The blockade of the effect of ethanol by norBNI observed in our study could be due to a ceiling effect implicating a common pool of GABA or a common site of action on the GABA release machinery. This possibility is consistent with the results we obtained by reversing the order of application. Indeed ethanol prevented the effect of norBNI, indicating a reciprocal blockade by the two drugs and pointing to a common pool of transmitter targeted by norBNI and ethanol. On the other hand, ethanol produced larger increases in GABAergic transmission than norBNI, but the norBNI effect was not augmented by subsequent application of ethanol, contrary to what one would expect if both drugs are targeting a common pool of GABA. Furthermore, a prior study from our lab showed that CB1 receptor antagonism increased inhibitory transmission to a level similar to that observed with norBNI in the present study (Roberto et al., 2010), an effect that was augmented by subsequent application of ethanol. This suggests there may be a fundamental difference in the way that KOR and other receptors (e.g., CB1) interact with ethanol-activated cascades at the presynaptic GABA terminal in CeA.
