Hanchar HJ, Wallner M, Olsen RW. Alcohol effects on -aminobutyric acid type A receptors: are extrasynaptic receptors the answer? Life Sci 76: 1-8

Department of Molecular and Medical Pharmacology, University of California Los Angeles, Room 23-338 CHS, 650 Charles Young Drive South, Los Angeles, CA 90095-1735, USA.
Life Sciences (Impact Factor: 2.7). 12/2004; 76(1):1-8. DOI: 10.1016/j.lfs.2004.05.035
Source: PubMed


GABA(A) receptors have long been implicated in mediating at least part of the actions of ethanol in mammalian brain. However, until very recently, reports of the actions of EtOH on recombinant receptors have required very high doses of ethanol and animals lacking receptor subunits shown to be important for ethanol actions in vitro did not support the view that these subunits are crucial in ethanol actions. Recombinant alpha4beta3delta and alpha6beta3delta GABA(A) receptors are uniquely sensitive to ethanol, with a dose-response relationship mirroring the well known effects of alcohol consumption on the human brain. Receptors containing the delta subunit are thought to be located extrasynaptically and it will be important to determine if these extrasynaptic GABA(A) receptor subunit combinations mediate low dose alcohol effects in vivo.

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    • "In cerebellar granule cells, acute EtOH robustly increases both tonic currents and phasic sIPSCs by increasing presynaptic Golgi cell firing, in part by inhibiting the Na + /K + -ATPase and depolarizing the membrane potential of Golgi cells (Botta et al., 2010; Diaz et al., 2013). It has been suggested that EtOH can also directly enhance a6-containing GABA A R function in cerebellar granule cells (Hanchar et al., 2004), but this has been a controversial finding (Baur et al., 2009; Botta et al., 2007). "
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    ABSTRACT: The central amygdala (CeA) has a unique role in integrating stress and the rewarding effects of ethanol (EtOH) and plays a major role in the development of EtOH dependence via signaling of corticotropin-releasing factor (CRF). A recent report by Herman and colleagues (2013) entitled "Novel Subunit-Specific Tonic GABA Currents and Differential Effects of Ethanol in the Central Amygdala of CRF Receptor-1 Reporter Mice" is the first study to investigate inhibitory tonic currents in relation to CRF signaling in the CeA. The findings of that study significantly enhance our understanding of inhibitory tonic currents in the CeA and give insight into how EtOH may differentially affect CRF signaling within the CeA, leading to the development of EtOH dependence. This commentary will focus on the recent findings of Herman and colleagues and will discuss the effects of EtOH on the entire anxiety/emotion circuitry.
    Full-text · Article · Nov 2013 · Alcoholism Clinical and Experimental Research
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    • "Ethanol (EtOH) influences the function of inhibitory γ-aminobutyric acid (GABA) type A receptors (GABAARs) by various direct and indirect mechanisms (Criswell and Breese, 2005; Breese et al., 2006; Weiner and Valenzuela, 2006; Kumar et al., 2009; Kelm et al., 2011). EtOH thus selectively enhances the function of recombinant GABAARs containing α4 or α6 as well as δ subunits expressed in Xenopus laevis oocytes (Sundstrom-Poromaa et al., 2002; Wallner et al., 2003) as well as tonic currents mediated by GABAARs containing α4 and δ subunits in hippocampal and thalamic slices in vitro (Hanchar et al., 2004; Wei et al., 2004; Glykys et al., 2007; Jia et al., 2007, 2008; Santhakumar et al., 2007). Indirect modulation of GABAARs by EtOH has been shown to be mediated both presynaptically, through an increase in the probability of GABA release (Roberto et al., 2003; Carta et al., 2004; Sanna et al., 2004; Zhu and Lovinger, 2006), and postsynaptically, through stimulation of the biosynthesis of neuroactive steroids (Barbaccia et al., 1999; Morrow et al., 1999, 2001; VanDoren et al., 2000; Sanna et al., 2004; Kumar et al., 2009). "
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    ABSTRACT: Ethanol (EtOH)–induced impairment of long-term potentiation (LTP) in the rat hippocampus is prevented by the 5α-reductase inhibitor finasteride, suggesting that this effect of EtOH is dependent on the increased local release of neurosteroids such as 3α,5α-THP that promote GABA–mediated transmission. Given that social isolation (SI) in rodents is associated with altered plasma and brain levels of such neurosteroids as well as with an enhanced neurosteroidogenic action of EtOH, we examined whether the inhibitory effect of EtOH on LTP at CA3-CA1 hippocampal excitatory synapses is altered in C57BL/6J mice subjected to SI for 6 weeks in comparison with group-housed (GH) animals. Extracellular recording of fEPSPs as well as patch-clamp analysis were performed in hippocampal slices prepared from both SI and GH mice. Consistent with previous observations, recording of fEPSPs revealed that the extent of LTP induced in the CA1 region of SI mice was significantly reduced compared with that in GH animals. EtOH (40 mM) inhibited LTP in slices from SI mice but not in those from GH mice, and this effect of EtOH was abolished by co-application of 1 µM finasteride. Current-clamp analysis of CA1 pyramidal neurons revealed a decrease in action potential frequency and an increase in the intensity of injected current required to evoke the first action potential in SI mice compared with GH mice, indicative of a decrease in neuronal excitability associated with SI. Together, our data suggest that SI results in reduced levels of neuronal excitability and synaptic plasticity in the hippocampus. Furthermore, the increased sensitivity to the neurosteroidogenic effect of EtOH associated with SI likely accounts for the greater inhibitory effect of EtOH on LTP in SI mice. The increase in EtOH sensitivity induced by SI may be important for the changes in the effects of EtOH on anxiety and on learning and memory associated with the prolonged stress attributable to social isolation.
    Full-text · Article · Oct 2011 · Frontiers in Endocrinology
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    • "In particular, extrasynaptic GABA A R subtypes that contain the δ subunit (δ GABA A Rs) can be potentiated by ethanol concentrations as low as 3 mM; humans report feeling intoxicated at blood alcohol concentrations of 2 to 7 mM (Eckardt et al., 1998; Sundstrom-Poromaa et al., 2002; Wallner et al., 2003). Therefore, it is now thought that extrasynaptic δ GABA A Rs may play a crucial role in mediating the behavioral effects of ethanol (Hanchar et al., 2004). "
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    ABSTRACT: In recent years, the effect of ethanol on tonic inhibition mediated by extrasynaptic GABA(A) receptors (GABA(A)Rs) has become a topic of intensive investigation and some controversy. The high ethanol sensitivity of extrasynaptic GABA(A) receptors containing the δ subunit combined with the role of tonic inhibition in maintaining the background inhibitory "tone" in hippocampal circuits has suggested that they may play a key role mediating certain behavioral effects of ethanol, including those related to learning and memory. We have found that ethanol disrupts learning and learning-related hippocampal function more potently in adolescent animals than in adults and that ethanol promotes extrasynaptic receptor-mediated GABAergic tonic currents more potently in adolescents than in adults. However, there have been no studies of potential mechanisms that may underlie the enhanced ethanol sensitivity of the tonic current in adolescents. In this study, we recorded GABA(A) receptor-mediated tonic currents in dentate gyrus granule cells in hippocampal slices from adolescent and adult rats. As previously reported, we found that ethanol potentiated the currents more efficaciously in cells from adolescents than in those from adults. We also found that the GAT-1 blocker NO-711 eliminated this developmental difference in ethanol sensitivity. These findings suggest that regulation of ambient GABA by GABA transporters may contribute to the difference in ethanol sensitivity between adolescents and adults.
    Full-text · Article · May 2011 · Alcohol (Fayetteville, N.Y.)
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