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The Journal of Neuroscience, November 24, 2004, 24(47):10679-10686; doi:10.1523/JNEUROSCI.1768-04.2004

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Cellular/Molecular
Ethanol Potentiation of GABAergic Synaptic Transmission May Be Self-Limiting: Role of Presynaptic GABA_B Receptors

Olusegun J. Ariwodola and Jeffrey L. Weiner

Department of Physiology and Pharmacology, Wake Forest University School of Medicine, Winston-Salem, North Carolina 27157

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_A 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 GABA_A receptor function in all brain regions or under all experimental conditions, and factors responsible for this variability remain mostly unknown. Notably, blockade of GABA_B receptors dramatically enhances ethanol potentiation of hippocampal GABA_A IPSPs and IPSCs, suggesting that some unknown GABA_B 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 GABA_B 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 GABA_B receptor tone, possibly via an increase in spontaneous GABA release, and that pretreatment with a subthreshold concentration of the GABA_B receptor agonist baclofen blocks ethanol but not flunitrazepam or pentobarbital potentiation of GABA_A IPSCs. These data suggest that an interaction between ethanol and presynaptic GABA_B 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 GABA_B receptor activity may play a role in regulating behavioral sensitivity to ethanol.

Key words: alcohol; GABA; hippocampus; IPSP; patch clamp; slice

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Received May 7, 2004; revised October 15, 2004; accepted October 15, 2004.

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