An Introduction to the Endogenous Cannabinoid System

Abstract

The endocannabinoid system (ECS) is a widespread neuromodulatory system that plays important roles in central nervous system development, synaptic plasticity, and the response to endogenous and environmental insults. The ECS comprises cannabinoid receptors, endogenous cannabinoids (endocannabinoids), and the enzymes responsible for the synthesis and degradation of the endocannabinoids. The most abundant cannabinoid receptors are the CB1 cannabinoid receptors; however, CB2 cannabinoid receptors, transient receptor potential channels, and peroxisome proliferator activated receptors are also engaged by some cannabinoids. Exogenous cannabinoids, such as tetrahydrocannabinol, produce their biological effects through their interactions with cannabinoid receptors. The best-studied endogenous cannabinoids are 2-arachidonoyl glycerol and arachidonoyl ethanolamide (anandamide). Despite similarities in chemical structure, 2-arachidonoyl glycerol and anandamide are synthesized and degraded by distinct enzymatic pathways, which impart fundamentally different physiologic and pathophysiologic roles to these two endocannabinoids. As a result of the pervasive social use of cannabis and the involvement of endocannabinoids in a multitude of biological processes, much has been learned about the physiologic and pathophysiologic roles of the ECS. This review provides an introduction to the ECS with an emphasis on its role in synaptic plasticity and how the ECS is perturbed in schizophrenia.

Keywords: Cannabinoid; Cannabis; Lipid signaling; Retrograde messenger; Schizophrenia; Synaptic plasticity.

Fig. 1. Overview of the localization of endocannabinoid system components at the synapse

Schematic of an inhibitory and excitatory terminal synapsing onto the dendritic shaft of a representative cortical principal neuron. Abbreviations: ABHD6, alpha/beta domain-containing hydrolase 6; CB₁, CB₁ cannabinoid receptor; CCK, cholecystokinin; COX-2, cyclooxygenase-2; DAGLα, diacylglycerol lipase α; M1, M1 muscarinic receptor; MAGL, monoacylglycerol lipase; mGluR5, metabotropic glutamate receptor 5; NAPE-PLD, N-arachidonoyl phosphatidyl ethanolamine-preferring phospholipase D; PLCβ, phospholipase C β. The increased number of CB₁ receptors on the CCK/GABA terminal represents the higher density of CB₁ receptors found on these axon terminals.

Fig. 2. Potential synthetic and degradative pathways for anandamide and 2-AG

A. Primary synthetic pathways for anandamide. B. Primary degradative pathways for anandamide. C. Primary synthetic pathways for 2-AG. D. Primary degradative pathways for 2-AG. Only major pathways are shown. More comprehensive details can be found in recent reviews (–133). Abbreviations: AA, arachidonic acid; ABHD4, alpha/beta domain-containing hydrolase 4; ABHD6, alpha/beta domain-containing hydrolase 6; ABHD12, alpha/beta domain-containing hydrolase 12; COX-2, cyclooxygenase-2; DAG, diacylglycerol; DAGL, diacylglycerol lipase; FAAH, fatty acid aminohydrolase; GDE-1, glycerophosphodiesterase GDE-1; IP₃, inositol tris-phosphate; LPA, lyso-phosphatidic acid; lyso-PLC, lyso-phospholipid-preferring phospholipase C; MAGL, monoacyl glycerol lipase; NAAA, N-acyl ethanolamine amino hydrolase; NAPE-PLD, N-arachidonoyl phosphatidyl ethanol-preferring phospholipase D; PIP₂, phosphatidyl inositol bis-phosphate; Pi, PO₄; PLA₂, phospholipase A₂; PLC, phospholipase C;

Fig. 3. Forms of endocannabinoid-mediated synaptic plasticity and endocannabinoid mediated cell-autonomous regulation of excitability

A. Depolarization-induced suppression of excitation/inhibition. B. Metabotropic-induced suppression of excitation/inhibition. C. Homosynaptic and heterosynaptic long-term depression. D. Slow self inhibition. See text for details.