Cannabinoid receptor-mediated inhibition of acetylcholine release from hippocampal and cortical synaptosomes

1 In previous studies cannabinoid agonists have been found to inhibit and c annabinoid antagonists to enhance electrically-evoked [H-3]-acetycholine (A Ch) release in hippocampal slices. The present study was undertaken to dete rmine if similar cannabinoid effects could be observed in synaptosomes. 2 [H-3]-ACh release was evoked by two methods, both sensitive to presynapti c receptor effects. The first involved the addition of 1.3 mM calcium follo wing perfusion with calcium-free I(rebs and the second the addition of 11 m M potassium following perfusion with normal Krebs. 3 In hippocampal synaptosomes the 1.3 mM calcium-evoked release and the hig h potassium-evoked [H-3]-ACh release were inhibited by the cannabinoid agon ist, WIN 55212-2, by 59 and 39%, respectively, and with an EC50 Of approxim ately 1 nM. WIN 55212-2 produced a similar, although less potent, inhibitio n of [H-3]-ACh release in cortical synaptosomes. No inhibitory effect of WI N 55212-2 on [H-3]-ACh release in striatal synaptosomes was observed, suppo rting previous data collected in this area with brain slices. 4 The cannabinoid antagonist, SR 141716A, produced a robust enhancement of 1.3 mM calcium-evoked [H-3]-ACh release in hippocampal synaptosomes (EC50 < 0.3 nM) but had no effect on potassium-evoked release or on [H-3]-ACh rele ase in the cortex or striatum. 5 In conclusion our data demonstrates the inhibitory effects of WIN 55212-2 observed on ACh release in brain slices can be observed in hippocampal and cortex synaptosomes, suggesting a direct action of these compounds on the synaptic terminals. The SR 141716A-induced enhancement of ACh release can s imilarly be observed in hippocampal synaptosomes and is probably due to an inverse agonist action at constitutively active receptors.