Chunk #8 — Endocannabinoid Variants and Childhood Adversity Predict Cannabis Dependence Symptoms and Amygdala Habituation — The Endocannabinoid System and Cannabis Involvement
Unlike most transmitter systems, endocannabinoid receptors have two major ligands, anandamide (AEA) and 2-arachidonoylglycerol (2-AG), as well as a host of other putative ligands (e.g., noladin, virodhamine). AEA and 2-AG are synthesized postsynaptically and released “on-demand,” presumably by an unknown endocannabinoid membrane transporter. Anandamide is synthesized directly from the phospholipid precursor N-arachidonoyl phosphatidylethanolamine (NAPE) by N-acyl-phosphatidylethanolamine-selective phosphodiesterase (NAPE-PLD); alternative indirect synthesis routes exist but have not yet been fully characterized. The other eCB ligand, 2-AG, is formed by the hydrolysis of diacylglycerols (DAGs) by sn-1-selective diacylglycerol lipases (DAGLs). Once released into the synapse, eCB ligands bind to cannabinoid type 1 (CB1) and type 2 (CB2) receptors. As with eCB ligands, other putative receptors exist (e.g., GPR55, TRPV1) but have yet to be well characterized. AEA is broken down primarily by fatty acid amide hydrolase-1 (FAAH), while 2-AG is mostly catabolized by monoacylglycerol lipase (MAGL).
