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

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 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.

A Conceptualization of Integrated Actions of Ethanol Contributing to its GABAmimetic Profile: A Commentary

“…Subsequently, Roberto et al (2003Roberto et al ( , 2004a provided evidence that ethanol enhanced the effect of stimulusinduced GABA-mediated IPSPs and mIPSCs from neurons in slices from the central nucleus of the amygdala and caused release of GABA into microdialysatesFclear evidence that ethanol could facilitate GABA release. This action of ethanol to release GABA can apparently be modified at presynaptic sites (see designation in Figure 4), by GABA B (Ariwodola and Weiner, 2004;Wan et al, 1996) and corticotrophin releasing factor (CRF; Nie et al, 2004) receptors. Additionally, other neurotransmitter receptors affected by ethanol can influence neural circuits that influence GABA transmission (Carta et al, 2003(Carta et al, , 2004; Figure 3 Effect of ethanol on neural rate from cerebellar Purkinje neurons.…”

“…This release of GABA by ethanol is thought to occur in some, but not all, regions of brain (see text). Data are noted in the text that presynaptic influences (note 'presynaptic receptor' designation in the figure) on GABA B (see Ariwodola and Weiner, 2004) and other transmitter receptors (Nie et al, 2004) can influence GABA released by ethanol. Additionally, following ethanol activation of the hypothalamicpituitary-adrenal (HPA) axis (denoted by the darkened arrows), ethanol increases neurosteroid precursors from the adrenal, which in turn results in increased neurosteroids in brain (Barbaccia et al, 1999;Khisti et al, 2003;O'Dell et al, 2004).…”

“…Several studies demonstrated that GABA B receptor antagonists enhance the ability of ethanol to facilitate GABA transmission in the hippocampus (Ariwodola and Weiner, 2004;Wan et al, 1996;Wu et al, 2004) and nucleus accumbens (Nie et al, 2000). Melis et al (2002) linked the long-lasting potentiation of GABAergic synapses on dopaminergic neurons in the ventral tegmental area by systemic ethanol to an effect on presynaptic GABA B receptors.…”

“…Melis et al (2002) linked the long-lasting potentiation of GABAergic synapses on dopaminergic neurons in the ventral tegmental area by systemic ethanol to an effect on presynaptic GABA B receptors. Ariwodola and Weiner (2004) recently suggested that the effect of ethanol to facilitate GABA transmission is limited because of GABA feedback on presynaptic GABA B receptors. Wu et al (2004) reported that the presence of GABA B receptors accounted for the difference in sensitivity to ethanol influences on GABA transmission in differing subfields of the hippocampus (see Weiner et al, 1997a).…”

Individualised Treatment of Alcohol Dependent Patients with Baclofen: A Clinical Observation

“…It was [6] postulated that pre-and postsynaptic GABA B receptors modulate alcohol related reward and reinforcement mechanisms. The activation of these receptors with the GABA B receptor agonist baclofen inhibits dopaminergic neurons indirectly and directly [7].…”