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

Abstract

Our laboratory is investigating ivermectin (IVM) and other members of the avermectin family as new pharmaco-therapeutics to prevent and/or treat alcohol use disorders (AUDs). Prior work found that IVM significantly reduced ethanol intake in mice and that this effect likely reflects IVM’s ability to modulate ligand-gated ion channels. We hypothesized that structural modifications that enhance IVM’s effects on key receptors and/or increase its brain concentration should improve its anti-alcohol efficacy. We tested this hypothesis by comparing the abilities of IVM and two other avermectins, abamectin (ABM) and selamectin (SEL), to reduce ethanol intake in mice, to alter modulation of GABA ARs and P2X4Rs expressed in Xenopus oocytes and to increase their ability to penetrate the brain. IVM and ABM significantly reduced ethanol intake and antagonized the inhibitory effects of ethanol on P2X4R function. In contrast, SEL did not affect either measure, despite achieving higher brain concentrations than IVM and ABM. All three potentiated GABAA receptor function. These findings suggest that chemical structure and effects on receptor function play key roles in the ability of avermectins to reduce ethanol intake and that these factors are more important than brain penetration alone. The direct relationship between the effect of these avermectins on P2X4R function and ethanol intake suggest that the ability to antagonize ethanol-mediated inhibition of P2X4R function may be a good predictor of the potential of an avermectin to reduce ethanol intake and support the use of avermectins as a platform for developing novel drugs to prevent and/or treat AUDs.

P2X4 Receptor Regulates Alcohol-Induced Responses in Microglia

“…Cell viability was determined by LIVE/DEAD assay (Invitrogen, Carlsbad, CA), and showed that ethanol (EtOH) 5-200 mM concentration had no toxic effects on microglia after 48 h of exposure (data not shown). The concentration of EtOH (100 mM) used in the present study is similar to other published studies 29, 33-36 . Blood alcohol concentration (BAC) and the effects of drinking alcohol significantly vary from person to person.…”

Oral delivery of ivermectin using a fast dissolving oral film: Implications for repurposing ivermectin as a pharmacotherapy for alcohol use disorder

“…The 24-h access two-bottle choice paradigm was performed as previously described (Asatryan et al, 2014; Wyatt et al, 2014; Yardley et al, 2012, 2014). Briefly, mice were single-housed and had access to 2 bottles of water for 3 days.…”

“…The limited use of pharmacotherapy for AUD is due, in part, to the relative lack of options to successfully treat these disorders (Edlund, Booth, & Han, 2012). To address this issue, our research group is investigating the utility of ivermectin (IVM) as a novel pharmacotherapy for the treatment and/or prevention of AUD (Asatryan et al, 2014; Wyatt et al, 2014; Yardley et al, 2012, 2014). …”

“…Studies from our laboratory using two-electrode voltage clamp methods demonstrate that IVM interferes with and antagonizes the inhibitory effect of ethanol on P2X4Rs (Asatryan et al, 2010). Furthermore, we have shown that IVM decreases ethanol consumption across multiple murine models of ethanol intake (Asatryan et al, 2014; Wyatt et al, 2014; Yardley et al, 2012, 2014) and reduces response for alcohol under an operant self-administration progressive ratio schedule (Kosten, 2011). We found that both acute and multi-day administration of IVM (1.25–10 mg/kg) reliably decreases ethanol intake and preference (Yardley et al, 2012, 2014) without causing overt signs of toxicity and having minimal effect on major domains of neuropsychiatric toxicity (Bortolato et al, 2013).…”

Involvement of Purinergic P2X4 Receptors in Alcohol Intake of High-Alcohol-Drinking (HAD) Rats

“…It typically enhances inhibitory neurotransmission and decreases excitatory transmission (Shan et al, 2001), although evidence suggests that ivermectin blocks some of the behavioral effects of GABA agonists as well (Davies et al, 2013). Similarly, molecular modeling suggests that ivermectin blocks some of the inhibitory effects of EtOH at P2X4Rs, possibly through interfering with EtOH at an overlapping site of action (Asatryan et al, 2010, 2014). …”