α-thujone reduces 5-HT3 receptor activity by an effect on the agonist-induced desensitization

The convulsant effects of α-thujone, the psychotropic component of absinthe, have been attributed to inhibitory actions at the GABA_A receptor. Here, we investigated for the first time the effect of α-thujone on the 5-HT₃ receptor as a potential site for psychotropic actions. Our patch-clamp experiments revealed an inhibitory effect of α-thujone on both homomeric and heteromeric 5-HT₃ receptors. This inhibitory action is mediated via channel blockade, even though α-thujone itself is not the channel blocking agent. In the homomeric receptors, α-thujone enhances the inherent channel blocking potency of the natural ligand 5-HT. In the heteromeric receptors, α-thujone recruits an additional channel blocking component of the agonist. Taken together, α-thujone reduces 5-HT₃ receptor activity by affecting the agonist-dependent mechanisms of receptor desensitization. It remains to be shown if this inhibitory action on serotonergic responses contributes to behavioural effects of α-thujone.