PMID- 10090641
OWN - NLM
STAT- MEDLINE
DCOM- 19990528
LR  - 20190726
IS  - 0033-3158 (Print)
IS  - 0033-3158 (Linking)
VI  - 141
IP  - 4
DP  - 1999 Feb
TI  - In vivo and in vitro hyperbaric studies in mice suggest novel sites of action for 
      ethanol.
PG  - 339-50
AB  - The present study uses increased atmospheric pressure as an ethanol antagonist to 
      test the hypothesis that allosteric coupling pathways in the GABA(A) 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, 
      3alpha-hydroxy-5beta-pregnan-20-one (3alpha,5beta-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 GABA(A) 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., 
      GABA(A)) and possibly across (e.g., GABA(A), NMDA, 5HT3) receptors.
FAU - Davies, D L
AU  - Davies DL
AD  - Department of Molecular Pharmacology and Toxicology, School of Pharmacy, 
      University of Southern California, Los Angeles 90033, USA.
FAU - Bolger, M B
AU  - Bolger MB
FAU - Brinton, R D
AU  - Brinton RD
FAU - Finn, D A
AU  - Finn DA
FAU - Alkana, R L
AU  - Alkana RL
LA  - eng
GR  - AA05234/AA/NIAAA NIH HHS/United States
GR  - F31AA0436/AA/NIAAA NIH HHS/United States
GR  - R01 AA03972/AA/NIAAA NIH HHS/United States
PT  - Journal Article
PT  - Research Support, U.S. Gov't, P.H.S.
PL  - Germany
TA  - Psychopharmacology (Berl)
JT  - Psychopharmacology
JID - 7608025
RN  - 0 (GABA Modulators)
RN  - 0 (Isoxazoles)
RN  - 0 (Receptors, GABA-A)
RN  - 3K9958V90M (Ethanol)
RN  - 620X0222FQ (Flunitrazepam)
RN  - BXO86P3XXW (Pregnanolone)
RN  - I4744080IR (Pentobarbital)
RN  - K1M5RVL18S (gaboxadol)
RN  - Q3JTX2Q7TU (Diazepam)
SB  - IM
MH  - Allosteric Regulation
MH  - Analysis of Variance
MH  - Animals
MH  - Diazepam/pharmacology
MH  - Ethanol/antagonists & inhibitors/*pharmacology
MH  - Flunitrazepam/pharmacology
MH  - GABA Modulators/*pharmacology
MH  - *Hyperbaric Oxygenation
MH  - Isoxazoles/pharmacology
MH  - Male
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - Pentobarbital/pharmacology
MH  - Pregnanolone/pharmacology
MH  - Receptors, GABA-A/drug effects/*metabolism
EDAT- 1999/03/25 00:00
MHDA- 1999/03/25 00:01
CRDT- 1999/03/25 00:00
PHST- 1999/03/25 00:00 [pubmed]
PHST- 1999/03/25 00:01 [medline]
PHST- 1999/03/25 00:00 [entrez]
AID - 10.1007/s002130050843 [doi]
PST - ppublish
SO  - Psychopharmacology (Berl). 1999 Feb;141(4):339-50. doi: 10.1007/s002130050843.