Recombinant GABA<sub>A</sub> receptor function and ethanol

Sigel, Erwin; Baur, Roland; Malherbe, Pari

doi:10.1016/0014-5793(93)81380-i

Cited by 102 publications

(56 citation statements)

References 23 publications

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“…These observations are in contrast to the present study where ethanol was without effect on GABA-gated currents from neurons from several brain sites, over a wide range of concentrations and over a wide range of neuronal types. This lack of effect of ethanol in vitro is in agreement with a number of recent studies that have failed to observe effects of ethanol even at high concentrations (100 -300 mM) (Sigel et al, 1993;Frye et al, 1994;Mori et al, 2000;Ming et al, 2001), but at odds with others (Reynolds et al, 1992;Weiner et al, 1994;Sapp and Yeh, 1998) and with the similarity of the behavioral effects of ethanol with those of agents acting at the GABA A receptor (Frye et al, 1980;Liljequist and Engel, 1982;Martz et al, 1983). One possible reason for the lack of a reliable effect of ethanol on GABA-gated currents in vitro is that GABA A receptors in acutely dissociated neurons Fig.…”

supporting

confidence: 92%

“…In vitro studies of the effect of ethanol on GABA-gated currents have been equivocal. Although some studies found an enhancement of GABA-gated currents by ethanol (Wafford et al, 1991;Reynolds et al, 1992), others did not find a direct effect of ethanol on GABA-gated currents (White et al, 1990;Sigel et al, 1993;Criswell et al, 1999;Ming et al, 2001) or found enhancement of GABA-gated currents by ethanol in some cases but not others (Weiner et al, 1994;Wan et al, 1996;Sapp and Yeh, 1998). The purpose of the present investigation was to examine the sensitivity to ethanol of NMDA and GABA A receptors in neurons acutely dissociated from several brain regions to determine whether different postsynaptic receptor sensitivity to ethanol across brain regions might explain the presence or absence of an effect of ethanol on neural activity observed in vivo.…”

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confidence: 99%

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Comparison of Effect of Ethanol onN-Methyl-d-aspartate- and GABA-Gated Currents from Acutely Dissociated Neurons: Absence of Regional Differences in Sensitivity to Ethanol

Criswell¹,

Zhang²,

Griffith³

et al. 2003

J Pharmacol Exp Ther

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In vivo, ethanol alters the effect of N-methyl-D-aspartate (NMDA) and GABA in some brain regions but is without effect in others. To determine whether these regional differences were due to differences in the effect of ethanol on postsynaptic NMDA or GABA A receptors, we examined the effect of ethanol on NMDA-and GABA-gated currents from neurons acutely dissociated from the lateral septal nucleus, substantia nigra, thalamus, hippocampus, and cerebellum. Ethanol decreased the effect of NMDA similarly in all brain areas tested and had similar effects on Chinese hamster ovary cells expressing NR2A or NR2B subunits with an NR1-1a subunit. However, ifenprodil reduced the inhibition by ethanol of NMDA-gated currents from neurons isolated from the lateral septum without affecting neurons from the substantia nigra. In contrast to the robust effect of ethanol on NMDA-gated currents, ethanol (25-300 mM) was without effect on GABA-gated currents at all brain sites tested or on Ltk Ϫ cells stably expressing the ␣1, ␤2, and ␥2L or ␥2S subunits. The neuroactive steroid alphaxalone profoundly enhanced GABA-gated currents in all brain areas and cell types tested, indicating a similar sensitivity to allosteric modulation; however, there was no interaction of alphaxalone with ethanol at any site tested. These data suggest that the regional differences in the effect of ethanol observed in vivo are not due to a differential action of ethanol at the postsynaptic NMDA or GABA A receptor subtypes.

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supporting

confidence: 92%

mentioning

confidence: 99%

Comparison of Effect of Ethanol onN-Methyl-d-aspartate- and GABA-Gated Currents from Acutely Dissociated Neurons: Absence of Regional Differences in Sensitivity to Ethanol

Criswell¹,

Zhang²,

Griffith³

et al. 2003

J Pharmacol Exp Ther

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“…The indirect modulation might involve protein phosphorylation, either of GABA A R protein or another protein (Harris et al, 1995). The first possibility was supported by the 'γ2 L subunit' hypothesis (Wafford et al, 1991), which is now considered unlikely (Sigel et al, 1993;Marszalec et al, 1994;Homanics et al, 1999;Wallner et al, 2003). The second hypothesis was also potentially related to the γ2 L splice variant, since it differed from γ2 S having added an 8-amino acid insert containing a protein kinase C (PKC) substrate site.…”

Section: Evidence For Low Concentration Alcohol Enhancement Of Gaba Amentioning

confidence: 99%

Low dose acute alcohol effects on GABAA receptor subtypes

Wallner

Hanchar

Olsen

2006

Pharmacology & Therapeutics

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GABA A receptors (GABA A Rs) are the main inhibitory neurotransmitter receptors and have long been implicated in mediating at least part of the acute actions of ethanol. For example, ethanol and GABAergic drugs including barbiturates and benzodiazepines share many pharmacological properties. Besides the prototypical synaptic GABA A R subtypes, nonsynaptic GABA A Rs have recently emerged as important regulators of neuronal excitability. While high doses (≥100 mM) of ethanol have been reported to enhance activity of most GABA A R subtypes, most abundant synaptic GABA A Rs are essentially insensitive to ethanol concentrations that occur during social ethanol consumption (<30 mM). However, extrasynaptic δ and β3 subunit-containing GABA A Rs, associated in the brain with α4or α6 subunits, are sensitive to low millimolar ethanol concentrations, as produced by drinking half a glass of wine. Additionally, we found that a mutation in the cerebellar α6 subunit (α6R100Q), initially reported in rats selectively bred for increased alcohol sensitivity, is sufficient to produce increased alcohol-induced motor impairment and further increases of alcohol sensitivity in recombinant α6β3δ receptors. Furthermore, the behavioral alcohol antagonist Ro15-4513 blocks the low dose alcohol enhancement on α4/6/β3δ receptors, without reducing GABA-induced currents. In binding assays α4β3δ GABA A Rs bind [ 3 H] Ro15-4513 with high affinity, and this binding is inhibited, in an apparently competitive fashion, by low ethanol concentrations, as well as analogs of Ro15-4513 that are active to antagonize ethanol or Ro15-4513's block of ethanol. We conclude that most low to moderate dose alcohol effects are mediated by alcohol actions on alcohol/Ro15-4513 binding sites on GABA A R subtypes.

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“…Most important to the concept that zolpidem predicted the action of ethanol on GABA function , ethanol at reasonable concentrations did not alter the effect of GABA responsiveness when the a 1 b 2 g 2L combination was expressed in various cell lines (see Criswell et al, 2003;Kleingoor et al, 1991;Mihic et al, 1994;Mori et al, 2000;Sapp and Yeh, 1998;Sigel et al, 1993) or in oocytes (Harris et al, 1997)Fa contrast to the positive effect found when the a 1 b 1 g 2L subunit combination was expressed in oocytes (Wafford et al, 1991) or L(tk À ) cells (Harris et al, 1995c). Consequently, the view concerning the specificity for ethanol to affect the type-1-BZD receptor directly to enhance GABA function was placed in doubt.…”

Section: In Vitro Examination Of Ethanol Action On Gaba a Receptor Fumentioning

confidence: 99%

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

Criswell

Breese

2005

Neuropsychopharmacol

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Early behavioral investigations supported the contention that systemic ethanol displays a GABAmimetic profile. Microinjection of GABA agonists into brain and in vivo electrophysiological studies implicated a regionally specific action of ethanol on GABA function. While selectivity of ethanol to enhance the effect of GABA was initially attributed an effect on type-1-benzodiazepine (BZD)-GABA A receptors, a lack of ethanol's effect on GABA responsiveness from isolated neurons with this receptor subtype discounted this contention. Nonetheless, subsequent work identified GABA A receptor subtypes, with limited distribution in brain, sensitive to enhancement of GABA at relevant ethanol concentrations. In view of these data, it is hypothesized that the GABAmimetic profile for ethanol is due to activation of mechanisms associated with GABA function, distinct from a direct action on the majority of postsynaptic GABA A receptors. The primary action proposed to account for ethanol's regional specificity on GABA transmission is its ability to release GABA from some, but not all, presynaptic GABAergic terminals. As systemic administration of ethanol increases neuroactive steroids, which can enhance GABA responsiveness, this elevated level of neurosteroids is proposed to magnify the effect of GABA released by ethanol. Additional factors contributing to the degree to which ethanol interacts with GABA function include an involvement of GABA B and other receptors that influence ethanol-induced GABA release, an effect of phosphorylation on GABA responsiveness, and a regional reduction of glutamatergic tone. Thus, an integration of these consequences induced by ethanol is proposed to provide a logical basis for its in vivo GABAmimetic profile.

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Recombinant GABA_A receptor function and ethanol

Abstract: Different combinationsof cloned subunits of the rat bram GABA, receptor were expressed in Xenuprrs oocytes.

Cited by 102 publications

References 23 publications

Comparison of Effect of Ethanol onN-Methyl-d-aspartate- and GABA-Gated Currents from Acutely Dissociated Neurons: Absence of Regional Differences in Sensitivity to Ethanol

Comparison of Effect of Ethanol onN-Methyl-d-aspartate- and GABA-Gated Currents from Acutely Dissociated Neurons: Absence of Regional Differences in Sensitivity to Ethanol

Low dose acute alcohol effects on GABAA receptor subtypes

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

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Recombinant GABAA receptor function and ethanol

Abstract: Different combinationsof cloned subunits of the rat bram GABA, receptor were expressed in Xenuprrs oocytes.

Cited by 102 publications

References 23 publications

Comparison of Effect of Ethanol onN-Methyl-d-aspartate- and GABA-Gated Currents from Acutely Dissociated Neurons: Absence of Regional Differences in Sensitivity to Ethanol

Comparison of Effect of Ethanol onN-Methyl-d-aspartate- and GABA-Gated Currents from Acutely Dissociated Neurons: Absence of Regional Differences in Sensitivity to Ethanol

Low dose acute alcohol effects on GABAA receptor subtypes

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

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Recombinant GABA_A receptor function and ethanol