The effects of cannabinoids on the brain

Cannabinoids have a long history of consumption for recreational and medica l reasons. The primary active constituent of the hemp plant Cannabis sativa is Delta(9)-tetrahydrocannabinol (Delta(9)-THC). In humans, psychoactive c annabinoids produce euphoria, enhancement of sensory perception, tachycardi a, antinociception, difficulties in concentration and impairment of memory. The cognitive deficiencies seem to persist after withdrawal. The toxicity of marijuana has been underestimated for a long time, since recent findings revealed Delta(9)-THC-induced cell death with shrinkage of neurons and DNA Fragmentation in the hippocampus, The acute effects of cannabinoids as well as the development of tolerance a re mediated by G protein-coupled cannabinoid receptors. The CB1 receptor an d its splice variant CB1A, are found predominantly in the brain with highes t densitities in the hippocampus, cerebellum and striatum. The CB2 receptor is found predominantly in the spleen and in haemopoietic c ells and has only 44% overall nucleotide sequence identity with the CB1 rec eptor. The existence of this receptor provided the molecular basis for the immunosuppressive actions of marijuana. The CB1 receptor mediates inhibitio n of adenylate cyclase, inhibition of N- and P/Q-type calcium channels, sti mulation of potassium channels, and activation of mitogen-activated protein kinase. The CB2 receptor mediates inhibition of adenylate cyclase and acti vation of mitogen-activated protein kinase. The discovery of endogenous cannabinoid receptor ligands, anandamide (N-ara chidonylethanolamine) and 2-arachidonylglycerol made the notion of a centra l cannabinoid neuromodulatory system plausible. Anandamide is released from neurons upon depolarization through a mechanism that requires calcium-depe ndent cleavage from a phospholipid precursor in neuronal membranes. The rel ease of anandamide is followed by rapid uptake into the plasma and hydrolys is by fatty-acid amidohydrolase. The psychoactive cannabinoids increase the activity of dopaminergic neurons in the ventral tegmental area-mesolimbic pathway. Since these dopaminergic circuits are known to play a pivotal role in mediating the reinforcing (re warding) effects of the most drugs of abuse, the enhanced dopaminergic driv e elicited by the cannabinoids is thought to underlie the reinforcing and a buse properties of marijuana. Thus, cannabinoids share a final common neuronal action with other major dr ugs of abuse such as morphine, ethanol and nicotine in producing facilitati on of the mesolimibic dopamine system. (C) 1999 Elsevier Science Ltd. All r ights reserved.