Hormonally regulated α4β2δ GABAA receptors are a target for alcohol

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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Figure 1: Low concentrations of alcohol potentiate GABA responses at α4β2δ receptors.
Figure 2: Progesterone withdrawal increases α4βδ GABAA receptors.
Figure 3: Low doses of alcohol potentiate GABA-gated currents in hippocampal pyramidal neurons and decrease behavioral excitability after progesterone withdrawal.

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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.).

Author information

Correspondence to Sheryl S. Smith.

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The authors declare no competing financial interests.

Supplementary information

Supplementary Methods (PDF 36 kb)

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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