title: Nicotine Enhances the Hypnotic and Hypothermic Effects of Alcohol in the Mouse.
abstract: BACKGROUND
  Ethanol (EtOH) and nicotine abuse are 2 leading causes of preventable mortality in the world, but little is known about the pharmacological mechanisms mediating co-abuse. Few studies have examined the interaction of the acute effects of EtOH and nicotine. Here, we examine the effects of nicotine administration on the duration of EtOH-induced loss of righting reflex (LORR) and characterize the nature of their pharmacological interactions in C57BL/6J mice.
  
  
  METHODS
  We assessed the effects of EtOH and nicotine and the nature of their interaction in the LORR test using isobolographic analysis after acute injection in C57BL/6J male mice. Next, we examined the importance of receptor efficacy using nicotinic partial agonists varenicline and sazetidine. We evaluated the involvement of major nicotinic acetylcholine receptor (nAChR) subtypes using nicotinic antagonist mecamylamine and nicotinic α4- and α7-knockout mice. The selectivity of nicotine's actions on EtOH-induced LORR was examined by testing nicotine's effects on the hypnotic properties of ketamine and pentobarbital. We also assessed the development of tolerance after repeated nicotine exposure. Last, we assessed whether the effects of nicotine on EtOH-induced LORR extend to hypothermia and EtOH intake in the drinking in the dark (DID) paradigm.
  
  
  RESULTS
  We found that acute nicotine injection enhances EtOH's hypnotic effects in a synergistic manner and that receptor efficacy plays an important role in this interaction. Furthermore, tolerance developed to the enhancement of EtOH's hypnotic effects by nicotine after repeated exposure of the drug. α4* and α7 nAChRs seem to play an important role in nicotine-EtOH interaction in the LORR test. In addition, the magnitude of EtOH-induced LORR enhancement by nicotine was more pronounced in C57BL/6J than DBA/2J mice. Furthermore, acute nicotine enhanced ketamine and pentobarbital hypnotic effects in the mouse. Finally, nicotine enhanced EtOH-induced hypothermia but decreased EtOH intake in the DID test.
  
  
  CONCLUSIONS
  Our results demonstrate that nicotine synergistically enhances EtOH-induced LORR in the mouse.
authors.affiliation: Department of Pharmacology and Toxicology, Virginia Commonwealth University, Richmond, Virginia.
authors.forename: Cassandra A
authors.initials: CA
authors.lastname: Slater
authors.affiliation: Department of Pharmacology and Toxicology, Virginia Commonwealth University, Richmond, Virginia.
authors.forename: Asti
authors.initials: A
authors.lastname: Jackson
authors.affiliation: Department of Pharmacology and Toxicology, Virginia Commonwealth University, Richmond, Virginia.
authors.forename: Pretal P
authors.initials: PP
authors.lastname: Muldoon
authors.affiliation: Department of Pharmacology and Toxicology, Virginia Commonwealth University, Richmond, Virginia.
authors.forename: Anton
authors.initials: A
authors.lastname: Dawson
authors.affiliation: Department of Pharmacology and Toxicology, Virginia Commonwealth University, Richmond, Virginia.
authors.forename: Megan
authors.initials: M
authors.lastname: O'Brien
authors.affiliation: Brudnick Neuropsychiatric Research Institute, Department of Psychiatry, University of Massachusetts Medical School, Worcester, Massachusetts.
authors.forename: Lindsey G
authors.initials: LG
authors.lastname: Soll
authors.affiliation: Department of Pharmacology and Toxicology, Virginia Commonwealth University, Richmond, Virginia.
authors.forename: Rehab
authors.initials: R
authors.lastname: Abdullah
authors.affiliation: Center for Organic and Medicinal Chemistry, Research Triangle Institute, Research Triangle Park, North Carolina.
authors.forename: F Ivy
authors.initials: FI
authors.lastname: Carroll
authors.affiliation: Brudnick Neuropsychiatric Research Institute, Department of Psychiatry, University of Massachusetts Medical School, Worcester, Massachusetts.
authors.forename: Andrew R
authors.initials: AR
authors.lastname: Tapper
authors.affiliation: Department of Pharmacology and Toxicology, Virginia Commonwealth University, Richmond, Virginia.
authors.forename: Michael F
authors.initials: MF
authors.lastname: Miles
authors.affiliation: Department of Pharmacology and Toxicology, Virginia Commonwealth University, Richmond, Virginia.
authors.forename: Matthew L
authors.initials: ML
authors.lastname: Banks
authors.affiliation: Department of Pharmacology and Toxicology, Virginia Commonwealth University, Richmond, Virginia.
authors.forename: Jill C
authors.initials: JC
authors.lastname: Bettinger
authors.affiliation: Department of Pharmacology and Toxicology, Virginia Commonwealth University, Richmond, Virginia.
authors.forename: Imad M
authors.initials: IM
authors.lastname: Damaj
mesh_terms: D000818:Animals; D001384:Azetidines / Q000494:pharmacology; D001831:Body Temperature / Q000187:drug effects*; D002492:Central Nervous System Depressants / Q000494:pharmacology*; D004347:Drug Interactions; D000431:Ethanol / Q000494:pharmacology*; D006993:Hypnotics and Sedatives / Q000494:pharmacology; D007035:Hypothermia; D007649:Ketamine / Q000494:pharmacology; D008464:Mecamylamine / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D018345:Mice, Knockout; D009538:Nicotine / Q000494:pharmacology*; D018722:Nicotinic Agonists / Q000494:pharmacology*; D018733:Nicotinic Antagonists / Q000494:pharmacology; D010424:Pentobarbital / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D011978:Receptors, Nicotinic / Q000235:genetics; D057897:Reflex, Righting / Q000187:drug effects*; D000068580:Varenicline / Q000494:pharmacology; D064569:alpha7 Nicotinic Acetylcholine Receptor / Q000235:genetics
chemical_list: D001384:Azetidines; D002492:Central Nervous System Depressants; D000431:Ethanol; D006993:Hypnotics and Sedatives; D007649:Ketamine; D008464:Mecamylamine; D009538:Nicotine; D018722:Nicotinic Agonists; D018733:Nicotinic Antagonists; D010424:Pentobarbital; D011725:Pyridines; D011978:Receptors, Nicotinic; D000068580:Varenicline; D064569:alpha7 Nicotinic Acetylcholine Receptor; C514816:sazetidine-A
keywords: Ethanol; Loss of Righting Reflex; Mice; Nicotine