RT Journal Article SR Electronic T1 Ethanol Potentiation of GABAergic Synaptic Transmission May Be Self-Limiting: Role of Presynaptic GABAB Receptors JF The Journal of Neuroscience JO J. Neurosci. FD Society for Neuroscience SP 10679 OP 10686 DO 10.1523/JNEUROSCI.1768-04.2004 VO 24 IS 47 A1 Olusegun J. Ariwodola A1 Jeffrey L. Weiner YR 2004 UL http://www.jneurosci.org/content/24/47/10679.abstract AB 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 GABAA receptors 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 GABAA receptor function in all brain regions or under all experimental conditions, and factors responsible for this variability remain mostly unknown. Notably, blockade of GABAB receptors dramatically enhances ethanol potentiation of hippocampal GABAA IPSPs and IPSCs, suggesting that some unknown GABAB receptor 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 GABAB autoreceptor function and that this interaction reduces the overall potentiating effect of ethanol at these synapses. We further show that ethanol significantly elevates basal presynaptic GABAB receptor tone, possibly via an increase in spontaneous GABA release, and that pretreatment with a subthreshold concentration of the GABAB receptor agonist baclofen blocks ethanol but not flunitrazepam or pentobarbital potentiation of GABAA IPSCs. These data suggest that an interaction between ethanol and presynaptic GABAB autoreceptor activity regulates the ethanol sensitivity of GABAergic synapses. Given that the in vitro ethanol sensitivity of these synapses correlates with in vivo ethanol responsiveness in a number of rodent lines, our data further suggest that presynaptic GABAB receptor activity may play a role in regulating behavioral sensitivity to ethanol.