The nonimmobilizer 1,2-dichlorohexafluorocyclobutane (F6; also known as 2N) causes amnesia and seizures at concentrations less than and more than, respectively, than that predicted to cause immobility (MACpred). The molecular and cellular basis of these effects is not known. We reported previously that F6 has no effect on synaptic gamma aminobutyric acid (GABA)A receptors located on the somata of hippocampal pyramidal cells. However, in hippocampal neurons, GABAA receptors that are located subsynaptically have different pharmacologic properties from those at extrasynaptic sites, and these classes of receptors may serve different physiologic functions. Therefore, we investigated the effects of F6 and isoflurane on currents mediated predominantly by extrasynaptic GABAA receptors harvested from hippocampal neurons by exposing nucleated excised patches to brief, high-concentration pulses of GABA. We found that extrasynaptic GABAA receptors in the majority of neurons located in the pyramidal cell layer are insensitive to F6 at concentrations up to 110 microM, although receptors harvested from one putative interneuron were potently inhibited by 43 microM of F6. By contrast, isoflurane consistently reduced the peak amplitude and slowed deactivation of currents mediated by extrasynaptic receptors, similar to its effect on synaptic receptors. These results demonstrate the selective sensitivity of extrasynaptic GABAA receptors on pyramidal neurons to isoflurane but not F6.