex (mPFC) and hippocampus, as well as the BLA [11,14], whereas CB2R is mainly found in the periphery but also in some microglia and neuronal populations in the central nervous system (CNS) [15,16]. Unlike most neurotransmitters, however, ECBs are not stored in readily releasable pools, but instead are rapidly synthesized `on-demand' upon depolarization-induced calcium increase. Such biosynthesis occurs tonically and, under strong neuronal activation, phasically. The ECB 2-arachidonoylglycerol (2-AG) is synthesized, postsynaptically, by diacylglycerol lipase, whereas the ECB anandamide (AEA) is predominantly synthesized by N-acyl phosphatidylethanolamine phospholipase D (NAPE-PLD), also at postsynaptic sites in regions including the BLA, but also presynaptically at others (e.g., hippocampus) [17,18]. Following their synthesis, ECBs are retrogradely transported into the extracellular space to bind ECB receptors present on presynaptic terminals [19–21].
