Gaboxadol: in vitro interaction studies with benzodiazepines and ethanol suggest functional selectivity

The interaction of gaboxadol (THIP; 4,5,6,7-tetrahydroisoxazolo-[5,4-c]pyridin-3-ol), ethanol and a series of benzodiazepine site agonists including diazepam, flunitrazepam, lorazepam, indiplon, zaleplon and zolpidem has been characterized at human alpha(1)beta(3)gamma(2S) gamma-aminobutyric acid type A (GABA(A)) receptors expressed in Xenopus oocytes and in the rat cortical wedge preparation. At the expressed receptors, gaboxadol and the benzodiazepine site agonists interacted synergistically and ethanol did not further enhance this potentiation. In contrast, in the rat cortical wedge preparation, where the inhibition of spontaneous activity was assessed, much weaker effects of the benzodiazepine site agonists were seen. Furthermore, ethanol did not further potentiate the effects of gaboxadol. These findings suggest that gaboxadol in functionally intact tissue may interact with a receptor population, which is insensitive to the modulation by benzodiazepines.