Thymol, a constituent of thyme essential oil, is a positive allosteric modulator of human GABAA receptors and a homo‐oligomeric GABA receptor from Drosophila melanogaster

Abstract

The GABA‐modulating and GABA‐mimetic activities of the monoterpenoid thymol were explored on human GABA A and Drosophila melanogaster homomeric RDL ac 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 EC 20 GABA response in oocytes injected with either α 1 β 3 γ 2s GABA A subunit cDNAs or the RDL ac 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 EC 50 for GABA at α 1 β 3 γ 2s GABA A 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 EC 20 GABA for α 1 β 1 γ 2s, α 6 β 3 γ 2s and α 1 β 3 γ 2s human GABA A receptors was almost identical, arguing against actions at benzodiazepine or loreclezole sites. Neither flumazenil, 3‐hydroxymethyl‐β‐carboline (3‐HMC), nor 5 α‐pregnane‐3 α, 20 α‐diol (5 α‐pregnanediol) affected thymol potentiation of the GABA response at α 1 β 3 γ 2s receptors, providing evidence against actions at the benzodiazepine/β‐carboline or steroid sites. Thymol stimulated the agonist actions of pentobarbital and propofol on α 1 β 3 γ 2s receptors, consistent with a mode of action distinct from that of either compound. These data suggest that thymol potentiates GABA A receptors through a previously unidentified binding site. British Journal of Pharmacology (2003) 140, 1363–1372. doi:10.1038/sj.bjp.0705542