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 receptors (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 GABAA receptors, 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.
Alcohol Use Disorder (AUD) is a major problem with more than an estimated 76 million people worldwide meeting the diagnostic criteria. Current treatments are limited to three FDA-approved medications that are largely ineffective even when combined with psychosocial intervention, as is evident by the high relapse rate. As such, the search for more novel treatments represents an important public health goal. To this end, the following protocol utilizes two simple rodent drinking models to assess the preclinical efficacy of lead anti-alcohol compounds: two-bottle choice (TBC) and drinking in the dark (DID). The former allows mice to voluntary drink in moderation while the latter induces mice to voluntary consume a large amount of alcohol in a short period that mimics binge drinking. The simple and high throughput nature of both of these paradigms allow for rapid screening of pharmacological agents or for identifying strains of mice that exhibit certain voluntary drinking behavior.
Prior to testing novel therapeutics in humans, short and long term preclinical (i.e., animal), repetitive pharmacological and toxicological testing is required. In most cases, the preferred route of administration is via oral delivery. At the present time, oral delivery is mostly accomplished using an oral gavage procedure, in part, because it can achieve consistent and precise dosing in the animal model. Although this method is well established it does have complications that can result in a high rate of animal attrition. To this end, the procedure introduced here describes an alternative to the oral gavage method in which the desired drug is incorporated into a tastant, orally dissolving strip (ODS) that can simply be presented to the test animal where it is then rapidly taken up with minimal manipulation of the test subject. Herein, we demonstrate that preclinical, oral drug delivery using the ODS method represents a safe, convenient, and humane alternative to oral gavage.
Alcohol use disorder (AUD) is a health crisis of unmet need. We propose that ivermectin (IVM), an FDA approved drug, can be repurposed to address this problem. Our group recently reported that long‐term (30 day) oral administration of IVM (10 mg/kg) significantly reduces murine ethanol intake without causing any overt signs of toxicity, suggesting that IVM represents a safe, tolerable, and effective agent for the treatment of AUDs. This first longer term study focused on an alcohol drinking paradigm that resulted in levels of alcohol intake that would more closely mimic the levels one would expect from someone drinking at a moderate level (i.e., social drinker). The current study extends this investigation and further assesses the safety and utility of multi‐day oral administration of IVM using a Drinking in the Dark (DID) paradigm, where animals in a very short period of time reach blood ethanol levels that are associated with “binge” drinking in humans. This was accomplished by investigating the effects of orally delivered IVM (10 mg/kg/day) in male alcohol preferring C57BL/6 over a 6 week (30 day, M‐F drinking) treatment period. We found that IVM significantly reduces ethanol intake and preference over the 6 week study without exerting any significant signs of toxicity, which was assessed using aspartate aminotransferase (AST) and alanine aminotransferase (ALT) liver enzyme level measurements. Histopathology assessments are currently ongoing. Taken together, findings, to date, continue to provide support for the development of of IVM for the treatment of AUD.Suport: Research grants SC CTSI NIH/NCRR/NCATS –UL1TR000130 (D.L. D.)
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