The neurobiology and evolution of cannabinoid signalling

The plant Cannabis saliva has been used by humans for thousands of years be cause of its psychoactivity The major psychoactive ingredient of cannabis i s Delta (9)-tetrahydrocannabinol, which exerts effects in the brain by bind ing to a G-protein-coupled receptor known as the CB1 cannabinoid receptor. The discovery of this receptor indicated that endogenous cannabinoids may o ccur in the brain, which act as physiological ligands for CB1. Two putative endocannabinoid ligands, arachidonylethanolamide ('anandamide') and 2-arac hidonylglycerol, have been identified, giving rise to the concept of a cann abinoid signalling system. Little is known about holy or where these compou nds are synthesized in the brain and how this relates to CB1 expression. Ho wever, detailed neuroanatomical and electrophysiological analysis of mammal ian nervous systems has revealed that the CB1 receptor is targeted to the p resynaptic terminals of neurons where it acts to inhibit release of 'classi cal' neurotransmitters. Moreover, an enzyme that inactivates endocannabinoi ds, fatty acid amide hydrolase, appears to be preferentially target-ed to t he somato dendritic compartment of neurons that are postsynaptic to CB1-exp ressing axon terminals. Based on these findings, we present here a model of cannabinoid signalling in which anandamide is synthesized by post-synaptic cells and acts as a retrograde messenger molecule to modulate neurotransmi tter release from presynaptic terminals. Using this model as a framework, w e discuss the role of cannabinoid signalling in different regions of the ne rvous system in relation to the characteristic physiological actions of can nabinoids in mammals, which include effects on movement, memory pain and sm ooth muscle contractility. The discovery of the cannabinoid signalling system in mammals has prompted investigation of the occurrence of this pathway in non-mammalian animals. H ere we review the evidence for the existence of cannabinoid receptors in no n-mammalian vertebrates and invertebrates and discuss the evolution of the cannabinoid signalling system. Genes encoding orthologues of the mammalian CB1 receptor have been identified in a fish, an amphibian and a bird, indic ating that CB1 receptors may occur throughout the vertebrates. Pharmacologi cal actions of cannabinoids and specific binding sites for cannabinoids hav e been reported in several invertebrate species, but the molecular basis fo r these effects is not known. Importantly, however, the genomes of the prot ostomian invertebrates Drosophila melanogaster and Caenorhabditis elegans d o not contain CB1 orthologues, indicating that CB1-like cannabinoid recepto rs may have evolved after the divergence of deuterostomes (e.g. vertebrates and echinoderms) and protostomes. Phylogenetic analysis of the relationshi p of vertebrate CB1 receptors with other G-protein-coupled receptors reveal s that the paralogues that appear to share the most recent common evolution ary origin with CB1 are lysophospholipid receptors, melanocortin receptors and adenosine receptors. Interestingly, as with CB1, each of these receptor types does not appear to have Drosophila orthologues, indicating that this group of receptors may not occur in protostomian invertebrates. We conclud e that the cannabinoid signalling system may be quite restricted in its phy logenetic distribution, probably occurring only in the deuterostomian clade of the animal kingdom and possible only vertebrates.