Biological Psychiatry: Cognitive Neuroscience and Neuroimaging
ReviewReview of the Endocannabinoid System
Section snippets
Cannabinoid Receptors
CB1 and CB2 are the best-characterized cannabinoid receptors. Both are G protein–coupled receptors (GPCRs), primarily coupling to inhibitory G proteins. They inhibit adenylyl cyclase and certain voltage-sensitive calcium channels, stimulate MAP (mitogen-activated protein) kinases and inwardly rectifying potassium channels (GIRKs), and recruit beta-arrestins, among other actions (7). The diversity of CB1 signaling is enhanced by their propensity to heterodimerize with other GPCRs, including
Signaling
As mentioned above, CB1 and CB2 receptors primarily couple to inhibitory G proteins (Gi/o) and engage the pathways associated with Gi/o (7). CB1 and CB2 receptors also recruit beta-arrestins and signal through arrestin-dependent pathways (30,31). Under some conditions, cannabinoid receptors can also stimulate cAMP (cyclic adenosine monophosphate) formation and engage Gq/11 pathways (32,33). Interestingly, astrocyte CB1 receptors strongly couple to Gq/11 (16). Like all GPCRs, CB1 and CB2
Allosteric Modulation
THC and the eCBs interact with CB1 and CB2 receptors at their orthosteric sites. However, the large size of GPCRs gives ample opportunity for sites where other molecules can bind and, under favorable conditions, modulate the function of the receptor. While not much is known about allosteric modulation of CB2 receptors, several positive and negative allosteric modulators of CB1 receptors have been described. Classically, allosteric modulators may affect the kinetics of orthosteric ligand
Multimerization and Cannabinoid Receptor–Interacting Proteins
Like most GPCRs (53), cannabinoid receptors can associate with other GPCRs, a process termed dimerization or multimerization. Association of cannabinoid receptors with other GPCRs has the potential to greatly enrich their signaling repertoire. While both CB1 and CB2 receptors have been found to associate with other GPCRs (54,55), this has been more widely studied with CB1 receptors. Prominent association partners of CB1 receptors include dopamine D2 receptors (56,57), orexin A receptors (58),
Endocannabinoids
Narrowly defined, endogenous cannabinoids (eCBs) are signaling lipids that activate cannabinoid receptors. While 2-AG (72, 73, 74) and anandamide (AEA [N-arachidonoyl ethanolamine]) (75) are the two best known eCBs, other structurally related lipids also engage cannabinoid receptors [e.g., N-arachidonoyl dopamine (76)]. Conversely, 2-AG and AEA have the potential to activate a wide range of GPCRs, nuclear receptors, and ion channels (77, 78, 79), although when considering this literature,
eCB Synthesis
Most of what we know about eCB synthesis comes from investigations of the mature nervous system and heterologous expression systems. These studies have led to the concept that the dominant form of eCB synthesis is “on demand” (81). The principal of on-demand synthesis is that the eCB exists as a precursor in membrane lipids and is liberated by the activation of enzymes, typically lipases, that are triggered by a specific signal (e.g., G proteins or elevation of intracellular calcium [see
eCB Transport
Transport of eCBs across the cell membrane is important following their synthesis and in preparation of their degradation. eCBs are synthesized from phospholipids on the inner leaflet of the membrane; thus, for eCBs to act on adjacent cells, a mechanism for their exit from the cell is necessary (96,97). Similarly, eCB degrading enzymes are primarily intracellular, so a process for eCB entry into cells is necessary to terminate their action. The polar nature of eCBs prevents their passage across
eCB Degradation
eCB signaling is frequently terminated by hydrolysis of the arachidonic group from either the glycerol (2-AG) or ethanolamine (AEA). 2-AG hydrolysis is primarily carried out in the CNS by MAGL (monoacylglycerol lipase) or ABDH6 (alpha/beta-hydrolase domain containing 6) (103,104), while FAAH (fatty acid amino hydrolase) primarily terminates AEA action (105). MAGL is found at the highest levels presynaptically (106), while ABHD6 is mostly found in dendrites (104), suggesting that the two
eCBs as Retrograde Messengers
A major function of the ECS in the mature nervous system is as a retrograde messenger mediating several forms of eCB-mediated synaptic plasticity (110). Here, eCBs synthesized by the postsynaptic cell travel retrogradely across the synapse to activate presynaptic cannabinoid receptors, suppressing neurotransmission from CB1-expressing terminals. There are both transient and long-lasting forms of eCB-mediated synaptic plasticity. Both forms involve stimulation of the postsynaptic neuron (either
Nonretrograde Effects of eCBs on Neuronal Excitability
While much attention is paid to the role of eCBs as retrograde messengers, it is important to appreciate that eCBs modify neuronal excitability in other ways. These can be summarized as 1) direct modulation of ion channels, 2) activation of GIRK channels, and 3) enhancement of a hyperpolarization-activated cation channels (Ih). eCBs also modulate several important ion channels, including 5HT3 (115), TRPV1 (116), GABA-A (79), glycine (117), and many others (118). As always, it is important to
Interactions Between eCBs and Exogenous Cannabinoids (THC and Spice Compounds)
The varying efficacies of 2-AG, AEA, THC, and the synthetic cannabinoids used recreationally (“spice”) gives rise to several potentially important and interesting interactions. For example, THC is a fairly potent, low-efficacy agonist, while 2-AG is a less potent but highly efficacious agonist (121). Thus, under conditions in which either CB1 receptor density or postreceptor coupling is limited, THC may antagonize endogenous 2-AG signaling [e.g., (97)]. On the one hand, this THC/2-AG
Dynamic Expression of ECS During Brain Development
The ECS is present from the earliest stage of pregnancy, in the preimplantation embryo and uterus (127), in the placenta (128), and in the developing fetal brain (129). In human fetal brains, CB1 receptors can be detected at week 14 of gestation, with preferential expression in the cerebral cortex, hippocampus, caudate nucleus, putamen, and cerebellar cortex, mirroring their adult distribution. By week 20, intense expression is evident in CA2 and CA3 of the hippocampus and in the basal nuclear
Summary
The ECS has been implicated in the risk for developing schizophrenia. Perturbingly, the ECS (i.e., through cannabis use) may influence the course of psychoses and acute intoxication with natural or synthetic cannabinoids can induce transient psychotic symptoms. Through the ECS’s role in the developing nervous system, it is well positioned to interact with factors that may predispose an individual to developing psychotic disease and the course of that disease. The ECS’s involvement in multiple
Acknowledgments and Disclosures
This work was supported by National Institutes of Health Grant Nos. NS086794 (to H-CL), DA043982 (to KM), and DA046196 (to KM).
KM receives consulting fees from Abalone Bio, FSD Pharma, and Nalu Bio. H-CL reports no biomedical financial interests or potential conflicts of interest.
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