UC Irvine

Key PointsEndocannabinoids are endogenous lipid messengers that act on the same receptors that are activated by the active component of cannabis. The most well-understood are anandamide and 2-arachidonoylglycerol (2-AG), the synthetic pathways of which have been elucidated. Other putative ligands include noladin ether and virodhamine.Endocannabinoids are synthesized in neurons, but it is unclear how they are released. In some cases, they might diffuse within the membrane to activate receptors on the cells in which they are generated, but there is evidence that they are also released to act on neighbouring cells.Endocannabinoid signalling is attenuated by transport and hydrolysis. Transport of endocannabinoids into neurons is rapid and selective, although the transporter has not been identified and transport might be mediated by facilitated diffusion. Once inside cells, anandamide is broken down by fatty acid amide hydrolase, whereas 2-AG is hydrolysed by two less well-characterized enzymatic activities.The cannabinoid receptor CB1 is the most abundant G-protein-coupled receptor in the brain, and mediates most of the behavioural actions of cannabinoid drugs. The signalling events initiated by this receptor include closure of Ca2+ channels, opening of K+ channels, inhibition of adenylyl cyclase activity and stimulation of protein kinases. These signalling pathways can modulate synaptic communication and neuronal gene expression.Cannabinoids do have some effect on CB1-null mice, and it has been proposed that another brain cannabinoid receptor might exist. However, the evidence is contradictory.An important function of cannabinoid receptors is the regulation of GABA (γ-aminobutyric acid) transmission. In the hippocampus, cannabinoids can modulate plasticity, and so might influence learning and memory. In the amygdala, CB1 inactivation causes anxiety-like and aggressive behaviour. In the basal ganglia, cannabinoids might modulate motor function. And in the hindbrain, cannabinoid agonists can influence the central processing of pain. All of these functions seem to involve depression of GABA release.Endocannabinoids can also suppress the release of glutamate at excitatory synapses in the hippocampus, cerebellum and other brain areas, although the function of this suppression is unclear. Cannabinoid agonists also seem to influence the release of other neurotransmitters such as acetylcholine and amines.Endocannabinoid-dependent long-term depression (LTD) in the striatum and nucleus accumbens might be involved in habit learning and addiction. Endocannabinoids seem also to be involved in inhibitory LTD in the hippocampus.