title: Synergistic blockade of alcohol escalation drinking in mice by a combination of novel kappa opioid receptor agonist Mesyl Salvinorin B and naltrexone.
abstract: Mesyl Salvinorin B (MSB) is a potent selective kappa opioid receptor (KOP-r) agonist that has potential for development as an anti-psychostimulant agent with fewer side-effects (e.g., sedation, depression and dysphoria) than classic KOP-r agonists. However, no such study has been done on alcohol. We investigated whether MSB alone or in combination with naltrexone (mu-opioid receptor antagonist) altered voluntary alcohol drinking in both male and female mice. Mice, subjected to 3weeks of chronic escalation drinking (CED) in a two-bottle choice paradigm with 24-h access every other day, developed rapid escalation of alcohol intake and high preference. We found that single, acute administration of MSB dose-dependently reduced alcohol intake and preference in mice after 3-week CED. The effect was specific to alcohol, as shown by the lack of any effect of MSB on sucrose or saccharin intake. We also used the drinking-in-the-dark (DID) model with limited access (4h/day) to evaluate the pharmacological effect of MSB after 3weeks of DID. However, MSB had no effect on alcohol drinking after 3-week DID. Upon investigation of potential synergistic effects between naltrexone and MSB, we found that acute administration of a combination of MSB and naltrexone reduced alcohol intake profoundly after 3-week CED at doses lower than those individual effective doses. Repeated administrations of this combination showed less tolerance development than repeated MSB alone. Our study suggests that the novel KOP-r agonist MSB both alone and in combination with naltrexone shows potential in alcoholism treatment models.
authors.affiliation: Laboratory of the Biology of Addictive Diseases, The Rockefeller University, NY, USA. Electronic address: zhouya@rockefeller.edu.
authors.forename: Yan
authors.initials: Y
authors.lastname: Zhou
authors.affiliation: Department of Medicinal Chemistry, University of Kansas School of Pharmacy, Lawrence, KS, USA.
authors.forename: Rachel Saylor
authors.initials: RS
authors.lastname: Crowley
authors.affiliation: Laboratory of the Biology of Addictive Diseases, The Rockefeller University, NY, USA.
authors.forename: Konrad
authors.initials: K
authors.lastname: Ben
authors.affiliation: Department of Medicinal Chemistry, University of Kansas School of Pharmacy, Lawrence, KS, USA.
authors.forename: Thomas E
authors.initials: TE
authors.lastname: Prisinzano
authors.affiliation: Laboratory of the Biology of Addictive Diseases, The Rockefeller University, NY, USA.
authors.forename: Mary Jeanne
authors.initials: MJ
authors.lastname: Kreek
mesh_terms: D000428:Alcohol Drinking / Q000188:drug therapy*; D000437:Alcoholism / Q000188:drug therapy; D000818:Animals; D002491:Central Nervous System Agents / Q000494:pharmacology; D004224:Diterpenes / Q000378:metabolism* / Q000493:pharmacokinetics* / Q000627:therapeutic use; D045785:Diterpenes, Clerodane; D004326:Drinking / Q000187:drug effects; D000431:Ethanol / Q000494:pharmacology; D005260:Female; D008297:Male; D008698:Mesylates / Q000378:metabolism* / Q000493:pharmacokinetics* / Q000627:therapeutic use; D051379:Mice; D009271:Naltrexone / Q000378:metabolism / Q000493:pharmacokinetics; D009292:Narcotic Antagonists / Q000494:pharmacology; D017473:Receptors, Opioid, kappa / Q000819:agonists; D017450:Receptors, Opioid, mu / Q000037:antagonists & inhibitors
chemical_list: D002491:Central Nervous System Agents; D004224:Diterpenes; D045785:Diterpenes, Clerodane; D008698:Mesylates; D009292:Narcotic Antagonists; D017473:Receptors, Opioid, kappa; D017450:Receptors, Opioid, mu; C000600932:mesyl salvinorin B; D000431:Ethanol; D009271:Naltrexone
keywords: Alcohol escalation drinking; Combined therapy; KOP-r; Mesyl Salvinorin B; Naltrexone