Anandamide cannabinoid receptor subtype

The biological functions of anandamide may extend beyond its ability to activate cannabinoid receptors. Recent evidence indicates that this arachidonate derivative may stimulate receptors that are pharmacologically distinct from known cannabinoid receptor subtypes. When applied to brain striatal astrocytes in primary culture, anandamide has a potent inhibitory effect on gap-junction conductance. As expected from a receptor-mediated event, this effect is specific for anandamide (e.g., N-eicosatrienoyl-ethanolamine is inactive and non-esterified arachidonate is 10-fold less active), and is prevented by treating the astrocytes with either pertussis toxin or N-ethylmaleimide (two agents that block the activation... 

Two subtypes of G protein-coupled receptors for cannabis s psychotropic component, A -tetrahydrocannabinol (THC), have been cloned to date, the cannabinoid CBi and CB2 receptors (Howlett et al. 2004). Yet, five different types of endogenous agonists for these cannabinoid receptors have been identified so far (Fig. 1). These compounds, named endocannabinoids by analogy with THC (Di Marzo and Fontana 1995), are all derived from long-chain polyunsaturated fatty acids. In particular (1) the anandamides are amides of ethanolamine with polyunsaturated fatty acids with at least 20 carbon atoms and three 1,4-diene double bonds. The C20 4 homologue in this series, V-arachidonoylethanolamine (AEA) (Devane et al. 1992), also known simply as anandamide, has been most studied. 

It clearly appears that if the endocannabinoid system really plays a role in the physiopathology of schizophrenia, the activation of CBj receptors does not seem to be a crucial point. Interestingly, CBi is not the sole CB receptor subtype expressed in the brain. Some studies using CB, KO mice supported the existence of G-protein-coupled non-CBj and non-CBj cannabinoid receptors, sensitive to endocannabinoids, synthetic agonists, and rimonabant (Di Marzo et al., 2000 Breivogel et al., 2001 Pride et al., 2003). In addition, anandamide has been found to activate both CB, and vanilloid VR, receptors (for review see Di Marzo et al., 2002). However, the localizations and functions of such types of receptors are unclear, and their putative role in schizophrenia remains to be demonstrated. Although cannabis use appears to be neither a sufficient nor a necessary cause for psychosis, the current status of research on cannabis-associated psychosis (Leweke et al., 2004) is inconclusive, and further research is needed to understand the mechanisms by which cannabis is associated with psychosis. 

The ability of cannabinoids to cause vascular effects implies that the vasculature contains a molecular target. Evidence to date suggests that there may be vascular cannabinoid receptors, which may either fall into the classical CBj/CBj classification or represent a new subtype. As stated above, the biphasic hypotension in response to anandamide is absent in CBi receptor knockout mice (Ledent et al., 1999). This clearly points to the involvement of the CBj receptor. However, it should be noted that this does not conclusively identify the cannabinoid receptors as being on the vascular smooth muscle or associated with neuronal tissue. The sensitivity of vasorelaxant responses to CB receptor antagonists has been controversial, with some studies indicating that the responses are... 

Subsequently, the pharmacological properties of anandamide have been explored in considerable detail and by using a variety of experimental models, all of which have confirmed and extended the validity of the early observations. There is now little doubt that anandamide is an endogenous lipid component present in the brain, which activates CBl cannabinoid receptors. Although anandamide binds also to peripheral CB2 receptors, it does so with a much lower affinity than to CBl. Moreover, its ability to activate the CB2 subtype remains controversial, and a role as endogenous CB2 receptor antagonist has been proposed. 

CB4 Endothehal caimabinoid receptor. A subtype that has been identified in arteries and human umbilical vein endothelial cells (HUVEC) and is present in vascnlar endothelium. It can be activated by anandamide, N-arachidonyl dopamine, virohdamine, and abnormal cannabidiol bnt not by the 2-AG and classical CB/CBj cannabinoid agonist to induce endothelium-dependent vasodilation that is present in CBj and CBj wild-type and mutant... 

CBjo A cannabinoid subtype receptor in mouse vas deferens at which AM630 is 20 times more potent as an antagonist of THC than of anandamide. 

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