Hormonally regulated α4β2δ GABAA receptors are a target for alcohol (2024)

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Abstract Access options Additional access options: Similar content being viewed by others Female-specific decreases in alcohol binge-like drinking resulting from GABAA receptor delta-subunit knockdown in the VTA Gene regulation by gonadal hormone receptors underlies brainsex differences Mechanisms of inhibition and activation of extrasynaptic αβ GABAA receptors References Acknowledgements Author information Authors and Affiliations Corresponding author Ethics declarations Competing interests Supplementary information Supplementary Methods (PDF 36 kb) Supplementary Fig. 1. Supplementary Fig. 2. Rights and permissions About this article Cite this article This article is cited by Cerebellar α6GABAA Receptors as a Therapeutic Target for Essential Tremor: Proof-of-Concept Study with Ethanol and Pyrazoloquinolinones Diazepam and ethanol differently modulate neuronal activity in organotypic cortical cultures Acute alcohol exposure dose-dependently alleviates social avoidance in adolescent mice and inhibits social investigation in adult mice Alcohol Impairs N100 Response to Dorsolateral Prefrontal Cortex Stimulation Alcohol reduces muscle fatigue through atomistic interactions with nicotinic receptors References

Abstract

Here we report that low concentrations of alcohol (1–3 mM) increased Cl− currents gated by a recombinant GABAA receptor, α4β2δ, by 40–50% in Xenopus laevis oocytes. We also found greater hippocampal expression of receptors containing α4 and δ subunits, using a rat model1 of premenstrual2 syndrome (PMS) in which 1–3 mM alcohol preferentially enhanced GABA-gated currents, and low doses of alcohol attenuated anxiety and behavioral reactivity. The alcohol sensitivity of δ-containing receptors may underlie the reinforcing effects of alcohol during PMS, when eye saccade responses to low doses of alcohol are increased2.

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Hormonally regulated α4β2δ GABAA receptors are a target for alcohol (1)
Hormonally regulated α4β2δ GABAA receptors are a target for alcohol (2)
Hormonally regulated α4β2δ GABAA receptors are a target for alcohol (3)

Similar content being viewed by others

Hormonally regulated α4β2δ GABAA receptors are a target for alcohol (4)

Female-specific decreases in alcohol binge-like drinking resulting from GABAA receptor delta-subunit knockdown in the VTA

Article Open access 30 May 2019

Hormonally regulated α4β2δ GABAA receptors are a target for alcohol (5)

Gene regulation by gonadal hormone receptors underlies brainsex differences

Article Open access 04 May 2022

Hormonally regulated α4β2δ GABAA receptors are a target for alcohol (6)

Mechanisms of inhibition and activation of extrasynaptic αβ GABAA receptors

Article Open access 09 February 2022

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Acknowledgements

The authors thank M. Akabas, D. Dow-Edwards, S. Melnick, R. Markowitz, A. Smirnov and Y. Ruderman for technical assistance. Supported by National Institutes of Health grants DA09618 and AA12958 (S.S.S.), NS35047 (K.W.) and Wallenberg and Swedish Brain Foundation grants (I.S.P.).

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Author notes

  1. Adam Light

    Present address: Department of Neurology, The University of Chicago, 5841 S. Maryland MC2030, Chicago, 60637, Illinois, USA

  2. Inger Sundstrom-Poromaa

    Present address: Department of Clinical Science, Obstetrics and Gynecology, University Hospital of Umea, 901 85, Umea, Sweden

Authors and Affiliations

  1. Department of Physiology and Pharmacology, SUNY Downstate Medical Center, 450 Clarkson Ave., Brooklyn, 11203, New York, USA

    Inger Sundstrom-Poromaa,Qi Hua Gong,Thomas N. Sabado,Keith Williams&Sheryl S. Smith

  2. Cellular Biochemistry and Biophysics Program, Memorial Sloan-Kettering Cancer Center, 435 E. 67th St., New York, 10021, New York, USA

    Deborah H. Smith&Martin Wiedmann

  3. Department of Neurobiology and Anatomy, MCP Hahnemann University, 2900 Queen Lane, Philadelphia, 19129, Pennsylvania, USA

    Xinshe Li

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  1. Inger Sundstrom-Poromaa

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Correspondence to Sheryl S. Smith.

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The authors declare no competing financial interests.

Supplementary information

Supplementary Fig. 1.

Progesterone withdrawal increases GABAA receptor δ subunit mRNA. Levels of the δ subunit mRNA in rat hippocampus were increased following progesterone withdrawal (P Wd), whereas levels of GAPDH were unaltered, assessed using semi-quantitative RT-PCR. a, A representative gel. b, Mean values for δ subunit mRNA levels in control and P Wd animals (n = 5-6, determined at two different cycle amplifications known to be in the linear range). (PDF 400 kb)

Supplementary Fig. 2.

Western blot of the α4 subunit (67 kDa)4 in rat hippocampus after progressive withdrawal. The increase in α4 protein following progesterone withdrawal (P Wd) was prevented by in vivo administration of alcohol (0.5 g/kg, i.p. × 3) during the final two hours of the withdrawal period (P Wd + Alc). Administration of alcohol to control rats (Alc) had no effect on levels of the α4 protein. The mean values for this experiment appear in the manuscript. (PDF 382 kb)

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Sundstrom-Poromaa, I., Smith, D., Gong, Q. et al. Hormonally regulated α4β2δ GABAA receptors are a target for alcohol. Nat Neurosci 5, 721–722 (2002). https://doi.org/10.1038/nn888

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Hormonally regulated α4β2δ GABAA receptors are a target for alcohol (2024)

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