The Endocannabinoid System (ECS) is a widespread neuromodulatory system that plays important roles in central nervous system (CNS) development, synaptic plasticity, and the response to endogenous and environmental insults. 

The ECS is comprised of cannabinoid receptors, endogenous cannabinoids (endocannabinoids), and the enzymes responsible for the synthesis and degradation of the endocannabinoids.

 The most abundant cannabinoid receptor is the CB1 cannabinoid receptors, however CB2 cannabinoid receptors, transient receptor potential (TRP) channels, and peroxisome proliferator activated receptors (PPAR’s) are also engaged by some cannabinoids. 

Exogenous cannabinoids, such as tetrahydrocannabinol, produce their biological effects through their interactions with cannabinoid receptors. 2-arachidonoyl glycerol (2-AG) and arachidonoyl ethanolamide (anandamide) are the best-studied endogenous cannabinoids.

 Despite similarities in chemical structure, 2-AG and anandamide are synthesized and degraded by distinct enzymatic pathways, which impart fundamentally different physiological and pathophysiological roles to these two endocannabinoids. 

Because of the pervasive social use of cannabis and the involvement of endocannabinoids in a multitude of biological processes, much has been learned about the physiological and pathophysiological roles of the ECS. 

Cannabinoid receptors

The effects of endocannabinoids are primarily mediated by CB1 and CB2 cannabinoid receptors  with other receptors (such as PPAR’s and Transient Receptor Potential (TRP)) channels (see below)) also mediating some endocannabinoid actions, particularly of the acylethanolamides.      

As discussed in more detail in Chapter 12, polymorphisms of cannabinoid receptor and endocannabinoid system genes are variably associated with schizophrenia and possibly with response to atypical antipsychotics. 

Both CB1 and CB2 cannabinoid receptors are G protein-coupled receptors (GPCR’s), which primarily couple to G proteins of the Gi and Go classes . 

As such, their activation inhibits adenylyl cyclases and certain voltage dependent calcium channels and activates several MAP kinases and inwardly rectifying potassium channels, with some variation depending on the particular type of cell. 

Thus, activation of CB1 or CB2 receptors exerts diverse consequences on cellular physiology, including synaptic function, gene transcription, cell motility, etc.

CB1 receptors are abundant in the central nervous system (CNS), particularly in cortex, basal ganglia, hippocampus, and cerebellum. 

The majority of CB1 receptors are present on axon terminals and pre-terminal axon segments, while sparing the active zone. 

Cortical and hippocampal CB1 receptors are particularly enriched on cholecystokinin (CCK) positive interneurons (low threshold spiking interneurons), and are widely expressed at lower (but still functionally important) levels in glutamatergic neurons. 

CB1 receptors are highly abundant in medium spiny neurons in both the dorsal and ventral striatum. 

Expression is particularly high on the direct pathway axons as they enter the globus pallidus heading towards the substantia nigra. 

Cerebellar CB1 receptors are found in parallel and climbing fibers, as well as in basket cells.

While CB1 has been detected on many neurons, functionally relevant expression of CB1 in glial elements has also been reported by a number of independent groups.

CB2 receptors are expressed at much lower levels in the CNS compared to CB1. This receptor is primarily present in microglia and vascular elements. 

However, CB2 does appear to be expressed by some neurons, particularly under certain pathological conditions (e.g., nerve injury), and for a discussion of the caveats on examining CB2 in the brain. 

Accumulating genetic and animal model evidence suggests a link between CB2 receptors and an increased risk for schizophrenia, however if this due to neuronal CB2, microglial CB2, or a neurodevelopmental role of CB2 remains an unknown, but important question.

 A particularly interesting feature of CB2 receptors is that they appear to be highly inducible, with expression in CB2 increasing up to 100 fold following tissue injury or during inflammation. 

It remains to be determined whether observed increases in CNS CB2 is due to increased expression of CB2 on cells intrinsic to the CNS, or is a result of the migration (e.g. CB2-expressing monocytes) of peripheral immune cells into the CNS.

TRP channels, especially TRPV1, are activated by anandamide under certain conditions. 

The relative roles of cannabinoid receptors and TRP channels in anandamide’s actions appear variable.

 Anandamide also activates PPARalpha and gamma, with significant effects on gene transcription. 

It is important to keep in mind that increasing anandamide by decreasing its degradation by inhibition of fatty acid aminohydrolase (FAAH) also increases levels of other N-acylamides, which can modulate PPARα.