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

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Abstract
In previous studies cannabinoid agonists have been found to inhibit and cannabinoid antagonists to enhance electrically‐evoked [3H]‐acetycholine (ACh) release in hippocampal slices. The present study was undertaken to determine if similar cannabinoid effects could be observed in synaptosomes. [3H]‐ACh release was evoked by two methods, both sensitive to presynaptic receptor effects. The first involved the addition of 1.3 mM calcium following perfusion with calcium‐free Krebs and the second the addition of 11 mM potassium following perfusion with normal Krebs. In hippocampal synaptosomes the 1.3 mM calcium‐evoked release and the high potassium‐evoked [3H]‐ACh release were inhibited by the cannabinoid agonist, WIN 55212‐2, by 59 and 39%, respectively, and with an EC50 of approximately 1 nM. WIN 55212‐2 produced a similar, although less potent, inhibition of [3H]‐ACh release in cortical synaptosomes. No inhibitory effect of WIN 55212‐2 on [3H]‐ACh release in striatal synaptosomes was observed, supporting previous data collected in this area with brain slices. The cannabinoid antagonist, SR 141716A, produced a robust enhancement of 1.3 mM calcium‐evoked [3H]‐ACh release in hippocampal synaptosomes (EC503H]‐ACh release in the cortex or striatum. 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 similarly be observed in hippocampal synaptosomes and is probably due to an inverse agonist action at constitutively active receptors. British Journal of Pharmacology (2000) 131, 645–650; doi:10.1038/sj.bjp.0703599