ELECTRICALLY-EVOKED ACETYLCHOLINE-RELEASE FROM HIPPOCAMPAL SLICES IS INHIBITED BY THE CANNABINOID RECEPTOR AGONIST, WIN-55212-2, AND IS POTENTIATED BY THE CANNABINOID ANTAGONIST, SR-141716A

This study examined the effect of the cannabinoid receptor agonist, WI N 55212-2, on the electrically evoked release of [C-14]acetylcholine ( ACh) from superfused brain slices from the hippocampus, a region with a high density of cannabinoid receptors. A comparison was also made wi th [C-14]ACh release from the nucleus accumbens, which has relatively fewer cannabinoid receptors. In the hippocampal slices, WIN 55212-2 pr oduced a dose-dependent inhibition of [C-14]ACh release, with an EC(50 ) of 0.03 mu M and a maximal inhibition of 81% at 1 mu M. In the nucle us accumbens slices, WIN 55212-2 produced a weak inhibition of [C-14]A Ch release, which did not quite reach statistical significance. The in hibition of electrically evoked hippocampal [C-14]ACh release by WIN 5 5212-2 could be prevented by the cannabinoid receptor antagonist, SR 1 41716A (EC(50), 0.3-1.0 mu M). In addition to antagonizing the effects of WIN 55212-2, SR 141716A alone produced a 2-fold potentiation of th e electrically stimulated [C-14]ACh release in this region (EC(50), 0. 1-0.3 mu M). By contrast, in nucleus accumbens slices, no potentiation of the stimulated release of [C-14]ACh release by SR 141716A was obse rved. Basal [C-14]ACh release was unaffected by WIN 55212-2 or SR 1417 16A in either area. These results suggest that cannabinoid receptor ac tivation can produce a strong inhibition of ACh release in the hippoca mpus. Furthermore, the potentiation of ACh release in the hippocampus by SR 141716A alone suggests either that this compound is an inverse a gonist at cannabinoid receptors or it is antagonizing the actions of a n endogenous ligand acting on these receptors.