anandamide and Ataxia

The endocannabinoid (eCB) system is an important part of both the human central nervous system (CNS) and peripheral tissues. It is involved in the regulation of various physiological and neuronal processes and has been associated with various diseases. The eCB system is a complex network composed of receptor molecules, their cannabinoid ligands, and enzymes regulating the synthesis, release, uptake, and degradation of the signalling molecules. Although the eCB system and the molecular processes of eCB signalling have been studied extensively over the past decades, the involved molecules and underlying signalling mechanisms have not been described in full detail. An example pose the two poorly characterised eCB-degrading enzymes α/β-hydrolase domain protein six (ABHD6) and ABHD12, which have been shown to hydrolyse 2-arachidonoyl glycerol-the main eCB in the CNS. We review the current knowledge about the eCB system and the role of ABHD6 and ABHD12 within this important signalling system and associated diseases. Homology modelling and multiple sequence alignments highlight the structural features of the studied enzymes and their similarities, as well as the structural basis of disease-related ABHD12 mutations. However, homologies within the ABHD family are very low, and even the closest homologues have widely varying substrate preferences. Detailed experimental analyses at the molecular level will be necessary to understand these important enzymes in full detail.

Topics: Animals; Arachidonic Acids; Ataxia; Cataract; Computational Biology; Endocannabinoids; Glycerides; Humans; Lipid Metabolism; Monoacylglycerol Lipases; Mutation; Neurodegenerative Diseases; Polyneuropathies; Polyunsaturated Alkamides; Receptor, Cannabinoid, CB1; Receptor, Cannabinoid, CB2; Retinitis Pigmentosa; Signal Transduction

The objective of the present study was to determine the neurobehavioral effects of the putative endogenous cannabinoid ligand, anandamide, and its influence on cannabinoid (CB1) receptor gene expression. The effect of acute administration of anandamide to C57BL/6, DBA/2, and ICR mice were evaluated in motor function and emotionality tests. The C57BL/6 and ICR mouse strains were more sensitive than the DBA/2 strain to the depression of locomotor activity and stereotyped behavior caused by anandamide. Although anandamide produced catalepsy in all three strains, anandamide induced ataxia in the minus-maze test only in the C57BL/6 animals and only at the lowest dose used. In the plus-maze test system, anandamide produced a mild aversive response, and by the third day of treatment the mouse strains developed an intense aversion to the open arms of the plus-maze. Northern analysis data using the recently cloned mouse cannabinoid receptor cDNA as a probe indicated that there was abundant expression of CB1 gene in the whole brain of the ICR mouse than in the brains of the C57BL/6 and DBA/2 strains with or without pretreatment with anandamide. The anandamide induced neurobehavioral profile does not seem to correspond to the CB1 gene expression in the mouse strains. It is, therefore, unlikely that the CB1 receptor mediates all the cannabinomimetic effects of anandamide in the brain.

Topics: Animals; Arachidonic Acids; Ataxia; Brain; Cannabinoids; Endocannabinoids; Male; Maze Learning; Mice; Mice, Inbred C57BL; Mice, Inbred DBA; Mice, Inbred ICR; Motor Activity; Polyunsaturated Alkamides; Receptors, Cannabinoid; Receptors, Drug; Species Specificity; Stereotyped Behavior