title: Melatonin administration alters nicotine preference consumption via signaling through high-affinity melatonin receptors.
abstract: BACKGROUND
  While it is known that tobacco use varies across the 24-h day, the time-of-day effects are poorly understood. Findings from several previous studies indicate a potential role for melatonin in these time-of-day effects; however, the specific underlying mechanisms have not been well characterized. Understanding of these mechanisms may lead to potential novel smoking cessation treatments.
  
  
  OBJECTIVE
  The objective of this study is examine the role of melatonin and melatonin receptors in nicotine free-choice consumption
  
  
  METHODS
  A two-bottle oral nicotine choice paradigm was utilized with melatonin supplementation in melatonin-deficient mice (C57BL/6J) or without melatonin supplementation in mice proficient at melatonin synthesis (C3H/Ibg) compared to melatonin-proficient mice lacking both or one of the high-affinity melatonin receptors (MT1 and MT2; double-null mutant DM, or MT1 or MT2). Preference for bitter and sweet tastants also was assessed in wild-type and MT1 and MT2 DM mice. Finally, home cage locomotor monitoring was performed to determine the effect of melatonin administration on activity patterns.
  
  
  RESULTS
  Supplemental melatonin in drinking water significantly reduced free-choice nicotine consumption in C57BL/6J mice, which do not produce endogenous melatonin, while not altering activity patterns. Independently, genetic deletion of both MT1 and MT2 receptors in a melatonin-proficient mouse strain (C3H) resulted in significantly more nicotine consumption than controls. However, single genetic deletion of either the MT1 or MT2 receptor alone did not result in increased nicotine consumption. Deletion of MT1 and MT2 did not impact taste preference.
  
  
  CONCLUSIONS
  This study demonstrates that nicotine consumption can be affected by exogenous or endogenous melatonin and requires at least one of the high-affinity melatonin receptors. The fact that expression of either the MT1 or MT2 melatonin receptor is sufficient to maintain lower nicotine consumption suggests functional overlap and potential mechanistic explanations.
authors.affiliation: Institute for Behavioral Genetics, University of Colorado, 1480 30th Street, Boulder, CO, 80303, USA.
authors.forename: William J
authors.initials: WJ
authors.lastname: Horton
authors.forename: Hannah J
authors.initials: HJ
authors.lastname: Gissel
authors.forename: Jennifer E
authors.initials: JE
authors.lastname: Saboy
authors.forename: Kenneth P
authors.initials: KP
authors.lastname: Wright
authors.forename: Jerry A
authors.initials: JA
authors.lastname: Stitzel
mesh_terms: D000818:Animals; D002755:Choice Behavior / Q000187:drug effects; D002940:Circadian Rhythm / Q000187:drug effects; D004326:Drinking; D008297:Male; D008550:Melatonin / Q000172:deficiency / Q000494:pharmacology*; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009043:Motor Activity / Q000187:drug effects; D009538:Nicotine / Q000494:pharmacology*; D018722:Nicotinic Agonists / Q000494:pharmacology*; D044122:Receptor, Melatonin, MT1 / Q000235:genetics; D044094:Receptors, Melatonin / Q000187:drug effects* / Q000235:genetics; D013649:Taste / Q000187:drug effects
chemical_list: D018722:Nicotinic Agonists; D044122:Receptor, Melatonin, MT1; D044094:Receptors, Melatonin; D009538:Nicotine; D008550:Melatonin