Ethanol Potentiation of GABAergic Synaptic Transmission May Be Self-Limiting: Role of Presynaptic GABABReceptors

Abstract

Ethanol enhances GABAergic synaptic inhibition, and this interaction contributes to many of the behavioral and cognitive effects of this drug. Most studies suggest that ethanol enhances GABAergic neurotransmission via an allosteric potentiation of the postsynaptic GABA_Areceptors that mediate fast synaptic inhibition in the mammalian CNS. Despite widespread acceptance of this hypothesis, direct support for such a mechanism has been difficult to obtain. Ethanol does not enhance GABA_Areceptor function in all brain regions or under all experimental conditions, and factors responsible for this variability remain mostly unknown. Notably, blockade of GABA_Breceptors dramatically enhances ethanol potentiation of hippocampal GABA_AIPSPs and IPSCs, suggesting that some unknown GABA_Breceptor mechanism limits the overall potentiating effect of ethanol on GABAergic synapses. In this study, we demonstrate that, at perisomatic synapses in the rat hippocampus, ethanol enhances presynaptic GABA_Bautoreceptor function and that this interaction reduces the overall potentiating effect of ethanol at these synapses. We further show that ethanol significantly elevates basal presynaptic GABA_Breceptor tone, possibly via an increase in spontaneous GABA release, and that pretreatment with a subthreshold concentration of the GABA_Breceptor agonist baclofen blocks ethanol but not flunitrazepam or pentobarbital potentiation of GABA_AIPSCs. These data suggest that an interaction between ethanol and presynaptic GABA_Bautoreceptor activity regulates the ethanol sensitivity of GABAergic synapses. Given that thein vitroethanol sensitivity of these synapses correlates within vivoethanol responsiveness in a number of rodent lines, our data further suggest that presynaptic GABA_Breceptor activity may play a role in regulating behavioral sensitivity to ethanol.