title: Chronic nicotine pretreatment is sufficient to upregulate α4* nicotinic receptors and increase oral nicotine self-administration in mice.
abstract: BACKGROUND
  Understanding the underlying causes of nicotine addiction will require a multidisciplinary approach examining the key molecular, cellular and neuronal circuit functional changes that drive escalating levels of nicotine self-administration. In this study, we examined whether mice pretreated with chronic nicotine, at a dosing regimen that results in maximal nicotinic acetylcholine receptor (nAChR) upregulation, would display evidence of nicotine-dependent behaviour during nicotine self-administration.
  
  
  RESULTS
  We investigated oral self-administration of nicotine using a two-bottle choice paradigm in which one bottle contained the vehicle (saccharine-sweetened water), while the other contained nicotine (200 μg/ml) in vehicle. Knock-in mice with YFP-tagged α4 nAChR subunits (α4YFP) were implanted with osmotic pumps delivering either nicotine (2 mg/kg/hr) or saline for 10 days. After 10 days of pretreatment, mice were exposed to the nicotine self-administration paradigm, consisting of four days of choice followed by three days of nicotine abstinence repeated for five weeks. Mice pre-exposed to nicotine had upregulated α4YFP nAChR subunits in the hippocampal medial perforant path and on ventral tegmental area GABAergic neurons as compared to chronic saline mice. Compared to control saline-pretreated mice, in a two bottle-choice experiment, nicotine-primed mice ingested a significantly larger daily dose of nicotine and also exhibited post-abstinence binge drinking of nicotine.
  
  
  CONCLUSIONS
  Chronic forced pre-exposure of nicotine is sufficient to induce elevated oral nicotine intake and supports the postulate that nAChR upregulation may be a key factor influencing nicotine self-administration.
authors.forename: Anthony
authors.initials: A
authors.lastname: Renda
authors.affiliation: Department of Biology, University of Victoria, PO Box 3020, Station CSC, Victoria, BC V8W 3 N5, Canada. raad@uvic.ca.
authors.forename: Raad
authors.initials: R
authors.lastname: Nashmi
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001426:Bacterial Proteins / Q000235:genetics / Q000378:metabolism; D002755:Choice Behavior / Q000187:drug effects / Q000502:physiology; D004327:Drinking Behavior / Q000187:drug effects / Q000502:physiology; D059330:GABAergic Neurons / Q000187:drug effects / Q000502:physiology; D055879:Gene Knock-In Techniques; D006624:Hippocampus / Q000187:drug effects / Q000503:physiopathology; D008164:Luminescent Proteins / Q000235:genetics / Q000378:metabolism; D008297:Male; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009538:Nicotine / Q000008:administration & dosage*; D018722:Nicotinic Agonists / Q000008:administration & dosage*; D019580:Perforant Pathway / Q000187:drug effects / Q000503:physiopathology; D011978:Receptors, Nicotinic / Q000235:genetics / Q000378:metabolism*; D012439:Saccharin / Q000008:administration & dosage; D012646:Self Administration; D014029:Tobacco Use Disorder / Q000503:physiopathology; D015854:Up-Regulation / Q000187:drug effects; D017557:Ventral Tegmental Area / Q000187:drug effects / Q000503:physiopathology
chemical_list: D001426:Bacterial Proteins; D008164:Luminescent Proteins; D009538:Nicotine; D018722:Nicotinic Agonists; D011978:Receptors, Nicotinic; D012439:Saccharin; C054562:yellow fluorescent protein, Bacteria