The Brain
How THC Affects The Brain
Cannabinoids
Cannabinoids have a long history of consumption for recreational and medical reasons. The primary active constituent of the marijuana plant is delta9-tetrahydrocannabinol (delta9-THC).
In humans, psychoactive cannabinoids produce euphoria, enhancement of sensory perception, tachycardia, antinociception, difficulties in concentration and impairment of memory. The cognitive deficiencies seem to persist after withdrawal.
The acute effects of cannabinoids as well as the development of tolerance are mediated by G protein-coupled cannabinoid receptors. The CB1 receptor and its splice variant CB1A, are found predominantly in the brain with highest densities in the hippocampus, cerebellum and striatum.
The CB2 receptor is found predominantly in the spleen and in haemopoietic cells and has only 44% overall nucleotide sequence identity with the CB1 receptor. The existence of this receptor provided the molecular basis for the immunosuppressive actions of marijuana.
The CB1 receptor mediates inhibition of adenylate cyclase, inhibition of N- and P/Q-type calcium channels, stimulation of potassium channels, and activation of mitogen-activated protein kinase.
The CB2 receptor mediates inhibition of adenylate cyclase and activation of mitogen-activated protein kinase. The discovery of endogenous cannabinoid receptor ligands, anandamide (N-arachidonylethanolamine) and 2-arachidonylglycerol made the notion of a central cannabinoid neuromodulatory system plausible.
Anandamide is released from neurons upon depolarization through a mechanism that requires calcium-dependent cleavage from a phospholipid precursor in neuronal membranes.
The release of anandamide is followed by rapid uptake into the plasma and hydrolysis 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 (rewarding) effects of the most drugs of abuse, the enhanced dopaminergic drive elicited by the cannabinoids is thought to underlie the reinforcing and abuse properties of marijuana.
From the biopsychiatry.com website
Pharmacology And Biochemistry Of Cannabinoid Receptors
Cannabis
The marijuana plant has been used for many years for recreational and therapeutic applications, although the mechanisms through which extracts of the cannabis plant brought about their actions were obscure.
However, with the cloning of two subtypes of cannabinoid receptor, together with the recent discovery of endogenous cannabinoid agents, has renewed interest in the investigation of the potential therapeutic application of these agents.
Cannabinoid Receptors
At least two subtypes of cannabinoid receptor exist which have been cloned from animal or human sources. These subtypes are termed CB1 and CB2 and appear to be differentially expressed in the nervous system and the periphery, respectively.
Cannabinoid receptors are members of the G-protein coupled receptor (GPCR) superfamily, and are typically thought to mediate inhibition of adenylyl cyclase activity, and hence reduce cyclic AMP levels.
The therapeutic exploitation of cannabinoid receptors is still in its' infancy, although the psychoactive properties of the cannabinoids have been known for centuries. A synthetic cannabinoid, nabilone, may be used for the treatment of glaucoma, and also to prevent the emesis associated with chemotherapy.
Endogenous Cannabinoids
The possibility of endogenous cannabis-like agents has been speculated upon for some time, although it is only recently that a serious candidate has arisen. This is the eicosanoid derivative, anandamide, which has been isolated from porcine brain, and appears to be more active at the CB1 receptor.
Recent evidence has linked this compound with an endothelium-derived hyperpolarizing factor, suggesting that endogenous cannabinoids may be important regulators of vascular tone.
By Steve Alexander (Wednesday 28 May 1997)
Department of Physiology and Pharmacology
at the University of Nottingham.
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Illegal Drugs
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