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Preclinical evaluation of avermectins as novel therapeutic agents for alcohol use disorders

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Abstract

The deleterious effects of alcohol use disorders (AUDs) on human health have been documented worldwide. The enormous socioeconomic burden coupled with lack of efficacious pharmacotherapies underlies the need for improved treatment strategies. At present, there is a growing body of preclinical evidence that demonstrates the potential of avermectins [ivermectin (IVM), selamectin (SEL), abamectin (ABM), and moxidectin (MOX)] in treatment of AUDs. Avermectins are derived by fermentation of soil micro-organism, Streptomyces avermitilis, and have been extensively used for treatment of parasitic infections. From the mechanistic standpoint, avermectins are positive modulators of purinergic P2X4 receptors (P2X4Rs). P2X4Rs belong to P2X superfamily of cation-permeable ion channels gated by adenosine 5′-triphosphate (ATP). Building evidence has implicated a role for P2X4Rs in regulation of ethanol intake and that ethanol can inhibit ATP-gated currents in P2X4Rs. Investigations using recombinant cell models and animal models of alcohol drinking have reported that IVM, ABM, and MOX, but not SEL, were able to antagonize the inhibitory effects of ethanol on P2X4Rs in vitro and reduce ethanol intake in vivo. Furthermore, IVM was shown to reduce ethanol consumption via P2X4R potentiation in vivo, supporting the involvement of P2X4Rs in IVM’s anti-alcohol effects and that P2X4Rs can be used as a platform for developing novel anti-alcohol compounds. Taken together, these findings support the utility of avermectins as a novel class of drug candidates for treatment of AUDs.

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Abbreviations

AADs:

Alcohol attributable deaths

ABM:

Abamectin

ACh:

Acetylcholine

AMPARs:

α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid

Arc:

Arcuate nucleus

ATP:

Adenosine 5′-triphosphate

AUDs:

Alcohol use disorders

CNS:

Central nervous system

CREB:

Cyclic-AMP response element-binding protein

DA:

Dopamine

DALYs:

Disability-adjusted life years

DARPP-32:

Dopamine and cyclic-AMP-regulated phosphoprotein of 32 kDa

DID:

Drinking in the dark

GABARs:

γ-Amino butyric acid receptors

GlyRs:

Glycine receptors

HAD 1/LAD 1, HAD-2/LAD-2:

Replicate lines of high alcohol/low alcohol drinking rats

iP:

Inbred alcohol-preferring rats

iNP:

Inbred alcohol-non-preferring rats

i.p.:

Intraperitoneal

IVM:

Ivermectin

LGICs:

Ligand-gated ion channels

MAPK/ERK:

Mitogen-activated protein kinase/extracellular regulated kinase

MOX:

Moxidectin

MSNs:

Medium spiny neurons

NAc:

Nucleus accumbens

nAChRs:

Nicotinic acetylcholine receptors

NMDARs:

N-methyl-d-aspartate receptors

P:

Alcohol-preferring rats

PAG:

Periaqueductal gray area

PAM:

Positive allosteric modulator

PI3-K:

Phosphatidylinositol 3-kinase

P2XRs:

P2X receptors

P2X4Rs:

P2X4 receptors

P2X7Rs:

P2X7 receptors

P2X4R KO:

P2X4 knockout

P-gp:

P-glycoprotein

SEL:

Selamectin

TM:

Transmembrane

VTA:

Ventral tegmental area

VMN:

Ventromedial nucleus

WT:

Wildtype

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Funding

This work was supported by National Institute on Alcohol Abuse and Alcoholism (NIAAA) grant R01 AA022448 (D.L.D) and USC School of Pharmacy.

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  1. Sheraz Khoja and Nhat Huynh have equal contribution as co-first authors.

Authors and Affiliations

  1. Titus Family Department of Clinical Pharmacy, School of Pharmacy, University of Southern California, 1985 Zonal Avenue, Los Angeles, CA, 90089, USA

    Sheraz Khoja, Nhat Huynh, Alicia M. P. Warnecke, Liana Asatryan & Daryl L. Davies

  2. Department of Neurology, Keck School of Medicine, University of Southern California, 1975 Zonal Avenue, Los Angeles, CA, 90033, USA

    Michael W. Jakowec

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  1. Sheraz Khoja
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  2. Nhat Huynh
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  3. Alicia M. P. Warnecke
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  4. Liana Asatryan
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  6. Daryl L. Davies
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Contributions

S.K. and N.H. contributed equally to this work as co-first authors. A.M.P.W., L.A., M.W.J. and D.L.D contributed to revising the manuscript.

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Correspondence to Daryl L. Davies.

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Conflict of interest

D.L.D and L.A. are inventors on a patent for the use of IVM for treatment alcohol use disorders.

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Khoja, S., Huynh, N., Warnecke, A.M.P. et al. Preclinical evaluation of avermectins as novel therapeutic agents for alcohol use disorders. Psychopharmacology 235, 1697–1709 (2018). https://doi.org/10.1007/s00213-018-4869-9

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