There is growing interest in developing pharmacological agents to reverse alcohol (ethanol) intoxication, akin to naloxone for opioids. GABAergic modulation offers a potential pathway for reversing alcohol effects, specifically by targeting extrasynaptic GABA-A receptors with a benzodiazepine partial inverse agonist. We tested the hypothesis that iomazenil, a benzodiazepine partial inverse agonist, can counteract alcohol intoxication.
Methods:
In a randomized, double-blind, placebo-controlled, within-subject design, healthy male volunteers (n = 33) were administered intravenous alcohol (ethanol) or placebo, followed by intravenous iomazenil or placebo. Biphasic Alcohol Affects Scale, which assesses the stimulant and sedative effects of alcohol, was used as the primary outcome measure. For secondary measures, the Visual Analog Scale was used to assess “high,” “drowsiness,” “Buzzed,” and “anxiety.” In addition, all subjects were asked to rate the number of standard alcohol drinks they believed had been administered.
Results:
Alcohol produced greater sedation and stimulation when compared to placebo. Iomazenil produced the expected effect of increased anxiety compared to the placebo. However, Iomazenil did not attenuate the sedative or stimulatory effects of alcohol intoxication. Similarly, iomazenil did not significantly change feelings of “High,” “Drowsy,” “Anxious,” or “Buzzed” produced by alcohol.
Conclusions:
Although GABA-A receptors are thought to mediate the subjective effects associated with ethanol intoxication, this study failed to demonstrate a significant attenuation of ethanol intoxication by the benzodiazepine partial inverse agonist, iomazenil. This study raises questions as to the role of particular GABA-A receptor subtypes in ethanol intoxication and the extent to which GABA-A receptor subtype function must be reduced to attenuate human ethanol intoxication.
AhnKGilRSeibylJ, et al. (2011) Probing GABA receptor function in schizophrenia with iomazenil. Neuropsychopharmacology36: 677–683.
2.
AhnK-HSewellAElanderJ, et al. (2015) Role of GABA deficit in sensitivity to the psychotomimetic effects of amphetamine. Neuropsychopharmacology40: 2822–2831.
3.
AlturaBMAlturaBTGebrewoldA (1983) Alcohol-induced spasms of cerebral blood vessels: Relation to cerebrovascular accidents and sudden death. Science220: 331–333.
4.
AMA (1986) Council on scientific affairs. Alcohol and the driver. JAMA255: 522–527.
5.
AsaiYTakanoAItoH, et al. (2008) GABAA/Benzodiazepine receptor binding in patients with schizophrenia using [11C] Ro15-4513, a radioligand with relatively high affinity for α5 subunit. Schizophr Res99: 333–340.
6.
BeerHBläuensteinPHaslerP, et al. (1990a) Iomazenil: Pharmacological and animal data. Iomazenil and other brain receptor tracers for SPECT. Basel: Editiones Roche, pp. 9–29.
7.
BeerHFBlauensteinPAHaslerPH, et al. (1990b). In vitro and in vivo evaluation of iodine-123-Ro 16-0154: A new imaging agent for SPECT investigations of benzodiazepine receptors. J Nucl Med31: 1007–1014.
8.
BirdKChesherGPerlJ, et al. (1982) Naloxone has no effect on ethanol-induced impairment of psychomotor performance in man. Psychopharmacology76: 193–197.
9.
BisagaAEvansSM (2006) The acute effects of gabapentin in combination with alcohol in heavy drinkers. Drug Alcohol Depend83: 25–32.
10.
BohnMJ (1993) Alcoholism. Psychiatr Clin North Am16: 679–692.
11.
BonettiEBurkardWGablM, et al. (1985) The partial inverse benzodiazepine agonist Ro 15-4513 antagonizes acute ethanol effects in mice and rats. Br J Pharmacol86: 463P.
12.
BonettiEPolcPPieriL (1984) An azido analogue of the benzodiazepine antagonist Ro 15-1788 (Ro 15-4513) behaves as a partial inverse benzodiazepine agonist. Neurosci Lett18: S30.
13.
BraestrupCNielsenMHonoreT, et al. (1983) Benzodiazepine receptor ligands with positive and negative efficacy. Neuropharmacology22: 1451–1457.
14.
BrittonKTEhlersCLKoobGF (1988) Is ethanol antagonist Ro15-4513 selective for ethanol?Science239: 648–650.
15.
BrunnerEDomhofSLangerF (2002) Nonparametric Analysis of Longitudinal Data in Factorial Experiments. Ann Arbor, MI: The University of Michigan.
16.
CalandreEPRico-VillademorosFSlimM (2016) Alpha2delta ligands, gabapentin, pregabalin and mirogabalin: A review of their clinical pharmacology and therapeutic use. Expert Rev Neurother16: 1263–1277.
17.
CatleyDJordanCFrithC, et al. (1981) Alcohol induced discoordination is not reversed by naloxone. Psychopharmacology75: 65–68.
D’SouzaDCGilRBZuzarteE, et al. (2006) Gamma-Aminobutyric acid-serotonin interactions in healthy men: Implications for network models of psychosis and dissociation. Biol Psychiatry59: 128–137.
20.
Dell’OssoBAlbertUAttiAR, et al. (2015) Bridging the gap between education and appropriate use of benzodiazepines in psychiatric clinical practice. Neuropsychiatr Dis Treat11: 1885–1909.
21.
DoleVPFishmanJGoldfrankL, et al. (1982) Arousal of ethanol-intoxicated comatose patients with naloxone. Alcohol Clin Exp Res6: 275–279.
22.
DorowRHorowskiRPaschelkeG, et al. (1983) Severe anxiety induced by FG 7142, a beta-carboline ligand for benzodiazepine receptors. Lancet2: 98–99.
23.
FirstMBFrancesAPincusHA (2002) DSM-IV-TR Handbook of Differential Diagnosis. Washington, DC: American Psychiatric Publishing, Inc.
24.
GlowaJRCrawleyJSuzdakPD, et al. (1988) Ethanol and the GABA receptor complex: Studies with the partial inverse benzodiazepine receptor agonist Ro 15-4513. Pharmacol Biochem Behav31: 767–772.
25.
GrantKALovingerDM (1995) Cellular and behavioral neurobiology of alcohol: Receptor-mediated neuronal processes. Clin Neurosci3: 155–164.
26.
HancharHJDodsonPDOlsenRW, et al. (2005) Alcohol-induced motor impairment caused by increased extrasynaptic GABA(A) receptor activity. Nat Neurosci8: 339–345.
27.
HancharHJWallnerMOlsenRW (2004) Alcohol effects on gamma-aminobutyric acid type A receptors: Are extrasynaptic receptors the answer?Life Sci76: 1–8.
28.
HorowskiRDorrowR (2002) Anxiogenic, not psychotogenic, properties of the partial inverse benzodiazepine receptor agonist FG 7142 in man. Psychopharmacology (Berl)162: 223–224.
29.
HunkelerWMohlerHPieriL, et al. (1981) Selective antagonists of benzodiazepines. Nature290: 514–516.
30.
ImHKImWBCarterDB, et al. (1995) Interaction of beta-carboline inverse agonists for the benzodiazepine site with another site on GABAA receptors. Br J Pharmacol114: 1040–1044.
31.
JeffcoateWHerbertMCullenM, et al. (1979) Prevention of effects of alcohol-intoxication by naloxone. Lancet2: 1157–1159.
32.
JohnsonEWWoodsSWZoghbiS, et al. (1990) Receptor binding characterization of the benzodiazepine radioligand 125I-Ro16-0154: Potential probe for SPECT brain imaging. Life Sci47: 1535–1546.
33.
JuneHLLewisMJ (1994) Interactions of Ro15-4513, Ro15-1788 (flumazenil) and ethanol on measures of exploration and locomotion in rats. Psychopharmacology116: 309–316.
34.
JuneHLTorresLCasonCR, et al. (1998) The novel benzodiazepine inverse agonist RO19-4603 antagonizes ethanol motivated behaviors: Neuropharmacological studies. Brain Res784: 256–275.
35.
KoskiAOjanperaIVuoriE (2002) Alcohol and benzodiazepines in fatal poisonings. Alcohol Clin Exp Res26: 956–959.
36.
KrystalJHStaleyJMasonG, et al. (2006) Gamma-aminobutyric acid type A receptors and alcoholism: Intoxication, dependence, vulnerability, and treatment. Arch Gen Psychiatry63: 957–968.
37.
KrystalJHTabakoffB (2002) Ethanol abuse, dependence, and withdrawal: Neurobiology and clinical implications. In: DavisKLCharneyDSCoyleJT, et al. (eds.) Psychopharmacology: A Fifth Generation of Progress. Philadelphia, PA: Lippincott Williams and Wilkins.
38.
KumarSFlemingRLMorrowAL, et al. (2004) Ethanol regulation of gamma-aminobutyric acid A receptors: Genomic and nongenomic mechanisms. Pharmacol Ther101: 211–226.
39.
LiangJCagettiEOlsenRW, et al. (2004a) Altered pharmacology of synaptic and extrasynaptic GABAA receptors on CA1 hippocampal neurons is consistent with subunit changes in a model of alcohol withdrawal and dependence. J Pharmacol Exp Ther310: 1234–1245.
40.
LiangJCagettiEOlsenRW, et al. (2004b) Altered pharmacology of synaptic and extrasynaptic GABAA receptors on CA1 hippocampal neurons is consistent with subunit changes in a model of alcohol withdrawal and dependence. J Pharmacol Exp Ther310: 1234–1245.
41.
LinnoilaMDubyoskiKRawlingsR, et al. (1985) Effects of chronic zimelidine and ethanol on psychomotor performance. J Clin Psychopharmacol5: 148–153.
42.
ListerRGNuttD (1988a) RO 15-4513 and its interaction with ethanol. Adv Alcohol Subst Abuse7: 119–123.
MarrosuFMereuGGiorgiO, et al. (1988) The benzodiazepine recognition site inverse agonists Ro 15-4513 and FG 7142 both antagonize the EEG effects of ethanol in the rat. Life Sci43: 2151–2158.
45.
MartinCSEarleywineMMustyRE, et al. (1993) Development and validation of the Biphasic Alcohol Effects Scale. Alcohol Clin Exp Res17: 140–146.
46.
MartinezDGilRSlifsteinM, et al. (2005) Alcohol dependence is associated with blunted dopamine transmission in the ventral striatum. Biol Psychiatry58: 779–786.
47.
MartinottiGDi NicolaMTedeschiD, et al. (2010) Pregabalin versus naltrexone in alcohol dependence: A randomised, double-blind, comparison trial. J Psychopharmacol24: 1367–1374.
48.
MohlerHFritschyJMRudolphU (2002) A new benzodiazepine pharmacology. J Pharmacol Exp Ther300: 2–8.
49.
NaranjoCSellersEKaplanH, et al. (1984a) Acute kinetic and dynamic interactions of zimelidine with ethanol. Clin Pharmacol Ther36: 654–660.
50.
NaranjoCSellersERoachC, et al. (1984b) Zimelidine-induced variations in alcohol intake by nondepressed heavy drinkers. Clin Pharmacol Ther35: 374–381.
NuttD (1999) Alcohol and the brain: Pharmacological insights for psychiatrists. Br J Psychiatry175: 114–119.
53.
NuttDJ (2014) The role of the opioid system in alcohol dependence. J Psychopharmacol28: 8–22.
54.
NuttDJBessonMWilsonSJ, et al. (2007) Blockade of alcohol’s amnestic activity in humans by an α5 subtype benzodiazepine receptor inverse agonist. Neuropharmacology53: 810–820.
55.
PolcPBonettiEPSchaffnerR, et al. (1982) A three-state model of the benzodiazepine receptor explains the interactions between the benzodiazepine antagonist Ro 15-1788, benzodiazepine tranquilizers, beta-carbolines, and phenobarbitone. Naunyn Schmiedebergs Arch Pharmacol321: 260–264.
56.
RadhakrishnanRSkosnikPDCortes-BrionesJ, et al. (2015) GABA deficits enhance the psychotomimetic effects of Δ9-THC. Neuropsychopharmacology40: 2047–2056.
57.
RalevskiEPerryEBJrD’SouzaDC, et al. (2012) Preliminary findings on the interactive effects of IV ethanol and IV nicotine on human behavior and cognition: A laboratory study. Nicotine Tob Res14: 596–606.
58.
Schnakenberg MartinAMFlynnLTSefikE, et al. (2023) Preliminary study of the interactive effects of THC and ethanol on self-reported ability and simulated driving, subjective effects, and cardiovascular responses. Psychopharmacology240: 1235–1246.
59.
SuzdakPDPaulSMCrawleyJN (1988) Effects of Ro15-4513 and other benzodiazepine receptor inverse agonists on alcohol-induced intoxication in the rat. J Pharmacol Exp Ther245: 880–886.
60.
TallmanJFGallagerDW (1985) The GABA-ergic system: A locus of benzodiazepine action. Ann Rev Neurosci8: 21–44.
61.
UchitelODDi GuilmiMNUrbanoFJ, et al. (2010) Acute modulation of calcium currents and synaptic transmission by gabapentinoids. Channels4: 490–496.
62.
WallnerMHancharHJOlsenRW (2003) 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. Proc Natl Acad Sci U S A100: 15218–15223.
63.
WeingartnerHBuchsbaumMLinnoilaM (1983a) Zimelidine effects on memory impairments produced by ethanol. Life Sci33: 2159–2163.
64.
WeingartnerHRudorferMBuchsbaumM, et al. (1983b) Effects of serotonin on memory impairments produced by ethanol. Science221: 472–474.
65.
WhitwamJGAmreinR (1995) Pharmacology of flumazenil. Acta Anaesthesiol Scand Suppl108: 3–14.
66.
WitkiewitzKLittenRLeggioL (2019) Advances in the science and treatment of alcohol use disorder. Sci Adv5: eaax4043.
Supplementary Material
Please find the following supplemental material available below.
For Open Access articles published under a Creative Commons License, all supplemental material carries the same license as the article it is associated with.
For non-Open Access articles published, all supplemental material carries a non-exclusive license, and permission requests for re-use of supplemental material or any part of supplemental material shall be sent directly to the copyright owner as specified in the copyright notice associated with the article.
