The effect of δ⁹-tetrahydrocannabinol on 5-HT₃ receptors depends on the current density

The effects of δ⁹-tetrahydrocannabinol (THC), the psychoactive component of cannabis, on the function of 5-HT type 3 (5-HT₃) receptors were investigated using a two-electrode voltage clamp technique in Xenopus oocytes, and a whole-cell patch clamp technique in rat nodose ganglion neurons. In oocytes injected with 3 ng cRNA of 5-HT_3A receptor, THC reversibly inhibited currents evoked with 5-HT (1 μM) in a concentration-dependent manner (IC₅₀=1.2 μM). The extent of THC inhibition was inversely correlated with the amount of cRNA injected and the mean 5-HT_3A receptor current densities. Pretreatment with actinomycin D, which inhibits transcription, decreased the mean 5-HT₃ receptor current density and increased the extent of THC inhibition on 5-HT₃ receptor-mediated currents. The IC₅₀ values for THC increased from 285 nM to 1.2 μM in oocytes injected with 1 and 3 ng of 5-HT_3A cRNA, respectively. In radioligand binding studies on membrane preparations of oocytes expressing 5-HT_3A receptors, THC did not alter the specific binding of a 5-HT_3A receptor antagonist, [³H]GR65630. In the presence of 1 μM THC, the maximum 5-HT-induced response was also inhibited without a significant change in 5-HT potency, indicating that THC acts as a noncompetitive antagonist on 5-HT₃ receptors. In adult rat nodose ganglion neurons, application of 1 μM THC caused a significant inhibition of 5-HT₃ receptors, extent of which correlated with the density of 5-HT-induced currents, indicating that the observed THC effects occur in mammalian neurons. The inhibition of 5-HT₃ receptors by THC may contribute to its pharmacological actions in nociception and emesis.