title: A lack of association between severity of nicotine withdrawal and individual differences in compensatory nicotine self-administration in rats.
abstract: BACKGROUND
  Compensatory smoking may represent an adverse consequence of smoking reduction or the use of reduced-nicotine tobacco products. Factors contributing to individual variability in compensation are poorly understood.
  
  
  OBJECTIVE
  The objective of this study was to examine whether severity of nicotine withdrawal as measured by elevated intracranial self-stimulation (ICSS) thresholds is related to individual differences in compensatory nicotine self-administration (NSA) following unit dose reduction.
  
  
  METHODS
  Rats were trained for ICSS and NSA (0.06 mg/kg per infusion). After stabilization, effects of reducing the nicotine unit dose to 0.03 mg/kg per infusion were examined. Following reacquisition of NSA (0.06 mg/kg per infusion), effects of antagonist-precipitated withdrawal and saline extinction (spontaneous withdrawal) were examined.
  
  
  RESULTS
  Reducing the NSA unit dose produced partial compensation as indicated by the increased infusion rates, but a 35% mean decrease in daily nicotine intake. The magnitude of compensation varied considerably among rats. Dose reduction did not elicit withdrawal in rats as a group, although there were substantial increases in ICSS thresholds in some animals. Intracranial self-stimulation thresholds were consistently elevated during precipitated and spontaneous withdrawal, confirming that rats were nicotine-dependent. Individual differences in compensation were not correlated with changes in ICSS thresholds during dose reduction, precipitated withdrawal, or spontaneous withdrawal. In a secondary analysis, greater precipitated withdrawal severity predicted greater initial nicotine seeking during extinction.
  
  
  CONCLUSIONS
  Severity of nicotine withdrawal was not related to the degree of compensation in this protocol. These data do not support a role for nicotine withdrawal in individual differences in compensation during reduced nicotine exposure, but do suggest that withdrawal may contribute to nicotine seeking during early abstinence.
authors.affiliation: Minneapolis Medical Research Foundation, 914 South 8th Street, S-3 Labs, 860, Minneapolis, MN 55404, USA. harr0547@umn.edu
authors.forename: Andrew C
authors.initials: AC
authors.lastname: Harris
authors.forename: Paul R
authors.initials: PR
authors.lastname: Pentel
authors.forename: Danielle
authors.initials: D
authors.lastname: Burroughs
authors.forename: Mylissa D
authors.initials: MD
authors.lastname: Staley
authors.forename: Mark G
authors.initials: MG
authors.lastname: Lesage
mesh_terms: D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D003216:Conditioning, Operant / Q000187:drug effects; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004567:Electrodes, Implanted; D005108:Extinction, Psychological / Q000187:drug effects*; D015918:Infusion Pumps, Implantable; D008297:Male; D009538:Nicotine / Q000008:administration & dosage* / Q000009:adverse effects*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012646:Self Administration; D012684:Sensory Thresholds / Q000187:drug effects; D013375:Substance Withdrawal Syndrome / Q000523:psychology*
chemical_list: D009538:Nicotine