Hormonally regulated α4β2δ GABAA receptors are a target for alcohol

Sundström‐Poromaa, Inger; Smith, Dorothy; Gong, Qiong; Sabado, Thomas N.; Li, Xinshe; Light, Adam; Williams, Keith; Smith, Sheryl S.

doi:10.1038/nn888

Cited by 311 publications

(347 citation statements)

References 15 publications

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“…As noted earlier, low ethanol concentrations (3-30 mM) enhance the effects of GABA from transfected a 4 b X d and a 6 b X d GABA A receptor subunits expressed in vitro in oocytes (Sundstrom-Poromaa et al, 2002;Wallner et al, 2003). Consistent with ethanol having an effect on neurons with BZD-insensitive receptors, low concentrations of ethanol also selectively augmented the tonic GABA inhibition of granule cells that contain the a 4 and d GABA A receptor subunits, but did not have an effect on CA1 pyramidal cells containing the a 5 b 3 g 2/3 subunits (Wei et al, 2004).…”

Section: Proposed Role For Bzd-insensitive Gaba a Receptors In Ethanomentioning

confidence: 58%

“…Consistent with ethanol having an effect on neurons with BZD-insensitive receptors, low concentrations of ethanol also selectively augmented the tonic GABA inhibition of granule cells that contain the a 4 and d GABA A receptor subunits, but did not have an effect on CA1 pyramidal cells containing the a 5 b 3 g 2/3 subunits (Wei et al, 2004). Likewise, hippocampal neurons with increased levels of the a 4 -receptor subunit following progesterone withdrawal were sensitive to low doses of ethanol (Smith et al, 2004;Sundstrom-Poromaa et al, 2002). Upregulation of the a 4 -receptor subunit has been associated with increased sensitivity to the anxiolytic action of ethanol (SundstromPoromaa et al, 2002).…”

Section: Proposed Role For Bzd-insensitive Gaba a Receptors In Ethanomentioning

confidence: 83%

“…Roberto et al (2003) recently reported that 44 mM ethanol enhanced the effect of exogenously applied GABA to amygdaloid neurons, indicative that ethanol had a direct postsynaptic action on GABA A receptors at this site. Finally, the specific a 4 b X d and a 6 b X d GABA A receptor subunits (BZD-insensitive receptor subtypes), when expressed in oocytes, exhibited a direct action of low ethanol concentration enhancement of GABA responsiveness (Sundstrom-Poromaa et al, 2002;Wallner et al, 2003). More will be said later about this latter observation.…”

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

confidence: 93%

“…Regardless, with current evidence not being persuasive that ethanol has a direct effect on zolpidem-sensitive receptors to account for its GABAmimetic profile, new initiatives were needed to understand the overwhelming behavioral and in vivo electrophysiological studies linking ethanol to a GABAlike action. Of course, one proposed component that could contribute to its GABAmimetic profile would be a direct action of ethanol on selected BZD-insensitive GABA A receptors (Sundstrom-Poromaa et al, 2002;Wallner et al, 2003). However, as will be discussed, these BZD-insensitive GABA A receptors are believed to have limited localization in brain (Peng et al, 2002).…”

Section: Hypothesis For the Gabamimetic Profile Of Ethanolmentioning

confidence: 99%

“…Given the sensitivity of these BZD-insensitive receptor subtypes to ethanol, work like that previously undertaken with 200 mM ethanol to identify critical sites for ethanol action should be performed at low ethanol concentrations (ie o60 mM) on the BZDinsensitive GABA A receptor subtypes to define the molecular basis of the difference between these receptors and those subtypes only sensitive to a high level of ethanol (ie 4100 mM). (Hanchar et al, 2004;Sundstrom-Poromaa et al, 2002;Wallner et al, 2003) could be a means by which ethanol is capable of enhancing GABA transmission in selected brain regions. Additionally, systemic administration of ethanol is proposed to result in an increase in GABA release from presynaptic terminals, as illustrated (right side under ETOH).…”

Section: Proposed Role For Bzd-insensitive Gaba a Receptors In Ethanomentioning

confidence: 99%

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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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Section: Proposed Role For Bzd-insensitive Gaba a Receptors In Ethanomentioning

confidence: 58%

Section: Proposed Role For Bzd-insensitive Gaba a Receptors In Ethanomentioning

confidence: 83%

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

confidence: 93%

Section: Hypothesis For the Gabamimetic Profile Of Ethanolmentioning

confidence: 99%

Section: Proposed Role For Bzd-insensitive Gaba a Receptors In Ethanomentioning

confidence: 99%

See 3 more Smart Citations

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

Criswell

Breese

2005

Neuropsychopharmacol

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γ-Aminobutyric Acid Type A Receptors and Alcoholism

Krystal

Staley

Mason

et al. 2006

Arch Gen Psychiatry

173

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Reductions in tonic GABAergic current in substantia gelatinosa neurons and GABA_A receptor δ subunit expression after chronic constriction injury of the sciatic nerve in mice

Iura

Takahashi

Hakata

et al. 2016

European Journal of Pain

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Background: Decreased Gamma-aminobutyric acid (GABA)-ergic phasic inhibitory transmission in the spinal cord is thought to be responsible for the development of neuropathic pain. However, the role of GABAergic tonic current in substantia gelatinosa (SG) neurons in neuropathic pain remains to be fully elucidated. In this study, we assessed GABAergic tonic currents of SG neurons in a sciatic nerve chronic constriction injury (CCI) mouse. Method: Whole-cell patch clamp recordings form lumbar spinal cord slices was performed to evaluate GABAergic currents. We also investigated the expression changes of GABA A receptor subunits which are considered to mediate tonic currents. Results: The percentage of SG neurons receiving GABAergic tonic currents decreased in CCI mice compared with Na€ ıve mice. No significant change was observed in the mean amplitude of GABAergic tonic currents. RT-PCR and Western blot revealed that the expression of GABA A receptor d subunits decreased following CCI. Conclusion: A reduction in the expression the d subunit of the GABA A receptor and diminished GABAergic tonic current in SG neurons were observed after CCI in mice. GABAergic tonic current plays a key role in neuropathic pain. The GABA A receptor d subunit may be a therapeutic target in neuropathic pain. What does this study add?: In spinal SG neurons, GABAergic inhibitory transmission operates through both phasic and tonic currents, but physiological role is largely unknown. In this study, we report dysregulation of GABA A receptor d subunit-mediated tonic current in SG neurons may result in spinal disinhibition resulting in neuropathic pain in CCI mice.

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Hormonally regulated α4β2δ GABAA receptors are a target for alcohol

Cited by 311 publications

References 15 publications

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

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

γ-Aminobutyric Acid Type A Receptors and Alcoholism

Reductions in tonic GABAergic current in substantia gelatinosa neurons and GABA_A receptor δ subunit expression after chronic constriction injury of the sciatic nerve in mice

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Hormonally regulated α4β2δ GABAA receptors are a target for alcohol

Cited by 311 publications

References 15 publications

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

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

γ-Aminobutyric Acid Type A Receptors and Alcoholism

Reductions in tonic GABAergic current in substantia gelatinosa neurons and GABAA receptor δ subunit expression after chronic constriction injury of the sciatic nerve in mice

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Reductions in tonic GABAergic current in substantia gelatinosa neurons and GABA_A receptor δ subunit expression after chronic constriction injury of the sciatic nerve in mice