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Keywords:

  • Thymol;
  • thyme essential oil;
  • monoterpenoids;
  • ionotropic GABA receptor;
  • Drosophila melanogaster;
  • allosteric modulation
  • The GABA-modulating and GABA-mimetic activities of the monoterpenoid thymol were explored on human GABAA and Drosophila melanogaster homomeric RDLac GABA receptors expressed in Xenopus laevis oocytes, voltage-clamped at −60 mV. The site of action of thymol was also investigated.

  • Thymol, 1–100 μM, resulted in a dose-dependent potentiation of the EC20 GABA response in oocytes injected with either α1β3γ2s GABAA subunit cDNAs or the RDLac subunit RNA. At 100 μM thymol, current amplitudes in response to GABA were 416±72 and 715±85% of controls, respectively. On both receptors, thymol, 100 μM, elicited small currents in the absence of GABA.

  • The EC50 for GABA at α1β3γ2s GABAA receptors was reduced by 50 μM thymol from 15±3 to 4±1 μM, and the Hill slope changed from 1.35±0.14 to 1.04±0.16; there was little effect on the maximum GABA response.

  • Thymol (1–100 μM) potentiation of responses to EC20 GABA for α1β1γ2s, α6β3γ2s and α1β3γ2s human GABAA receptors was almost identical, arguing against actions at benzodiazepine or loreclezole sites.

  • Neither flumazenil, 3-hydroxymethyl-β-carboline (3-HMC), nor 5α-pregnane-3α, 20α-diol (5α-pregnanediol) affected thymol potentiation of the GABA response at α1β3γ2s receptors, providing evidence against actions at the benzodiazepine/β-carboline or steroid sites. Thymol stimulated the agonist actions of pentobarbital and propofol on α1β3γ2s receptors, consistent with a mode of action distinct from that of either compound. These data suggest that thymol potentiates GABAA receptors through a previously unidentified binding site.

British Journal of Pharmacology (2003) 140, 1363–1372. doi:10.1038/sj.bjp.0705542