title: Preclinical development of moxidectin as a novel therapeutic for alcohol use disorder.
abstract: Current pharmacotherapies for alcohol used disorder (AUD) are few and relatively ineffective illustrating the need for the development of new, effective medications. Using a translational approach, our laboratory reported that ivermectin, an FDA-approved, human and animal anti-parasitic agent, can significantly reduce ethanol intake in male and female mice across different drinking paradigms. Extending this line of investigation, the current paper investigated the utility of moxidectin (MOX), an analogue of ivermectin, to reduce ethanol intake. Notably, MOX is widely held to have lower neurotoxicity potential and improved margin of safety compared to ivermectin. Using a 24-h-two-bottle choice paradigm, MOX significantly reduced ethanol intake in a dose dependent manner in both male and female C57BL/6J mice, respectively (1.25-7.5 mg/kg) and (1.25-10 mg/kg). Further, multi-day administration of MOX (2.5 mg/kg; intraperitoneal injection) for 5 consecutive days significantly reduced ethanol intake in both the 24-h-two-bottle choice and Drinking-in-the-Dark paradigms in female mice. No overt signs of behavioral toxicity were observed. Notably in both male and female mice, MOX significantly reduced ethanol intake starting approximately 4 h post-injection. Using a Xenopus oocyte expression system, we found that MOX significantly potentiated P2X4 receptor (P2X4R) function and antagonized the inhibitory effects of ethanol on ATP-gated currents in P2X4Rs. This latter finding represents the first report of MOX having activity on P2X4Rs. In addition, MOX potentiated GABAAreceptors, but to a lesser degree as compared to ivermectin supporting the hypothesis that MOX would be advantageous (compared to ivermectin) with respect to reducing contraindications. Overall, the results illustrate the potential for development of MOX as a novel pharmacotherapy for the treatment of AUD.
authors.affiliation: Titus Family Department of Clinical Pharmacy, School of Pharmacy, University of Southern California, 1985 Zonal Avenue, Los Angeles, CA 90089, USA.
authors.forename: Nhat
authors.initials: N
authors.lastname: Huynh
authors.affiliation: Titus Family Department of Clinical Pharmacy, School of Pharmacy, University of Southern California, 1985 Zonal Avenue, Los Angeles, CA 90089, USA.
authors.forename: Natalie
authors.initials: N
authors.lastname: Arabian
authors.affiliation: Titus Family Department of Clinical Pharmacy, School of Pharmacy, University of Southern California, 1985 Zonal Avenue, Los Angeles, CA 90089, USA.
authors.forename: Anna
authors.initials: A
authors.lastname: Naito
authors.affiliation: Titus Family Department of Clinical Pharmacy, School of Pharmacy, University of Southern California, 1985 Zonal Avenue, Los Angeles, CA 90089, USA.
authors.forename: Stan
authors.initials: S
authors.lastname: Louie
authors.affiliation: Department of Neurology, Keck School of Medicine, University of Southern California, 1333 San Pablo Street, Los Angeles, CA 90033, USA.
authors.forename: Michael W
authors.initials: MW
authors.lastname: Jakowec
authors.affiliation: Titus Family Department of Clinical Pharmacy, School of Pharmacy, University of Southern California, 1985 Zonal Avenue, Los Angeles, CA 90089, USA.
authors.forename: Liana
authors.initials: L
authors.lastname: Asatryan
authors.affiliation: Titus Family Department of Clinical Pharmacy, School of Pharmacy, University of Southern California, 1985 Zonal Avenue, Los Angeles, CA 90089, USA. Electronic address: ddavies@usc.edu.
authors.forename: Daryl L
authors.initials: DL
authors.lastname: Davies
mesh_terms: D000428:Alcohol Drinking / Q000188:drug therapy; D019973:Alcohol-Related Disorders / Q000188:drug therapy* / Q000503:physiopathology; D000818:Animals; D000871:Anthelmintics / Q000008:administration & dosage* / Q000627:therapeutic use; D002755:Choice Behavior / Q000187:drug effects*; D000431:Ethanol / Q000008:administration & dosage*; D005260:Female; D018942:Macrolides / Q000008:administration & dosage* / Q000627:therapeutic use; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D011963:Receptors, GABA-A / Q000502:physiology; D058848:Receptors, Purinergic P2X4 / Q000502:physiology; D014982:Xenopus laevis
chemical_list: D000871:Anthelmintics; D018942:Macrolides; D011963:Receptors, GABA-A; D058848:Receptors, Purinergic P2X4; D000431:Ethanol; C027837:moxidectin
keywords: Alcoholism therapy; Drug repurposing; Medication development