Monoterpenoid α-thujone is a compound found in absinthe, alcoholic beverage commonly abused (often by famous artists) in late XIX and early XX century. It has been long speculated that α-thujone is responsible for some adverse effects of this liquor including seizures. It has been investigated that the effect of α-thujone is related to its action on GABAA receptors but a precise pharmacological analysis is lacking. In the present work we investigated mechanism of α-thujone action on GABAergic currents (current responses to exogenous GABA and miniature synaptic currents) in cultured hippocampal neurons. We found that high concentrations (100 - 300 μM) of α-thujone have only modest effect on amplitude of responses elicited by low (3 μM) [GABA], but it prolonged the current rise-time by nearly fivefold and significantly decreased the current fading during prolonged GABA application. At saturating [GABA] (10 mM), the amplitude of current response, elicited by rapid agonist applications, was significantly reduced by 300 µM α-thujone and current onset was also slowed down almost three times but this effect was markedly smaller than for currents evoked by low [GABA]. To assess the impact of α-thujone on desensitization, the time course of currents elicited by prolonged applications of saturating [GABA] were analyzed. In the presence of α-thujone the steady-state to peak value was markedly increased indicating a decrease in the extent of macroscopic desensitization. To check for the effect of α-thujone on synaptic transmission, we measured miniature inhibitory currents (mIPSC) and found that at 300 μM of α-thujone, amplitude and frequency of mIPSC were significantly reduced. In conclusion, our results suggest that α-thujone may act as a low potency allosteric modulator of GABAARs. Preliminary kinetic analysis suggests that this compound affects both binding and gating of neuronal GABAARs. This study was funded by the FNP award Mistrz (contract No 7/2008).
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