FIGURE 1. Organization of the cannabinoid system.

Increased intracellular calcium in the postsynaptic bouton is thought to be a major signal for the production of endocannabinoid transmitters (anandamide and 2-AG are shown). The mechanisms by which these local increases are mediated may vary by cell type and may involve NMDA receptors, mGluRs, mAChRs as well as G-protein induced increases in calcium release from intracellular stores. Reuptake and degradation of anandamide is thought to be a coupled process of transport across the membrane by the EMT, and degradation by FAAH, which degrades anandamide and related eCBs, and/or MAG lipase, which degrades 2-AG and related eCBs. Once they are produced in the postsynaptic cell, eCBs are thought to diffuse in a retrograde fashion to activate pre-synaptic CB1 receptors. Activation of CB1 receptors leads to decreases in transmitter release from the pre-synaptic terminal, by decreasing calcium influx through voltage-gated calcium channels, and by increasing inwardly-rectifying potassium currents. Several pharmacologic manipulators of eCB transmission are noted; including the CB1 agonists WIN 55,212-2 and HU-210, the CB1 antagonists rimonabant and AM251, and two inhibitors of eCB reuptake and/or breakdown (AM404 and URB597).

mAChRs=muscarinic acetylcholine receptors; mGluRs=metabotropic glutamate receptors; eCB=endogenous cannabinoid; CB1=cannabinoid-type 1; EMT=endocannabinoid membrane transporter; FAAH=fatty acid amide hydrolase; MAG=monoacyl-glycerol; 2-AG=2-arachidonoyl glycerol; NMDA=N/-methyl -D- asparte.

Chhatwal JP, Ressler KJ. CNS Spectr. Vol 12, No 3. 2007.