TY - JOUR
T1 - In vivo and in vitro hyperbaric studies in mice suggest novel sites of action for ethanol
AU - Davies, Daryl L.
AU - Bolger, Michael B.
AU - Brinton, Roberta D.
AU - Finn, Deborah A.
AU - Alkana, Ronald L.
N1 - Funding Information:
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Nature 367:607–614 193–269 Franks NP, Lieb WR (1997) Anaesthetics set their sites on ion Alkana RL, Malcolm RD (1981) Low-level hyperbaric ethanol an-channels. Nature 389:334–335 tagonism in mice. Dose and pressure response. Pharmacology Gee KW, Bolger MB, Brinton RE, Coirini H, McEwen BS (1988) 22:199–208 Steroid modulation of the chloride ionophore in rat brain: Alkana RL, Malcolm RD (1982a) Hyperbaric ethanol antagonism structure-activity requirements, regional dependence and in mice: time course. Subst Alcohol Actions Misuse 3:41–46 mechanism of action. J Pharmacol Exp Ther 246:803–812 Alkana RL, Malcolm RD (1982b) Hyperbaric ethanol antagonism Halsey MJ (1982) Effects of high pressure on the central nervous in mice: studies on oxygen, nitrogen, strain and sex. Psycho-system. Physiol Rev 62:1341–1377 pharmacology 77:11–16 Harris RA, Allan AM (1985) Functional coupling of g -aminobu-Alkana RL, Boone DC, Finn DA (1985a) Temperature depen-tyric acid receptors to chloride channels in brain membranes. dence of ethanol depression: linear models in male and female Science 228:1108–1110 mice. Pharmacol Biochem Behav 23:309–316 Harris RA, Allan AM (1989a) Alcohol intoxication: ion channels Alkana RL, Finn DA, Galleisky GG, Syapin PJ, Malcolm RD and genetics. FASEB J 3:1689–1695 (1985b) Ethanol withdrawal in mice precipitated and exacer-Harris RA, Allan AM (1989b) Genetic differences in coupling of bated by hyperbaric exposure. Science 229:772–774 benzodiazepine receptors to chloride channels. Brain Res 490: Alkana RL, Syapin PJ, Galleisky GG, Finn DA (1987) Hyperbaric 26–32 exposure acts as an ethanol antagonist: evidence from chronic Harris RA, Brodie MS, Dunwiddie TV (1992) Possible substrates ethanol studies. Alcohol Alcohol [Suppl] 1:417–421 of ethanol reinforcement: GABA and dopamine. Ann NY Acad Alkana RL, Debold JF, Finn DA, Babbini M, Syapin PJ (1991a) Eth-Sci 654:61–69 anol-induced depression of aggression in mice antagonized by Janoff AS, Pringle MJ, Miller KW (1981) Correlation of general hyperbaric exposure. Pharmacol Biochem Behav 38:639–644 anesthetic potency with solubility in membranes. Biochim Alkana RL, Kobayashi LS, Jones BL, Finn DA, Syapin PJ (1991b) Biophys Acta 649:125–128 Low-level hyperbaric heliox does not affect drug-induced sei-Jones MV, Harrison NL (1993) Effects of volatile anesthetics on zure latency in mice. Ann NY Acad Sci 625:770–773 the kinetics of inhibitory postsynaptic currents in cultured rat Alkana RL, Finn DA, Jones BL, Kobayashi LS, Babbini M, Be-hippocampal neurons. J Neurophysiol 70:1339–1349 janian M, Syapin PJ (1992) Genetically determined differ-Kendig JJ (1984) Pressure dependence of excitable cell function. ences in the antagonistic effect of pressure on ethanol-induced Trends Neurol Sci 7:483–486 loss of righting reflex in mice. Alcohol Clin Exp Res 16:17–22 Korpi ER (1994) Role of GABAA receptors in the actions of alcohol Alkana RL, Davies DL, Morland J, Parker ES, Bejanian M (1995) and in alcoholism: recent advances. Alcohol Alcohol 29:115–129 Low level hyperbaric exposure antagonizes locomotor effects Little HJ (1996) How has molecular pharmacology contributed to of ethanol and n-propanol but not morphine in C57BL mice. our understanding of the mechanism(s) of general anesthesia? Alcohol Clin Exp Res 19:693–700 Pharmacol Ther 69:37–58 Allan AM, Harris RA (1986) g -aminobutyric acid and alcohol ac-Longoni B, Demontis GC, Olsen RW (1993) Enhancement of g - tions: neurochemical studies of long sleep and short sleep aminobutyric acidA receptor function and binding by volatile mice. Life Sci 39:2005–2015 anesthetic halothane. J Pharmacol Exp Ther 266:153–159 Acknowledgements The authors thank Dr. Nandita Pal, Ms. Christina de Luna, Ms. Tahira Mirza, Mr. Minh Ha and Mr. Khe-ang Long for their technical assistance. This work was supported by United States Public Health Service Research Grants RO1 AA03972, AA05234 and F31AA0436, National Institute on Alcohol Abuse and Alcoholism, NIH. This work was conducted as partial fulfilment of the requirements for the Ph.D. degree in Molecular Pharmacology and Toxicology, School of Pharmacy, University of Southern California (D. L. D.).
PY - 1999
Y1 - 1999
N2 - 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 drags 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 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.
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 drags 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 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.
KW - 3α-Hydroxy-5β-pregnan-20-one (3α, 5β-P)
KW - 4,5,6,7-Tetrahydroisoxazolo-pyridin-3-ol (THIP)
KW - Allosteric coupling hypothesis
KW - Anticonvulsant effect
KW - Barbiturates
KW - Benzodiazepines
KW - C57BL/6 mice
KW - Central nervous system
KW - Ethanol antagonist
KW - GABA(A) receptor complex
KW - GABA-activated chloride ion uptake
KW - Helium-oxygen gas mixture
KW - Hyperbaric exposure
KW - Ligand-gated ion channels
KW - Loss of righting reflex (LORR)
KW - N-Methyl-D-aspartate (NMDA)
KW - Neuroactive steroid
KW - γ-Aminobutryic acid (GABA)
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U2 - 10.1007/s002130050843
DO - 10.1007/s002130050843
M3 - Article
C2 - 10090641
AN - SCOPUS:0032947573
SN - 0033-3158
VL - 141
SP - 339
EP - 350
JO - Psychopharmacology
JF - Psychopharmacology
IS - 4
ER -