title: Larval zebrafish model for FDA-approved drug repositioning for tobacco dependence treatment.
abstract: Cigarette smoking remains the most preventable cause of death and excess health care costs in the United States, and is a leading cause of death among alcoholics. Long-term tobacco abstinence rates are low, and pharmacotherapeutic options are limited. Repositioning medications approved by the U.S. Food and Drug Administration (FDA) may efficiently provide clinicians with new treatment options. We developed a drug-repositioning paradigm using larval zebrafish locomotion and established predictive clinical validity using FDA-approved smoking cessation therapeutics. We evaluated 39 physician-vetted medications for nicotine-induced locomotor activation blockade. We further evaluated candidate medications for altered ethanol response, as well as in combination with varenicline for nicotine-response attenuation. Six medications specifically inhibited the nicotine response. Among this set, apomorphine and topiramate blocked both nicotine and ethanol responses. Both positively interact with varenicline in the Bliss Independence test, indicating potential synergistic interactions suggesting these are candidates for translation into Phase II clinical trials for smoking cessation.
authors.affiliation: Mayo Addiction Research Center, Mayo Clinic, Rochester, Minnesota, United States of America; Center for Clinical and Translational Science, Mayo Clinic, Rochester, Minnesota, United States of America.
authors.forename: Margot A
authors.initials: MA
authors.lastname: Cousin
authors.affiliation: Mayo Addiction Research Center, Mayo Clinic, Rochester, Minnesota, United States of America; Nicotine Dependence Center, Mayo Clinic, Rochester, Minnesota, United States of America.
authors.forename: Jon O
authors.initials: JO
authors.lastname: Ebbert
authors.affiliation: Mayo Addiction Research Center, Mayo Clinic, Rochester, Minnesota, United States of America.
authors.forename: Amanda R
authors.initials: AR
authors.lastname: Wiinamaki
authors.affiliation: Mayo Addiction Research Center, Mayo Clinic, Rochester, Minnesota, United States of America.
authors.forename: Mark D
authors.initials: MD
authors.lastname: Urban
authors.affiliation: Mayo Addiction Research Center, Mayo Clinic, Rochester, Minnesota, United States of America.
authors.forename: David P
authors.initials: DP
authors.lastname: Argue
authors.affiliation: Mayo Addiction Research Center, Mayo Clinic, Rochester, Minnesota, United States of America; Center for Clinical and Translational Science, Mayo Clinic, Rochester, Minnesota, United States of America.
authors.forename: Stephen C
authors.initials: SC
authors.lastname: Ekker
authors.affiliation: Mayo Addiction Research Center, Mayo Clinic, Rochester, Minnesota, United States of America; Center for Clinical and Translational Science, Mayo Clinic, Rochester, Minnesota, United States of America.
authors.forename: Eric W
authors.initials: EW
authors.lastname: Klee
mesh_terms: D000818:Animals; D001552:Benzazepines / Q000737:chemistry; D058492:Drug Repositioning; D023421:Models, Animal; D009538:Nicotine / Q000494:pharmacology; D011810:Quinoxalines / Q000737:chemistry; D014029:Tobacco Use Disorder; D014481:United States; D014486:United States Food and Drug Administration; D000068580:Varenicline; D015027:Zebrafish
chemical_list: D001552:Benzazepines; D011810:Quinoxalines; D009538:Nicotine; D000068580:Varenicline