Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Brief Communication
  • Published:

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.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

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.

Similar content being viewed by others

References

  1. Smith, S.S. et al. Nature 392, 926–930 (1998).

    Article  CAS  Google Scholar 

  2. Sundstrom, I. et al. Neuroendocrinology 67, 126–138 (1998).

    Article  CAS  Google Scholar 

  3. Ueno, S., et al. Alcohol Clin. Exp. Res. 25, 76S–81S (2001).

    Article  CAS  Google Scholar 

  4. Mihic, S.J. et al. Nature 389, 385–389 (1997).

    Article  CAS  Google Scholar 

  5. Mahmoudi, M., Kang, M.H., Tillakaratne, N., Tobin, A.J. & Olsen, R.W. J. Neurochem. 68, 2485–2492 (1997).

    Article  CAS  Google Scholar 

  6. Koob, G.F. et al. Alcohol 5, 437–443 (1988).

    Article  CAS  Google Scholar 

  7. Wan, F.J., Berton, F., Madamba, S.G., Francesconi, W. & Siggins, G.R. Proc. Natl. Acad. Sci. USA 93, 5049–5054 (1996).

    Article  CAS  Google Scholar 

  8. Nusser, Z., Sieghart, W. & Somogyi, P. J. Neurosci. 18, 1693–1703 (1998).

    Article  CAS  Google Scholar 

  9. Adkins, C.E. et al. J. Biol. Chem. 276, 38934–38939 (2001).

    Article  CAS  Google Scholar 

  10. Mihalek, R.M. et al. Alcohol Clin. Exp. Res. 25, 1708–1718 (2001).

    CAS  PubMed  Google Scholar 

  11. Brickley, S.G., Revilla, V., Cull-Candy, S.G., Wisden, W. & Farrant, M. Nature 409, 88–92 (2001).

    Article  CAS  Google Scholar 

  12. Kalant, H., LeBlanc, A.E., Wilson, A. & Homatidis, S. Can. Med. Assoc. J. 112, 953–958 (1975).

    CAS  PubMed  PubMed Central  Google Scholar 

  13. Holford, N.H. Clin. Pharmacokinet. 13, 273–292 (1987).

    Article  CAS  Google Scholar 

  14. McLeod, D.R., Foster, G.V., Hoehn-Saric, R., Svikis, D.S. & Hipsley, P.A. Alcohol Clin. Exp. Res. 18, 664–670 (1994).

    Article  CAS  Google Scholar 

  15. Cohen, H.L., Poresz, B. & Begleiter, H. Electroencepalogr. Clin. Neurophysiol. 86, 368–376 (1993).

    Article  CAS  Google Scholar 

Download references

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

Authors and Affiliations

Authors

Corresponding author

Correspondence to Sheryl S. Smith.

Ethics declarations

Competing interests

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)

Rights and permissions

Reprints and permissions

About this article

Cite this article

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

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nn888

This article is cited by

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing