Cannabinoids and the Brain

Abstract

The cannabinoid system in the brain is targetted in the use and abuse of preparations from the Cannabis plant. 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 CB1 cannabinoid receptor, a G protein‐coupled receptor expressed to unusually high levels. Δ9‐Tetrahydrocannabinol (THC) appears to be the sole psychoactive entity present in Cannabis plant, 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 CB1 cannabinoid 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 the Cannabis plant.

  • Δ9‐Tetrahydrocannabinol acts as a partial agonist at the CB1 cannabinoid receptor.

  • CB1 cannabinoid receptors appear to be the most densely expressed G protein‐coupled receptors in the brain.

  • CB1 cannabinoid receptors couple functionally to an inhibition of transmitter release.

  • CB2 cannabinoid 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).

Keywords: cannabis; CB1 cannabinoid receptors; tetrahydrocannabinol; anandamide; 2‐arachidonoylglycerol; fatty acid amide hydrolase; monoacylglycerol lipase

Figure 1.

Chemical structures of some cannabinoid ligands. Illustrated is the archetypal plant‐derived cannabinoid THC (Δ9‐tetrahydrocannabinol) and the structurally related synthetic agonist HU210. Note the increased chain length of the dimethylheptyl sidechain. The dimethylheptyl sidechain is also present in CP55940, also a synthetic agonist, whereas one of the rings is opened up. A third chemical class of cannabinoid agonists is represented by WIN55212‐2. Two endogenous agonists, based on arachidonic acid derivatives, anandamide (AEA) and 2‐arachidonoylglycerol (2AG) are also represented. The central structure is rimonabant, a CB1 cannabinoid receptor‐selective antagonist.

Figure 2.

Short‐term plasticity mediated by endocannabinoids. Illustrated is a synapse at which the amino acid glutamate acts as an excitatory transmitter, although for clarity, a number of components have been omitted. (a) Depolarisation of the prejunctional (upper) neurone leads to release of glutamate, which (at sufficient concentrations) activates α‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazolepropionic acid (AMPA) glutamate receptors in the postsynaptic specialisation leading to postjunctional neuronal depolarisation. (b) Upon high‐frequency stimulation, there is increased glutamate release, which ‘spills over’ to activate NMDA glutamate receptors and mGlu1/5 metabotropic glutamate receptors. The calcium influx via the NMDA receptor and the increased phosphoinositide turnover via mGlu1/5 receptors combine to produce 2‐arachidonoylglycerol. (c) The 2‐arachidonoylglycerol diffuses in an anterograde manner to activate a prejunctional CB1 cannabinoid receptor, which is coupled to a G protein‐activated inwardly rectifying potassium channel (GIRK). Opening of the potassium channel leads to hyperpolarisation of the prejunctional neurone, thereby reducing the subsequent release of glutamate for a short period. Recovery is mediated by dissociation of 2‐arachidonoylglycerol and subsequent metabolism.

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Further Reading

Alexander SPH and Kendall DA (2007) The complications of promiscuity: endocannabinoid action and metabolism. British Journal of Pharmacology 152: 602–623. PMID: 17876303.

Blankman JL and Cravatt BF (2013) Chemical probes of endocannabinoid metabolism. Pharmacological Reviews 65: 849–871. PMID: 23512546.

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Mechoulam R and Parker LA (2013) The endocannabinoid system and the brain. Annual Review of Psychology 64: 21–47. PMID: 22804774.

Murataeva N, Straiker A and Mackie K (2014) Parsing the players: 2‐arachidonoylglycerol synthesis and degradation in the CNS. British Journal of Pharmacology 171: 1379–1391. PMID: 24102242.

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Pertwee RG, Howlett AC, Abood ME et al. (2010) International union of basic and clinical pharmacology. LXXIX. Cannabinoid receptors and their ligands: beyond CB1 and CB2. Pharmacological Reviews 62: 588–631. PMID: 21079038.

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Alexander, Stephen PH(Sep 2014) Cannabinoids and the Brain. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0024017]