Avermectins differentially affect ethanol intake and receptor function: implications for developing new therapeutics for alcohol use disorders.
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). Earlier 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 GABAARs 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 GABAAR 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.
Titus Family Department of Clinical Pharmacy and Pharmaceutical Economics and Policy, School of Pharmacy, 1985 Zonal Avenue, Los Angeles, CA 90033, USA.
Liana
L
Asatryan
Department of Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, 1985 Zonal Avenue, Los Angeles, CA 90033, USA.
Megan M
MM
Yardley
Department of Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, 1985 Zonal Avenue, Los Angeles, CA 90033, USA.
Sheraz
S
Khoja
Department of Anesthesia and Beckman Program for Molecular and Genetic Medicine, Stanford School of Medicine, Stanford, CA 94305, USA.
James R
JR
Trudell
Titus Family Department of Clinical Pharmacy and Pharmaceutical Economics and Policy, School of Pharmacy, 1985 Zonal Avenue, Los Angeles, CA 90033, USA.
Nhat
N
Hyunh
Titus Family Department of Clinical Pharmacy and Pharmaceutical Economics and Policy, School of Pharmacy, 1985 Zonal Avenue, Los Angeles, CA 90033, USA.
Stan G
SG
Louie
Department of Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, 1985 Zonal Avenue, Los Angeles, CA 90033, USA.
Nicos A
NA
Petasis
Titus Family Department of Clinical Pharmacy and Pharmaceutical Economics and Policy, School of Pharmacy, 1985 Zonal Avenue, Los Angeles, CA 90033, USA.
Ronald L
RL
Alkana
Titus Family Department of Clinical Pharmacy and Pharmaceutical Economics and Policy, School of Pharmacy, 1985 Zonal Avenue, Los Angeles, CA 90033, USA.
Daryl L
DL
Davies
D000428:Alcohol Drinking / Q000188:drug therapy* / Q000503:physiopathology*; D019973:Alcohol-Related Disorders / Q000517:prevention & control; D000818:Animals; D001921:Brain / Q000187:drug effects / Q000503:physiopathology; D002492:Central Nervous System Depressants / Q000008:administration & dosage / Q000494:pharmacology; D000431:Ethanol / Q000008:administration & dosage / Q000494:pharmacology; D018690:Excitatory Amino Acid Agonists / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D007559:Ivermectin / Q000031:analogs & derivatives* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D008297:Male; D008810:Mice, Inbred C57BL; D011963:Receptors, GABA-A / Q000235:genetics / Q000378:metabolism; D058848:Receptors, Purinergic P2X4 / Q000235:genetics / Q000378:metabolism; D014981:Xenopus
D002492:Central Nervous System Depressants; D018690:Excitatory Amino Acid Agonists; D011963:Receptors, GABA-A; D058848:Receptors, Purinergic P2X4; D000431:Ethanol; C048324:abamectin; D007559:Ivermectin; C414354:selamectin