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Proc Natl Acad Sci U S A
2006 May 30;10322:8540-5. doi: 10.1073/pnas.0600194103.
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Low-dose alcohol actions on alpha4beta3delta GABAA receptors are reversed by the behavioral alcohol antagonist Ro15-4513.
Wallner M, Hanchar HJ, Olsen RW.
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Although it is now more than two decades since it was first reported that the imidazobenzodiazepine Ro15-4513 reverses behavioral alcohol effects, the molecular target(s) of Ro15-4513 and the mechanism of alcohol antagonism remain elusive. Here, we show that Ro15-4513 blocks the alcohol enhancement on recombinant "extrasynaptic" alpha4/6beta3delta GABA(A) receptors at doses that do not reduce the GABA-induced Cl(-) current. At low ethanol concentrations (< or =30 mM), the Ro15-4513 antagonism is complete. However, at higher ethanol concentrations (> or =100 mM), there is a Ro15-4513-insensitive ethanol enhancement that is abolished in receptors containing a point mutation in the second transmembrane region of the beta3 subunit (beta3N265M). Therefore, alpha4/6beta3delta GABA receptors have two distinct alcohol modulation sites: (i) a low-dose ethanol site present in alpha4/6beta3delta receptors that is antagonized by the behavioral alcohol antagonist Ro15-4513 and (ii) a site activated at high (anesthetic) alcohol doses, defined by mutations in membrane-spanning regions. Receptors composed of alpha4beta3N265Mdelta subunits that lack the high-dose alcohol site show a saturable ethanol dose-response curve with a half-maximal enhancement at 16 mM, close to the legal blood alcohol driving limit in most U.S. states (17.4 mM). Like in behavioral experiments, the alcohol antagonist effect of Ro15-4513 on recombinant alpha4beta3delta receptors is blocked by flumazenil and beta-carboline-ethyl ester (beta-CCE). Our findings suggest that ethanol/Ro15-4513-sensitive GABA(A) receptors are important mediators of behavioral alcohol effects.
Aguayo,
GABA(A) receptors as molecular sites of ethanol action. Direct or indirect actions?
2002, Pubmed
Aguayo,
GABA(A) receptors as molecular sites of ethanol action. Direct or indirect actions?
2002,
Pubmed Allan,
Gamma-aminobutyric acid and alcohol actions: neurochemical studies of long sleep and short sleep mice.
1986,
Pubmed Belelli,
The interaction of the general anesthetic etomidate with the gamma-aminobutyric acid type A receptor is influenced by a single amino acid.
1997,
Pubmed
,
Xenbase Benson,
Pharmacology of recombinant gamma-aminobutyric acidA receptors rendered diazepam-insensitive by point-mutated alpha-subunits.
1998,
Pubmed Blednov,
A pervasive mechanism for analgesia: activation of GIRK2 channels.
2003,
Pubmed Boileau,
The relative amount of cRNA coding for gamma2 subunits affects stimulation by benzodiazepines in GABA(A) receptors expressed in Xenopus oocytes.
2002,
Pubmed
,
Xenbase Bonetti,
Ro 15-4513: partial inverse agonism at the BZR and interaction with ethanol.
1988,
Pubmed Borghese,
The delta subunit of gamma-aminobutyric acid type A receptors does not confer sensitivity to low concentrations of ethanol.
2006,
Pubmed
,
Xenbase Brickley,
Adaptive regulation of neuronal excitability by a voltage-independent potassium conductance.
2001,
Pubmed Britton,
Is ethanol antagonist Ro15-4513 selective for ethanol?
1988,
Pubmed Brown,
Pharmacological characterization of a novel cell line expressing human alpha(4)beta(3)delta GABA(A) receptors.
2002,
Pubmed Carta,
Alcohol enhances GABAergic transmission to cerebellar granule cells via an increase in Golgi cell excitability.
2004,
Pubmed Costa,
G-protein-gated potassium (GIRK) channels containing the GIRK2 subunit are control hubs for pharmacologically induced hypothermic responses.
2005,
Pubmed Criswell,
A conceptualization of integrated actions of ethanol contributing to its GABAmimetic profile: a commentary.
2005,
Pubmed Dar,
Antagonism by intracerebellar Ro15-4513 of acute ethanol-induced motor incoordination in mice.
1995,
Pubmed Dar,
Possible role of adenosine in the CNS effects of ethanol.
1983,
Pubmed Davies,
Insensitivity to anaesthetic agents conferred by a class of GABA(A) receptor subunit.
1997,
Pubmed Davies,
A central role of the BK potassium channel in behavioral responses to ethanol in C. elegans.
2003,
Pubmed Davies,
Ethanol potentiation of glycine receptors expressed in Xenopus oocytes antagonized by increased atmospheric pressure.
2003,
Pubmed
,
Xenbase Farrant,
Variations on an inhibitory theme: phasic and tonic activation of GABA(A) receptors.
2005,
Pubmed Foreman,
A study of the histamine H2-receptor mediating relaxation of the parenchymal lung strip preparation of the guinea-pig.
1985,
Pubmed Glowa,
Ethanol and the GABA receptor complex: studies with the partial inverse benzodiazepine receptor agonist Ro 15-4513.
1988,
Pubmed Hanchar,
Ethanol potently and competitively inhibits binding of the alcohol antagonist Ro15-4513 to alpha4/6beta3delta GABAA receptors.
2006,
Pubmed Hanchar,
Alcohol-induced motor impairment caused by increased extrasynaptic GABA(A) receptor activity.
2005,
Pubmed
,
Xenbase Hoffman,
Effect of an imidazobenzodiazepine, Ro15-4513, on the incoordination and hypothermia produced by ethanol and pentobarbital.
1987,
Pubmed Hu,
Interaction between flurazepam and ethanol.
1987,
Pubmed Ikeda,
Molecular mechanisms of analgesia induced by opioids and ethanol: is the GIRK channel one of the keys?
2002,
Pubmed June,
Ro15-4513 attenuates the consumption of ethanol in deprived rats.
1991,
Pubmed June,
Interactions of Ro15-4513, Ro15-1788 (flumazenil) and ethanol on measures of exploration and locomotion in rats.
1994,
Pubmed June,
Ethanol self-administration in freely feeding and drinking rats: effects of Ro15-4513 alone, and in combination with Ro15-1788 (flumazenil).
1994,
Pubmed Jurd,
General anesthetic actions in vivo strongly attenuated by a point mutation in the GABA(A) receptor beta3 subunit.
2003,
Pubmed Khanna,
Rapid tolerance and crosstolerance to motor impairment effects of benzodiazepines, barbiturates, and ethanol.
1998,
Pubmed Kobayashi,
Ethanol opens G-protein-activated inwardly rectifying K+ channels.
1999,
Pubmed
,
Xenbase Kolata,
New drug counters alcohol intoxication.
1986,
Pubmed Korpi,
Benzodiazepine-induced motor impairment linked to point mutation in cerebellar GABAA receptor.
1993,
Pubmed Laurie,
The distribution of thirteen GABAA receptor subunit mRNAs in the rat brain. III. Embryonic and postnatal development.
1992,
Pubmed Liang,
Chronic intermittent ethanol-induced switch of ethanol actions from extrasynaptic to synaptic hippocampal GABAA receptors.
2006,
Pubmed Liljequist,
Effects of GABAergic agonists and antagonists on various ethanol-induced behavioral changes.
1982,
Pubmed Liu,
Essential role for smooth muscle BK channels in alcohol-induced cerebrovascular constriction.
2004,
Pubmed Mihalek,
GABA(A)-receptor delta subunit knockout mice have multiple defects in behavioral responses to ethanol.
2001,
Pubmed Mihic,
Sites of alcohol and volatile anaesthetic action on GABA(A) and glycine receptors.
1997,
Pubmed
,
Xenbase Ming,
Differential modulation of GABA- and NMDA-gated currents by ethanol and isoflurane in cultured rat cerebral cortical neurons.
2001,
Pubmed Nabeshima,
Reversal of alcohol-induced amnesia by the benzodiazepine inverse agonist Ro 15-4513.
1988,
Pubmed Nusser,
Selective modulation of tonic and phasic inhibitions in dentate gyrus granule cells.
2002,
Pubmed Nusser,
Segregation of different GABAA receptors to synaptic and extrasynaptic membranes of cerebellar granule cells.
1998,
Pubmed Nutt,
Antagonizing the anticonvulsant effect of ethanol using drugs acting at the benzodiazepine/GABA receptor complex.
1988,
Pubmed Palmer,
Antagonism of ethanol effects on cerebellar Purkinje neurons by the benzodiazepine inverse agonists Ro 15-4513 and FG 7142: electrophysiological studies.
1988,
Pubmed Paul,
Alcohol-sensitive GABA receptors and alcohol antagonists.
2006,
Pubmed Petry,
Ro 15-4513 selectively attenuates ethanol, but not sucrose, reinforced responding in a concurrent access procedure; comparison to other drugs.
1995,
Pubmed Popp,
Factors that enhance ethanol inhibition of N-methyl-D-aspartate receptors in cerebellar granule cells.
1999,
Pubmed Rassnick,
GABA antagonist and benzodiazepine partial inverse agonist reduce motivated responding for ethanol.
1993,
Pubmed Reynolds,
Ethanol modulation of GABA receptor-activated Cl- currents in neurons of the chick, rat and mouse central nervous system.
1992,
Pubmed Saxena,
Properties of putative cerebellar gamma-aminobutyric acid A receptor isoforms.
1996,
Pubmed Sigel,
Mapping of the benzodiazepine recognition site on GABA(A) receptors.
2002,
Pubmed Suzdak,
Ethanol stimulates gamma-aminobutyric acid receptor-mediated chloride transport in rat brain synaptoneurosomes.
1986,
Pubmed Suzdak,
A selective imidazobenzodiazepine antagonist of ethanol in the rat.
1986,
Pubmed Suzdak,
Response: is ethanol antagonist rol5-4513 selective for ethanol?
1988,
Pubmed Suzdak,
Effects of Ro15-4513 and other benzodiazepine receptor inverse agonists on alcohol-induced intoxication in the rat.
1988,
Pubmed Syapin,
Ro15-4513 differentially affects ethanol-induced hypnosis and hypothermia.
1987,
Pubmed Syapin,
Interactions between benzodiazepine antagonists, inverse agonists, and acute behavioral effects of ethanol in mice.
1990,
Pubmed Thompson,
Overexpression of the GABA(A) receptor epsilon subunit results in insensitivity to anaesthetics.
2002,
Pubmed
,
Xenbase Wafford,
A novel allosteric modulatory site on the GABAA receptor beta subunit.
1994,
Pubmed
,
Xenbase Wallner,
Ethanol enhances alpha 4 beta 3 delta and alpha 6 beta 3 delta gamma-aminobutyric acid type A receptors at low concentrations known to affect humans.
2003,
Pubmed
,
Xenbase Wei,
Low ethanol concentrations selectively augment the tonic inhibition mediated by delta subunit-containing GABAA receptors in hippocampal neurons.
2004,
Pubmed Wei,
Perisynaptic localization of delta subunit-containing GABA(A) receptors and their activation by GABA spillover in the mouse dentate gyrus.
2003,
Pubmed White,
Differential effects of ethanol on motor coordination in adolescent and adult rats.
2002,
Pubmed
