title: Effects of repeated withdrawal episodes, nicotine dose, and duration of nicotine exposure on the severity and duration of nicotine withdrawal in rats.
abstract: BACKGROUND
  The aversive aspects of nicotine withdrawal contribute to high relapse rates to tobacco smoking after cessation attempts.
  
  
  OBJECTIVE
  To investigate the influence of nicotine dose, duration of nicotine exposure, and withdrawal history on the severity of nicotine withdrawal in rats, as assessed by brain stimulation reward thresholds and somatic signs of withdrawal.
  
  
  METHODS
  Repeated spontaneous and precipitated withdrawals were investigated through four successive removals of osmotic minipumps delivering nicotine/saline, or with daily injections of the nicotinic receptor antagonist dihydro-beta-erythroidine during chronic nicotine/saline exposure, respectively. The effects of dose and duration of exposure were investigated using minipumps of varying duration delivering different nicotine doses.
  
  
  RESULTS
  Increased duration of nicotine exposure: a). prolonged the duration but did not alter the magnitude of withdrawal-associated threshold elevations; b). increased somatic signs early during withdrawal. Increased total nicotine exposure (i.e. increased dose and exposure duration) increased the duration of threshold elevations (no effect on magnitude) but had no effect on somatic signs. Neither repeated spontaneous nor repeated precipitated withdrawals altered the magnitude of withdrawal significantly.
  
  
  CONCLUSIONS
  Increases in total nicotine dose resulted in increased severity of the affective aspects of withdrawal. Further, continuous drug exposure resulted in longer lasting withdrawal than intermittent administration even when the total nicotine dose was the same. There was no correlation between threshold elevations and somatic signs of withdrawal. In conclusion, the severity of nicotine withdrawal is mitigated by characteristics of the drug exposure regimen such as drug dose, duration of exposure and whether exposure is continuous or intermittent.
authors.affiliation: Department of Neuropharmacology, CVN-7, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA.
authors.forename: Karen L
authors.initials: KL
authors.lastname: Skjei
authors.forename: Athina
authors.initials: A
authors.lastname: Markou
mesh_terms: D000818:Animals; D000697:Central Nervous System Stimulants / Q000008:administration & dosage / Q000009:adverse effects*; D004079:Dihydro-beta-Erythroidine / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D015918:Infusion Pumps, Implantable; D008297:Male; D009538:Nicotine / Q000008:administration & dosage / Q000009:adverse effects*; D018733:Nicotinic Antagonists / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D012201:Reward; D012653:Self Stimulation; D012684:Sensory Thresholds; D013375:Substance Withdrawal Syndrome / Q000523:psychology*
chemical_list: D000697:Central Nervous System Stimulants; D018733:Nicotinic Antagonists; D004079:Dihydro-beta-Erythroidine; D009538:Nicotine