title: Effects of nicotine and minor tobacco alkaloids on intracranial-self-stimulation in rats.
abstract: BACKGROUND
  While nicotine is the primary addictive compound in tobacco, other tobacco constituents including minor alkaloids (e.g., nornicotine, anabasine) may also contribute to tobacco addiction by mimicking or enhancing the effects of nicotine. Further evaluating the behavioral effects of minor alkaloids is essential for understanding their impact on tobacco addiction and informing development of tobacco product standards by the FDA.
  
  
  METHODS
  This study compared the addiction-related effects of nicotine and the minor alkaloids nornicotine, anabasine, myosmine, anatabine, and cotinine on intracranial self-stimulation (ICSS) thresholds in rats.
  
  
  RESULTS
  Acute injection of nicotine produced reinforcement-enhancing (ICSS threshold-decreasing) effects at low to moderate doses, and reinforcement-attenuating/aversive (ICSS threshold-increasing) effects at high doses. Nornicotine and anabasine produced similar biphasic effects on ICSS thresholds, although with lower potency compared to nicotine. Myosmine only elevated ICSS thresholds at relatively high doses, while anatabine and cotinine did not influence ICSS thresholds at any dose. None of the alkaloids significantly influenced ICSS response latencies, indicating a lack of nonspecific motoric effects.
  
  
  CONCLUSIONS
  These findings indicate that some minor tobacco alkaloids can either fully (nornicotine, anabasine) or partially (myosmine) mimic nicotine's addiction-related effects on ICSS, albeit at reduced potency. These findings emphasize the need for further study of the abuse potential of minor alkaloids, including evaluation of their effects when combined with nicotine and other tobacco constituents to better simulate tobacco exposure in humans. Such work is essential for informing FDA regulation of tobacco products and could also lead to the development of novel pharmacotherapies for tobacco addiction.
authors.affiliation: Minneapolis Medical Research Foundation, Minneapolis, MN, United States; Department of Medicine, University of Minnesota Medical School, Minneapolis, MN, United States; Department of Psychology, University of Minnesota, Minneapolis, MN, United States. Electronic address: harr0547@umn.edu.
authors.forename: Andrew C
authors.initials: AC
authors.lastname: Harris
authors.affiliation: Minneapolis Medical Research Foundation, Minneapolis, MN, United States.
authors.forename: Laura
authors.initials: L
authors.lastname: Tally
authors.affiliation: Minneapolis Medical Research Foundation, Minneapolis, MN, United States; Department of Ecology, Evolution, and Behavior, University of Minnesota, Minneapolis, MN, United States.
authors.forename: Peter
authors.initials: P
authors.lastname: Muelken
authors.affiliation: Minneapolis Medical Research Foundation, Minneapolis, MN, United States; Department of Psychology, University of Minnesota, Minneapolis, MN, United States.
authors.forename: Andrew
authors.initials: A
authors.lastname: Banal
authors.affiliation: Minneapolis Medical Research Foundation, Minneapolis, MN, United States; Department of Neuroscience, University of Minnesota, Minneapolis, MN, United States.
authors.forename: Clare E
authors.initials: CE
authors.lastname: Schmidt
authors.affiliation: Masonic Cancer Center Biostatistics and Bioinformatics Core, University of Minnesota, Minneapolis, MN, United States.
authors.forename: Qing
authors.initials: Q
authors.lastname: Cao
authors.affiliation: Minneapolis Medical Research Foundation, Minneapolis, MN, United States; Department of Medicine, University of Minnesota Medical School, Minneapolis, MN, United States; Department of Psychology, University of Minnesota, Minneapolis, MN, United States.
authors.forename: Mark G
authors.initials: MG
authors.lastname: LeSage
mesh_terms: D000470:Alkaloids / Q000494:pharmacology*; D000691:Anabasine / Q000494:pharmacology; D000818:Animals; D001921:Brain / Q000187:drug effects* / Q000502:physiology; D003367:Cotinine / Q000494:pharmacology; D008297:Male; D009538:Nicotine / Q000031:analogs & derivatives / Q000494:pharmacology*; D011725:Pyridines / Q000494:pharmacology; D051381:Rats; D012653:Self Stimulation / Q000187:drug effects*
chemical_list: D000470:Alkaloids; D011725:Pyridines; C012737:anatabine; D009538:Nicotine; C005311:nornicotine; C002398:myosmine; D003367:Cotinine; D000691:Anabasine
keywords: Intracranial self-stimulation; Minor alkaloids; Nicotine; Non-nicotine tobacco constituents; Rat