Central nervous system cannabinoid receptors

Gifford AN, Bruneus M, Gatley SJ, Lan R, Makriyannis A, Volkow ND. Large receptor reserve for cannabinoid actions in the central nervous system. J Pharmacol Exp Ther 1999 2 478-483. 

Cannabis sativa plants contain at least 400 different compounds, of which as many as 60 are structurally related to 5 -tetrahydrocannabinol (5 -THC), the primary psychoactive constituent of cannabis. When cannabis is smoked, hundreds of additional compounds are produced by pyrolysis, which may contribute to both acute and chronic effects (Abood and Martin, 1992). The central nervous system actions of canna-binoids are mediated primarily through the CBj receptor. A second type of cannabinoid receptor, termed the CB2 receptor, is distributed primarily in the periphery (Gifford et ah, 1999). Activation of central cannabinoid receptors modulates neurotransmitter release at... 

The first identified cannabinoid receptor subtype, CB was cloned and demonstrated to have an amino acid sequence consistent with a tertiary structure typical of the seven transmembrane-spanning proteins that are coupled to G proteins. In addition to being found in the central nervous system, mRNA for CB has also been identified in testes. The central nervous system responses to cannabinoid compounds are believed to be mediated exclusively by CB, inasmuch as CB2 transcripts could not be found in brain tissue by either Northern analysis or in situ hybridization studies. CBj transduces signals in response to central-nervous-system-active constituents of C. sativa as well as synthetic bicyclic and tricyclic cannabinoid analogs, aminoalkylindole, and eicosanoid cannabimimetic compounds. CB is coupled to G, to inhibit adenylate cyclase activity and to a pertussis-sensitive G protein to regulate Ca2+ currents. 

Tsou K, Brown S, Sanudo-Pena MC, Mackie K, Walker JM (1997) Immunohistochemical distribution of cannabinoid CB1 receptors in the rat central nervous system. Neurosci 83(2) 393 411 Van Beugen BJ, Nagaraja RY, Hansel C (2006) Climbing fiber-evoked endocannabinoid signaling heterosynaptically suppresses presynaptic cerebellar long-term potentiation. J Neurosci 26(32) 8289-94... 

Doherty, J., and Dingledine, R. (2003). Functional interactions between cannabinoid and metabotropic glutamate receptors in the central nervous system. Cun. Opin. Pharmacol. 3, 46-53. 

Dean B, Sundram S, Bradbury R, Scarr E, Copolov D. 2001. Studies on [3H] CP-55940 binding in the human central nervous system Regional specific changes in density of cannabinoid-1 receptors associated with schizophrenia and cannabis use. Neuroscience 103 9-15. 

Tsou K, Brown S, Sanudo-Pena MC, Mackie K, Walker JM. 1998. Immunohistochemical distribution of cannabinoid CB1 receptors in the rat central nervous system. Neuroscience 83 393-411. 

The primary active component of cannabis is A9-tetrahy-drocannabinol (THC), which is responsible for the greater part of the pharmacological effects of the cannabis complex. A8-THC is also active. However, the cannabis plant contains more than 400 chemicals, of which some 60 are chemically related to A9-THC, and it is evident that the exact proportions in which these are present can vary considerably, depending on the way in which the material has been harvested and prepared. In man, A9-THC is rapidly converted to 11-hydroxy-A9-THC (5), a metabolite that is active in the central nervous system. A specific receptor for the cannabinols has been identified it is a member of the G-protein-linked family of receptors (6). The cannabinoid receptor is linked to the inhibitory G-protein, which is linked to adenyl cyclase in an inhibitory fashion (7). The cannabinoid receptor is found in highest concentrations in the basal ganglia, the hippocampus, and the cerebellum, with lower concentrations in the cerebral cortex. 

Rimonabant is an inverse agonist for CBl cannabinoid receptors, which is approved in Europe for weight-loss therapy, but has significant side effects on the central nervous system. 

The mechanisms involved in THC s central nervous system (CNS) and cardiovascular effects have not been well delineated. Specific cannabinoid receptors in the cerebral cortex may be responsible for the pharmacologic effects of THC. THC also has immunosuppressive effects and results in depression... 

The effects of cannabinoids are due to an interaction with high affinity specific receptors present in the central nervous system (Devane et al.. Molecular Pharmacology (1988) 34, 605-613) and peripheral nervous system (Nye et al.. The Journal of Pharmacology and Experimental Therapeutics (1985) 234, 784-791 30 Kaminski et al.. Molecular Pharmacology (1992) 42, 736-742 Munro et at.. Nature (1993) 365, 61-65). 

Anandamide amidohydrolase is likely to play an important role in the physiological degradation of anandamide. Three lines of evidence support this possibility. First, anandamide amidohydrolase is highly selective. Second, anandamide amidohydrolase is discretely distributed in the central nervous system, where its localization parallels that of cannabinoid receptors. 

Sim-Selley LJ (2003) Regulation of cannabinoid CBI receptors in the central nervous system by chronic cannabinoids. Crit Rev Neurobiol 15 91-119... 

Cottone E, Salio C, Conrath M, Franzoni MF (2003) Xenopus laevis CBI cannabinoid receptor molecular cloning and mRNA distribution in the central nervous system. J Comp Neurol 464 487-496... 

Griffin G, Wray E, Tao Q, McAllister S, Rorrer W, Aung M, Martin B, Abood M (1999) Evaluation of the cannabinoid CB2 receptor-selective antagonist, SR144528 further evidence for cannabinoid CB2 receptor absence in the rat central nervous system. Eur J Pharmacol 377 117-125... 

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