Ivermectin reduces alcohol intake and preference in mice

Megan M. Yardley; Letisha Wyatt; Sheraz Khoja; Liana Asatryan; Marcia J. Ramaker; Deborah A. Finn; Ronald L. Alkana; Nhat Huynh; Stan G. Louie; Nicos A. Petasis; Marco Bortolato; Daryl L. Davies

doi:10.1016/j.neuropharm.2012.03.014

Ivermectin reduces alcohol intake and preference in mice

Megan M. Yardley, Letisha Wyatt, Sheraz Khoja, Liana Asatryan, Marcia J. Ramaker, Deborah A. Finn, Ronald L. Alkana, Nhat Huynh, Stan G. Louie, Nicos A. Petasis, Marco Bortolato, Daryl L. Davies

Behavioral Neuroscience

Research output: Contribution to journal › Article › peer-review

51 Scopus citations

Abstract

The high rate of therapeutic failure in the management of alcohol use disorders (AUDs) underscores the urgent need for novel and effective strategies that can deter ethanol consumption. Recent findings from our group showed that ivermectin (IVM), a broad-spectrum anthelmintic with high tolerability and optimal safety profile in humans and animals, antagonized ethanol-mediated inhibition of P2X4 receptors (P2X4Rs) expressed in Xenopus oocytes. This finding prompted us to hypothesize that IVM may reduce alcohol consumption; thus, in the present study we investigated the effects of this agent on several models of alcohol self-administration in male and female C57BL/6 mice. Overall, IVM (1.25-10 mg/kg, intraperitoneal) significantly reduced 24-h alcohol consumption and intermittent limited access (4-h) binge drinking, and operant alcohol self-administration (1-h). The effects on alcohol intake were dose-dependent with the significant reduction in intake at 9 h after administration corresponding to peak IVM concentrations (C_max) in the brain. IVM also produced a significant reduction in 24-h saccharin consumption, but did not alter operant sucrose self-administration. Taken together, the findings indicate that IVM reduces alcohol intake across several different models of self-administration and suggest that IVM may be useful in the treatment of AUDs.

Original language	English (US)
Pages (from-to)	190-201
Number of pages	12
Journal	Neuropharmacology
Volume	63
Issue number	2
DOIs	https://doi.org/10.1016/j.neuropharm.2012.03.014
State	Published - Aug 2012

Keywords

Alcohol use disorders
Alcoholism therapy
Animal models
Drug repurposing
Ethanol

ASJC Scopus subject areas

Pharmacology
Cellular and Molecular Neuroscience

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10.1016/j.neuropharm.2012.03.014

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@article{4897d71daac448b3b4502b005ec97c35,

title = "Ivermectin reduces alcohol intake and preference in mice",

abstract = "The high rate of therapeutic failure in the management of alcohol use disorders (AUDs) underscores the urgent need for novel and effective strategies that can deter ethanol consumption. Recent findings from our group showed that ivermectin (IVM), a broad-spectrum anthelmintic with high tolerability and optimal safety profile in humans and animals, antagonized ethanol-mediated inhibition of P2X4 receptors (P2X4Rs) expressed in Xenopus oocytes. This finding prompted us to hypothesize that IVM may reduce alcohol consumption; thus, in the present study we investigated the effects of this agent on several models of alcohol self-administration in male and female C57BL/6 mice. Overall, IVM (1.25-10 mg/kg, intraperitoneal) significantly reduced 24-h alcohol consumption and intermittent limited access (4-h) binge drinking, and operant alcohol self-administration (1-h). The effects on alcohol intake were dose-dependent with the significant reduction in intake at 9 h after administration corresponding to peak IVM concentrations (Cmax) in the brain. IVM also produced a significant reduction in 24-h saccharin consumption, but did not alter operant sucrose self-administration. Taken together, the findings indicate that IVM reduces alcohol intake across several different models of self-administration and suggest that IVM may be useful in the treatment of AUDs.",

keywords = "Alcohol use disorders, Alcoholism therapy, Animal models, Drug repurposing, Ethanol",

author = "Yardley, {Megan M.} and Letisha Wyatt and Sheraz Khoja and Liana Asatryan and Ramaker, {Marcia J.} and Finn, {Deborah A.} and Alkana, {Ronald L.} and Nhat Huynh and Louie, {Stan G.} and Petasis, {Nicos A.} and Marco Bortolato and Davies, {Daryl L.}",

note = "Funding Information: We thank the two anonymous reviewers for their critical comments and helpful suggestions, which greatly improved the manuscript. We also thank Ayeetin Azah, Daniel Kuo, Christina Minh and Vanessa Fimreite for technical assistance. This work was supported, in whole or in part, by the American Foundation for Pharmaceutical Education Fellowship (MY); and National Institutes of Health (NIH), NIAAA , Grants F31AA018926 (LW), KO-1-AA017243 (LA), AA013922 (DLD), Integrative Neurosciences Initiative on Alcoholism [Pilot project AA013517 (DLD)], USC School of Pharmacy (RA and DLD), USC Undergraduate Research Associates Program (DLD, MB,CM) and Rose Hills Foundation Science and Engineering Fellowships (DLD and VF). This work was conducted as partial fulfillment of the requirements for the Ph.D. degree in Molecular Pharmacology and Toxicology, University of Southern California (MY and LW). ",

year = "2012",

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doi = "10.1016/j.neuropharm.2012.03.014",

language = "English (US)",

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AU - Yardley, Megan M.

AU - Wyatt, Letisha

AU - Khoja, Sheraz

AU - Asatryan, Liana

AU - Ramaker, Marcia J.

AU - Finn, Deborah A.

AU - Alkana, Ronald L.

AU - Huynh, Nhat

AU - Louie, Stan G.

AU - Petasis, Nicos A.

AU - Bortolato, Marco

AU - Davies, Daryl L.

N1 - Funding Information: We thank the two anonymous reviewers for their critical comments and helpful suggestions, which greatly improved the manuscript. We also thank Ayeetin Azah, Daniel Kuo, Christina Minh and Vanessa Fimreite for technical assistance. This work was supported, in whole or in part, by the American Foundation for Pharmaceutical Education Fellowship (MY); and National Institutes of Health (NIH), NIAAA , Grants F31AA018926 (LW), KO-1-AA017243 (LA), AA013922 (DLD), Integrative Neurosciences Initiative on Alcoholism [Pilot project AA013517 (DLD)], USC School of Pharmacy (RA and DLD), USC Undergraduate Research Associates Program (DLD, MB,CM) and Rose Hills Foundation Science and Engineering Fellowships (DLD and VF). This work was conducted as partial fulfillment of the requirements for the Ph.D. degree in Molecular Pharmacology and Toxicology, University of Southern California (MY and LW).

PY - 2012/8

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N2 - The high rate of therapeutic failure in the management of alcohol use disorders (AUDs) underscores the urgent need for novel and effective strategies that can deter ethanol consumption. Recent findings from our group showed that ivermectin (IVM), a broad-spectrum anthelmintic with high tolerability and optimal safety profile in humans and animals, antagonized ethanol-mediated inhibition of P2X4 receptors (P2X4Rs) expressed in Xenopus oocytes. This finding prompted us to hypothesize that IVM may reduce alcohol consumption; thus, in the present study we investigated the effects of this agent on several models of alcohol self-administration in male and female C57BL/6 mice. Overall, IVM (1.25-10 mg/kg, intraperitoneal) significantly reduced 24-h alcohol consumption and intermittent limited access (4-h) binge drinking, and operant alcohol self-administration (1-h). The effects on alcohol intake were dose-dependent with the significant reduction in intake at 9 h after administration corresponding to peak IVM concentrations (Cmax) in the brain. IVM also produced a significant reduction in 24-h saccharin consumption, but did not alter operant sucrose self-administration. Taken together, the findings indicate that IVM reduces alcohol intake across several different models of self-administration and suggest that IVM may be useful in the treatment of AUDs.

AB - The high rate of therapeutic failure in the management of alcohol use disorders (AUDs) underscores the urgent need for novel and effective strategies that can deter ethanol consumption. Recent findings from our group showed that ivermectin (IVM), a broad-spectrum anthelmintic with high tolerability and optimal safety profile in humans and animals, antagonized ethanol-mediated inhibition of P2X4 receptors (P2X4Rs) expressed in Xenopus oocytes. This finding prompted us to hypothesize that IVM may reduce alcohol consumption; thus, in the present study we investigated the effects of this agent on several models of alcohol self-administration in male and female C57BL/6 mice. Overall, IVM (1.25-10 mg/kg, intraperitoneal) significantly reduced 24-h alcohol consumption and intermittent limited access (4-h) binge drinking, and operant alcohol self-administration (1-h). The effects on alcohol intake were dose-dependent with the significant reduction in intake at 9 h after administration corresponding to peak IVM concentrations (Cmax) in the brain. IVM also produced a significant reduction in 24-h saccharin consumption, but did not alter operant sucrose self-administration. Taken together, the findings indicate that IVM reduces alcohol intake across several different models of self-administration and suggest that IVM may be useful in the treatment of AUDs.

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Ivermectin reduces alcohol intake and preference in mice

Abstract

Keywords

ASJC Scopus subject areas

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