Skip to main content

Advertisement

Log in

In vivo and in vitro hyperbaric studies in mice suggest novel sites of action for ethanol

  • Original Investigation
  • Published:
Psychopharmacology Aims and scope Submit manuscript

Abstract

 The present study uses increased atmospheric pressure as an ethanol antagonist to test the hypothesis that allosteric coupling pathways in the GABAA receptor complex represent initial sites of action for ethanol. This was accomplished using behavioral and in vitro measures to determine the effects of pressure on ethanol and other GABAergic drugs in C57BL/6 and LS mice. Behaviorally, exposure to 12 times normal atmospheric pressure (ATA) of a helium-oxygen gas mixture (heliox) antagonized loss of righting reflex (LORR) induced by the allosteric modulators ethanol and pentobarbital, but did not antagonize LORR induced by the direct GABA agonist 4,5,6,7-tetrahydroisoxazolo-pyridin-3-ol (THIP). Similarly, exposure to 12 ATA heliox antagonized the anticonvulsant effects verses isoniazid of ethanol, diazepam and pentobarbital. Biochemically, exposure to 12 ATA heliox antagonized potentiation of GABA-activated 36Cl uptake by ethanol, flunitrazepam and pentobarbital in LS mouse brain preparations, but did not alter GABA-activated 36Cl uptake per se. In contrast to its antagonist effect versus other allosteric modulators, pressure did not antagonize these behavioral or in vitro effects induced by the neuroactive steroid, 3α-hydroxy-5β-pregnan-20-one (3α,5β-P). These findings add to evidence that pressure directly and selectively antagonizes drug effects mediated through allosteric coupling pathways. The results fit predictions, and thus support the hypothesis that allosteric coupling pathways in GABAA receptors represent initial sites of action for ethanol. Collectively, the results suggest that there may be common physicochemical and underlying structural characteristics that define ethanol sensitive regions of receptor proteins and/or their associated membranes that can be identified by pressure within (e.g., GABAA) and possibly across (e.g., GABAA, NMDA, 5HT3) receptors.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

Author information

Authors and Affiliations

Authors

Additional information

Received: 15 December 1997 / Final version: 23 July 1998

Rights and permissions

Reprints and permissions

About this article

Cite this article

Davies, D., Bolger, M., Brinton, R. et al. In vivo and in vitro hyperbaric studies in mice suggest novel sites of action for ethanol. Psychopharmacology 141, 339–350 (1999). https://doi.org/10.1007/s002130050843

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1007/s002130050843

Navigation