The nonpsychoactive cannabinoid cannabidiol inhibits 5- hydroxytryptamine_3A receptor-mediated currents in xenopus laevis oocytes

The effect of the plant-derived nonpsychotropic cannabinoid, cannabidiol (CBD), on the function of hydroxytryptamine (5-HT)_3A receptors expressed in Xenopus laevis oocytes was investigated using two-electrode voltage-clamp techniques. CBD reversibly inhibited 5-HT (1 μM)-evoked currents in a concentration-dependent manner (IC₅₀ = 0.6 μM). CBD (1 μM) did not alter specific binding of the 5-HT_3A antagonist [³H]3-(5-methyl-1H-imidazol-4-yl)-1-(1-methylindol-3-yl)propan-1-one (GR65630), in oocytes expressing 5-HT_3A receptors. In the presence of 1 μM CBD, the maximal 5-HT-induced currents were also inhibited. The EC ₅₀ values were 1.2 and 1.4 μM, in the absence and presence of CBD, indicating that CBD acts as a noncompetitive antagonist of 5-HT₃ receptors. Neither intracellular BAPTA injection nor pertussis toxin pretreatment (5 μg/ml) altered the CBD-evoked inhibition of 5-HT-induced currents. CBD inhibition was inversely correlated with 5-HT_3A expression levels and mean 5-HT₃ receptor current density. Pretreatment with actinomycin D, which inhibits protein transcription, decreased the mean 5-HT₃ receptor current density and increased the magnitude of CBD inhibition. These data demonstrate that CBD is an allosteric inhibitor of 5-HT₃ receptors expressed in X. laevis oocytes. They further suggest that allosteric inhibition of 5-HT₃ receptors by CBD may contribute to its physiological roles in the modulation of nociception and emesis.