Humans have been using Cannabis and its extracts for a few thousand years as a medicinal and recreational drug. However, the chemical component in Cannabis sativa, Δ9-tetrahydrocannabinol (Δ9-THC), an exogenous cannabinoid, remained unknown until it was isolated and identified as the main psychoactive ingredient (Gaoni and Mechoulam, 1964). Discovery of the cannabinoid Δ9-THC was a milestone in the field of cannabinoids, since this led to the unveiling of a new biological regulation system in our body, i.e., the endocannabinoid (eCB) system. The composition of the eCB system has been depicted by researchers in the cannabinoid field over the past three decades (Figure 1), which consists of endogenous cannabinoids (eCBs), G protein coupled cannabinoid receptors (CB1R and CB2R), the enzymes synthesizing and metabolizing eCBs, and transporters or carriers for eCBs (Di Marzo et al., 2015; Xu and Chen, 2015).
CB1R is widely expressed in neurons and astrocytes in the brain, while CB2R is present primarily in the immune system and microglial cells, the resident immune cells of the brain. There are some reports regarding neuronal expression of CB2R in the brain, but the expression is not as abundant as that of CB1R (Kano et al., 2009). The distribution of CB1R and CB2R in the brain determines their functional roles in cellular and molecular events and behaviors. Although several endogenous cannabinoids have been identi- fied, N-arachidonoyl ethanolamide (AEA or anandamide) and 2-arachidonoylglycerol (2-AG) are the two most-studied eCBs (Kano et al., 2009; Di Marzo et al., 2015). AEA was the first identified eCB, which is synthesized from N-arachidonoyl phosphatidylethanolamine (NAPE) by NAPE-specific phospholipase D (NAPE-PLD) and metabolized by fatty acid amide hydrolase (FAAH) to arachidonic acid (AA), precursor of prostaglandins. 2-AG was the second identified eCB, which is produced largely from diacylglycerol (DAG) by diacylglycerol lipase α and β (DAGLα/β) and primari- ly hydrolyzed by monoacylglycerol lipase (MAGL) to AA. 2-AG is also degraded by the enzymes α, β hydrolase 6 and 12 (ABHD6/12) and oxidized by cyclooxygenase 2 (COX-2). At present, the identities of eCB transporters or carriers are still controversial. 2-AG is the most abundant eCB and a full agonist for CB1R and CB2R, while AEA is a partial agonist for CB1R and CB2R and an agonist for the vanilloid receptor or transient receptor potential cation channel subfamily V member 1 (TRPV1), which is important for sensation of temperature and pain.
The abundance of CB1R expressed in the brain is similar to that of glutamate receptors. Notably, CB1R expressed in neurons preferentially resides on the presynaptic ends both at inhibitory GABAergic and excitatory glutamatergic synapses. This suggests that the primary role of the eCB system in regulation of brain function is through mediating or modulating synaptic transmission and plasticity (Kano et al., 2009; Castillo et al., 2012). While AEA may mediate synaptic transmission and other functions via CB1R/2 and TRPV1, accumulated information shows that 2-AG is a principal eCB signaling molecule in regulation of synaptic efficacy by acting on presynaptically expressed CB1R. The presence of MAGL and DAGLα/β at pre- and post-synaptic sites and the alterations in synaptic transmission and plasticity produced by pharmacological or genetic inhibition of DAGLα/β or MAGL provide strong evidence that 2-AG is a retrograde sig- naling molecule synthesized postsynaptically and inactivated presynaptically (Kano et al., 2009; Castillo et al., 2012). The release of GABA or glutamate is inhibited at GABAergic or glutamatergic synapses as a result of presynaptic CB1R activa- tion by 2-AG signaling. This may underlie short- (depolariza- tion-induced suppression of inhibition, DSI; and depolariza- tion-induced suppression of excitation, DSE) and long-term synaptic plasticity (inhibitory long-term depression, iLTD, and excitatory LTD, eLTD), implying that eCB signaling plays an important role in preventing excess synaptic activities, thereby retaining integrity and efficacy of synapses. This is particularly important in neurological diseases. However, eCB signaling also contributes to potentiation of glutamatergic synaptic transmission through the suppression of GABAergic synaptic release (Castillo et al., 2012; Xu and Chen, 2015), suggesting that while eCB signaling preferentially mediates inhibitory effects on both GABAergic and glutamatergic syn- aptic transmissions, it is also important for facilitating glutamatergic synaptic transmission by concurrent depression of inhibitory synaptic activity (Xu and Chen, 2015).