Ivermectin reduces alcohol intake and preference in mice - PubMed (original) (raw)

. 2012 Aug;63(2):190-201.

doi: 10.1016/j.neuropharm.2012.03.014. Epub 2012 Mar 23.

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

Affiliations

Ivermectin reduces alcohol intake and preference in mice

Megan M Yardley et al. Neuropharmacology. 2012 Aug.

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.

Copyright © 2012 Elsevier Ltd. All rights reserved.

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Conflict of interest statement

Conflict of interest

The authors declare no conflict of interest.

Figures

Figure 1

Figure 1

IVM (10 mg/kg) reduces A) 10% v/v ethanol (10E) intake and B) preference ratio for 10E in male C57BL/6J mice using a 24-h access two-bottle choice paradigm. After attaining stable drinking levels for 3 consecutive days, IVM was administered. Bars represent levels from the day prior to IVM injection (white; Pre IVM), the day of the IVM injection (black; IVM) and the day after the IVM injection (gray; Post IVM). Values represent the mean ±SEM for 11 mice.*P<0.05, ***P<0.001 versus Pre IVM, Tukey multiple comparison post-hoc test.

Figure 2

Figure 2

IVM dose response study in male C57BL/6J mice using a 24-h access two bottle choice paradigm. Each dose of IVM was administered after achieving stabilized drinking for 3 consecutive days. Bars represent levels from the day prior to IVM injection (white; Pre IVM) and the day of the IVM injection (black; IVM). A) IVM (2.5 and 10 mg/kg) significantly reduced 10E intake. B) IVM (2.5 and 10 mg/kg) significantly reduced preference ratio for 10E. The effects of IVM on water and total fluid intake are presented in panels C and D, respectively. Values represent the mean ±SEM for 11 mice per dose group. **P<0.01, ***P<0.001 versus respective pre IVM condition, Bonferroni’s post-hoc test.

Figure 3

Figure 3

IVM (10 mg/kg) administered to male C57BL/6J mice significantly reduced 10E intake approximately 9 hours after IVM administration. The intake was measured on an hourly basis, up to 10 hours following IVM (closed) or saline (open) administration. Values represent the mean ±SEM cumulative intake for 10–11 male mice per treatment group. **P<0.01 versus saline-treated group, Bonferroni’s post-hoc test.

Figure 4

Figure 4

IVM AUC in plasma and brain tissue was determined following injection of various IVM dose groups. A dose-dependent IVM AUC was found in the plasma (open bars) and brain tissue (black bars).

Figure 5

Figure 5

IVM dose response study in female C57BL/6J mice using a 24-h access two bottle choice paradigm. Each dose of IVM was administered after achieving stabilized drinking for 3 consecutive days. Bars represent levels from the day prior to IVM injection (white; Pre IVM) and the day of the IVM injection (black; IVM). A) IVM (2.5–10 mg/kg) significantly reduced 10E intake and B) preference ratio for 10E. The effects of IVM on water and total fluid intake are presented in panels C and D, respectively. Values represented the mean ±SEM for 19 mice per dose group. **P<0.01, ***P<0.001 pre IVM condition, Bonferroni’s post-hoc test.

Figure 5

Figure 5

IVM dose response study in female C57BL/6J mice using a 24-h access two bottle choice paradigm. Each dose of IVM was administered after achieving stabilized drinking for 3 consecutive days. Bars represent levels from the day prior to IVM injection (white; Pre IVM) and the day of the IVM injection (black; IVM). A) IVM (2.5–10 mg/kg) significantly reduced 10E intake and B) preference ratio for 10E. The effects of IVM on water and total fluid intake are presented in panels C and D, respectively. Values represented the mean ±SEM for 19 mice per dose group. **P<0.01, ***P<0.001 pre IVM condition, Bonferroni’s post-hoc test.

Figure 6

Figure 6

Daily administration of IVM (1.25 mg/kg/day X 7 days) reduced 10E intake in female C57BL/6J mice using a 24-h access two bottle choice paradigm. After achieving stable drinking levels for 3 consecutive days, IVM was administered for 7 consecutive days. Bars represent levels from the day prior to IVM injections (white; Pre IVM), the 7 day average of the IVM injection (black; IVM) and the day after the IVM injections (gray; Post IVM). Values represented the mean ±SEM for 11 mice. **P<0.01 versus Pre-IVM, Tukey multiple comparison post-hoc test.

Figure 7

Figure 7

IVM administration reduced saccharin (0.033% w/v) intake in female C57BL/6J mice using a 24-h access two bottle choice paradigm following doses of A) 2.5 mg/kg and B) 5 mg/kg. After achieving stable drinking levels for 3 consecutive days, IVM was administered (separate studies for each dose). Bars represent levels from the day prior to IVM injection (white; Pre IVM), the day of the IVM injection (black; IVM) and the day after the IVM injection (gray; Post IVM). Values represent the mean ±SEM for 19 mice per dose group. ***P<0.001 versus Pre IVM, Tukey multiple comparison post-hoc test.

Figure 8

Figure 8

10 mg/kg IVM administration reduced ethanol (10% v/v) intake in female C57BL/6 mice using an intermittent, limited (4-h) access paradigm. After attaining stable drinking levels, IVM was administered. Bars represent levels from the day prior to IVM injection (white; Pre IVM), the day of the IVM injection (black; IVM) and the day after the IVM injection (gray; Post IVM). Values represent the mean ± SEM for 8 mice. ***P<0.001 versus Pre IVM, Tukey multiple comparison post-hoc test.

Figure 9

Figure 9

Effect of IVM on operant self-administration of 10% ethanol (10E) in male C57BL/6J mice during 60 minute sessions. IVM tended to decrease 10E intake in animals with a long history of ethanol self-administration (panel A) or in animals that were experimentally naïve (panel B). Importantly, the data from the two cohorts did not differ, so the combined data indicated that IVM significantly decreased 10E intake (panel C). Panel D depicts the effect of IVM injection on the temporal distribution of 10E licks in 10 min intervals across the 60 min session in the combined data from the two cohorts (n=16). Values represent the mean ± SEM for the numbers of animals in parentheses for panels A–C. +p ≤ 0.10, *p < 0.05 versus saline (0 mg/kg), paired t-test.

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