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Avermectins differentially affect ethanol intake and receptor function: implications for developing new therapeutics

Liana Asatryan¹, Megan M Yardley², Sheraz Khoja²

¹Titus Family Department of Clinical Pharmacy and Pharmaceutical Economics and Policy, School of Pharmacy, 1985 Zonal Avenue, Los Angeles, CA 90033, USA.

The International Journal of Neuropsychopharmacology

|January 24, 2014

Summary

Ivermectin and abamectin reduce alcohol intake in mice by modulating specific ion channels. Chemical structure and receptor effects, not just brain penetration, are key for avermectins treating alcohol use disorders.

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Area of Science:

Neuropharmacology
Drug Discovery

Background:

Alcohol use disorders (AUDs) represent a significant public health challenge.
Avermectins, including ivermectin (IVM), show potential as novel therapeutics for AUDs.
Previous research indicated IVM reduces ethanol intake by modulating ligand-gated ion channels.

Purpose of the Study:

To investigate the potential of IVM and related avermectins (abamectin, selamectin) as pharmacotherapeutics for AUDs.
To determine if structural modifications enhancing receptor modulation and brain concentration improve anti-alcohol efficacy.
To explore the role of GABAARs and P2X4Rs in the anti-alcohol effects of avermectins.

Main Methods:

Comparison of ethanol intake in mice treated with IVM, abamectin (ABM), and selamectin (SEL).
Assessment of avermectin modulation of GABAARs and P2X4Rs in Xenopus oocytes.
Measurement of brain penetration of IVM, ABM, and SEL in mice.

Main Results:

IVM and ABM significantly reduced ethanol intake in mice.
IVM and ABM antagonized ethanol's inhibitory effects on P2X4R function.
SEL did not reduce ethanol intake, despite higher brain concentrations, suggesting brain penetration is insufficient alone.
All tested avermectins potentiated GABAAR function.

Conclusions:

Avermectin efficacy in reducing ethanol intake is linked to their chemical structure and specific effects on receptor function, particularly P2X4R antagonism.
Modulation of P2X4R function by avermectins is a strong predictor of their potential to reduce alcohol consumption.
Avermectins represent a promising platform for developing new drugs to prevent and treat AUDs.