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, were attributed to inhibitory actions at the GABAA receptor. Here, we investigated for the first time the 5-HT3 receptor as a potential site of the psychotropic actions of α-thujone. This cation permeable ligand-gated ion channel shows considerable homology to the GABAA receptor. We previously demonstrated that in homomeric assemblies of cloned human 5-HT3A receptor subunits, the endogenous agonist 5-HT induced desensitization via channel blockade. When the 5-HT3B receptor subunit was co-expressed, the resulting heteromeric assemblies desensitized independent from channel blockade. In the present study, patch-clamp experiments revealed an inhibitory action of α-thujone on both homomeric and heteromeric 5-HT3 receptors. This inhibitory action was mediated via channel blockade. However, it was not α-thujone itself which blocked the channel. The present experiments suggested that, in homomeric receptors, α-thujone enhanced the inherent channel-blocking potency of the natural ligand, 5-HT. In heteromeric receptors, α-thujone recruited an additional channel-blocking component of the agonist. By means of kinetic modeling, we simulated possible mechanisms by which α-thujone decreased the 5-HT-induced responses. It is suggested that α-thujone reduced 5-HT3 receptor activity by an effect on mechanisms involved in receptor desensitization, which depend on receptor subunit composition. It remains to be shown if this inhibitory action on serotonergic responses contributes to behavioral effects of α-thujone. [Copyright &y& Elsevier]