title: Modulation of GABAergic synaptic currents and current responses by α-thujone and dihydroumbellulone.
abstract: α-Thujone (1a), a constituent of wormwood, has been suspected to cause adverse psychoactive reactions in addicted drinkers of absinthe. While the content of 1a in absinthe is too low for such effects, at higher doses it can indeed induce seizures and inhibit GABA(A) receptors (GABA(A)Rs). The effect of 1a on GABAergic synaptic currents and the mechanisms by which it modulates GABA(A)Rs remain unknown. To address these issues, cultured hippocampal neurons were used to investigate the action of 1a on GABAergic miniature inhibitory postsynaptic currents (mIPSCs) and on responses to exogenous GABA applications. Since lipophilic compounds often show nonspecific actions related to their hydrophobicity, the action of 1a was compared to that of dihydroumbellulone (2), a configurationally pseudoenantiomeric constitutional isomer. α-Thujone (1a) reduced mIPSC frequency and amplitude and also moderately affected their kinetics, indicating both pre- and postsynaptic mechanisms. Analysis of current responses to exogenous GABA revealed that 1a reduced their amplitude, affecting their onset, desensitization, and deactivation, suggesting an effect on receptor gating. In contrast, 2 caused only a weak or negligible effect on GABAergic currents, supporting the effects of 1a on GABAergic inhibition as being due to specific interactions with GABA(A)Rs.
authors.affiliation: Laboratory of Neuroscience, Department of Biophysics, Wrocław Medical University, ul. Chałubińskiego 3, 50-367 Wrocław, Poland. mszczot@gazeta.pl
authors.forename: Marcin
authors.initials: M
authors.lastname: Szczot
authors.forename: Marta Magdalena
authors.initials: MM
authors.lastname: Czyzewska
authors.forename: Giovanni
authors.initials: G
authors.lastname: Appendino
authors.forename: Jerzy Wladyslaw
authors.initials: JW
authors.lastname: Mozrzymas
mesh_terms: D018646:Absinthe / Q000009:adverse effects; D000818:Animals; D019306:Artemisia / Q000737:chemistry*; D000081008:Bicyclic Monoterpenes; D006624:Hippocampus / Q000187:drug effects; D006801:Humans; D053444:Inhibitory Postsynaptic Potentials / Q000187:drug effects; D007700:Kinetics; D015394:Molecular Structure; D039821:Monoterpenes / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D011963:Receptors, GABA-A / Q000187:drug effects* / Q000502:physiology; D013237:Stereoisomerism; D009435:Synaptic Transmission / Q000187:drug effects; D005680:gamma-Aminobutyric Acid / Q000494:pharmacology*
chemical_list: D000081008:Bicyclic Monoterpenes; D039821:Monoterpenes; D011963:Receptors, GABA-A; D005680:gamma-Aminobutyric Acid; C005790:beta-thujone