Endocannabinoids: Getting the message across

The endocannabinoids have emerged as important intercellular signals in the nervous system. The fatty acid amide arachidonylethanolamide (anandamide) is the prototypical endocannabinoid, i.e., an endogenous ligand of the G protein-coupled cannabinoid receptor in the brain, CB1, which binds the main psychoactive component of marijuana and other derivatives of Cannabis sativa (1). After a rise in intracellular calcium or activation of certain neurotransmitter receptors, endocannabinoids are synthesized by cleavage of phospholipid precursors that are present in cellular membranes (2). They often act as retrograde messengers, emanating from morphologically undifferentiated regions of postsynaptic principal cells and traveling backwards across synapses, where they transiently inhibit the release of either the inhibitory neurotransmitter γ-aminobutyric acid (GABA) or the excitatory transmitter glutamate (see Fig. 1 and ref. 3 for a review). This powerful influence on synaptic transmission enables the endocannabinoids to help regulate behaviors, such as feeding (4), fear (5), and anxiety (6). Retrograde signaling by endocannabinoids. The endocannabinoids anandamide and 2-AG are synthesized in postsynaptic target cells such as hippocampal pyramidal cells (right). Synthesis is initiated by calcium influx through voltage-gated calcium channels, or by the activation of G protein-coupled neurotransmitter receptors, including type I metabotropic glutamate receptors (mGluR) or muscarinic acetylcholine receptors (mAChR) (3). The endocannabinoids gain access to the extracellular space and activate CB1 cannabinoid receptors found concentrated on certain nerve terminals, e.g., of cholecystokinin-containing GABAergic interneurons in hippocampus (2). CB1 activation causes presynaptic inhibition of GABA or glutamate release by inhibiting calcium channels, interfering with vesicle release, and activating potassium channels. The endocannabinoids are taken up into postsynaptic or presynaptic cells by the anandamide transporter (AT). The degradative enzyme FAAH is present in postsynaptic cells, and monoglyceride lipase (not shown), which degrades 2-AG, is found in presynaptic terminals (2). As is true of other intercellular messengers, the time course …