Further pharmacological characterization of a preclinical model of the early development of nicotine withdrawal

Drug Alcohol Depend. 2021 Sep 1;226:108870. doi: 10.1016/j.drugalcdep.2021.108870. Epub 2021 Jun 25.


Background: Establishing preclinical models of the development of nicotine withdrawal following acute nicotine exposure could inform tobacco addiction-related research, treatment, and policy. To this end, this lab has previously reported that rats exhibit withdrawal-like elevations in intracranial self-stimulation (ICSS) thresholds (anhedonia-like behavior) following acute nicotine exposure. The goal of this study was to provide further pharmacological characterization of ICSS as a measure of spontaneous and antagonist-precipitated withdrawal from acute nicotine.

Methods and results: Rats exhibited a small increase in ICSS thresholds over time following a single nicotine injection (1.0 mg/kg, s.c.), suggesting a modest spontaneous withdrawal effect (Experiment 1). In Experiment 2, the antidepressant bupropion (5.0 mg/kg, i.p.), which is used to treat tobacco addiction and attenuates nicotine withdrawal in both humans and rodents, blocked elevations in ICSS thresholds induced by a single injection of nicotine (0.5 mg/kg, s.c.) followed ≈ 2 h later by the non-selective, non-competitive nicotinic acetylcholine receptor (nAChR) antagonist mecamylamine (3.0 mg/kg, s.c.). In Experiment 3a, s.c. administration of the competitive, relatively selective α4ß2 nAChR antagonist dihydro-beta-erythroidine (DHßE) (5.6 mg/kg, but not 3.0 mg/kg) following each of 5 daily injections of nicotine (0.5 mg/kg, s.c.) elevated ICSS thresholds. Mecamylamine (3.0 mg/kg, s.c.) also elevated ICSS thresholds when administered following all 5 daily nicotine injections (0.5 mg/kg, s.c., Experiment 3b).

Conclusions: These findings provide further characterization of elevations in ICSS thresholds as a measure of withdrawal from acute nicotine exposure. Further use of these models may be useful for understanding the early development of nicotine withdrawal.

Keywords: Bupropion; Dihydro-beta-erythroidine; Intracranial self-stimulation; Mecamylamine; Nicotine; Withdrawal.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Mecamylamine / pharmacology
  • Nicotine*
  • Nicotinic Antagonists / pharmacology
  • Rats
  • Self Stimulation
  • Substance Withdrawal Syndrome* / drug therapy


  • Nicotinic Antagonists
  • Mecamylamine
  • Nicotine