Cannabinoids and the Brain

Abstract The cannabinoid system in the brain is targetted in the use and abuse of preparations from theCannabisplant. This system is composed of synthetic enzymes for the endogenous lipid‐derived ligands, the cannabinoid receptors they activate and the enzymes which transform them. These endocannabinoids are amides, such as anandamide, or esters, such as 2‐arachidonoylglycerol, whose primary target in the central nervous system is the CB1cannabinoid receptor, a G protein‐coupled receptor expressed to unusually high levels. Δ9‐Tetrahydrocannabinol (THC) appears to be the sole psychoactive entity present inCannabisplant, which elicits the characteristic responses in man and animals. The pharmacology and biochemistry of the endocannabinoid system has been thoroughly investigated since the identification of CB1cannabinoid receptors. As yet, however, the translation of this knowledge into a clinical setting has been of limited success. Key Concepts: Δ9‐Tetrahydrocannabinol appears to be the major psychoactive agent present in theCannabisplant. Δ9‐Tetrahydrocannabinol acts as a partial agonist at the CB1cannabinoid receptor. CB1cannabinoid receptors appear to be the most densely expressed G protein‐coupled receptors in the brain. CB1cannabinoid receptors couple functionally to an inhibition of transmitter release. CB2cannabinoid receptors are primarily associated with the immune system, but may also be found in the CNS. Endogenous cannabinoids, termed endocannabinoids, are fatty acid derivatives. Endocannabinoids are not stored in vesicles, but rather are made on demand. Endocannabinoid production is involved in two neurophysiological phenomena, termed depolarisation‐evoked suppression of excitation (DSE) and depolarisation‐evoked suppression of inhibition (DSI). Endocannabinoids may also act at particular ligand‐gated ion channels (notably the TRPV1 vanilloid receptor) and nuclear hormone receptors (notably peroxisome proliferator‐activated receptors).