Cannabinoids inhibit the release of [3H]glutamate from rodent hippocampal synaptosomes via a novel CB1 receptor-independent action

In this study we investigated the effect of cannabinoids on [H-3]glutamate release from hippocampal synaptosomes of rat and CB1-null mutant mouse. In the rat, cannabinoid receptor agonists, i.e. CP55,940 (EC50, 0.84 mum), WIN55,212-2 (EC50, 3.47 mum), ACEA (EC50, 17.8 mum), and R-(+)-methanandamide (EC50, 19.8 mum) concentration-dependently inhibited the 25-mm-K+ depolarization-evoked release of [H-3]glutamate and, among them, WIN55,212-2 displayed the greatest efficacy. The CB1 receptor antagonists SR141716A (1-5 mum) and AM251 (1 mum) and the VR1 vanilloid receptor antagonist capsazepine (10 mum) did not antagonize the effect of the agonists. SR141716A by itself attenuated the evoked [H-3]glutamate release. WIN55,212-2 inhibited the release of [H-3]glutamate in CB1-/- mice as well. These data demonstrate that the action of cannabinoids on glutamate release in the hippocampus is pharmacologically distinct and independent from the cloned CB1 receptor.