Large receptor reserve for cannabinoid actions in the central nervous system.
Academic Article
Overview
abstract
The receptor occupancy required to produce cannabinoid effects in the central nervous system was determined in both a neurochemical and a behavioral assay for cannabinoid actions. In the neurochemical experiments, performed on superfused rat hippocampal slices, electrically evoked [3H]acetylcholine release was inhibited by the cannabinoid agonist, WIN 55212 to 2 with an EC50 of 0.005 microM and maximum effect of 79%. In parallel experiments examining binding of the radiolabeled CB1 antagonist [131I]AM 281 (N-(morpholin-4-yl)-5-(4-[131I]iodophenyl)-1-(2, 4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide) to living hippocampal slices, WIN 55212 to 2 inhibited [131I]AM 281 binding with an EC50 of 1.3 microM. From these two sets of data it was determined that 50% of maximal inhibition of [3H]acetylcholine release in hippocampal slices occurs at a receptor occupancy of only 0.13% and 95% of maximal inhibition at a receptor occupancy of 7.5%, suggesting the presence of a receptor reserve that is large compared with other G protein-coupled receptor systems in the central nervous system. In behavioral experiments, WIN 55212 to 2 inhibited spontaneous locomotor activity in mice with an ED50 of 0.3 mg/kg, i. v. In in vivo binding experiments using [131I]AM 281, WIN 55212 to 2 failed to produce significant inhibition of radiotracer binding in the mouse brains, except at very high doses (10 mg/kg or greater, i. v.). By contrast, the CB1 antagonist SR 141716A (10 mg/kg, i.p.), completely abolished specific [131I]AM 281 binding. These experiments suggest that behavioral effects of cannabinoids, like neurochemical effects, are produced at very low receptor occupancy.
