Differential effects of withdrawal from intermittent and continuous nicotine exposure on reward deficit and somatic aspects of nicotine withdrawal and expression of α4β2* nAChRs in Wistar male rats

Pharmacol Biochem Behav. 2018 Aug:171:54-65. doi: 10.1016/j.pbb.2018.06.002. Epub 2018 Jun 14.


Background: Chronic nicotine exposure produces neuroadaptations in brain reward systems and α4β2 nicotinic acetylcholine receptors (nAChRs) in the corticolimbic brain areas. We previously demonstrated opposite effects of nicotine exposure delivered by self-administration or pumps on brain reward thresholds that can be attributed to the different temporal pattern and contingency of nicotine exposure. We investigated the effects of these two factors on reward thresholds and somatic signs during nicotine withdrawal, and on nAChRs binding in corticolimbic brain areas.

Methods: The intracranial self-stimulation procedure was used to assess reward thresholds in rats prepared with pumps delivering various doses of nicotine continuously or intermittently. Separate group of rats were randomly exposed to nicotine via pumps (non-contingent) or nicotine self-administration (contingent) to determine [125I]-epibatidine binding at α4β2* nAChRs.

Results: Withdrawal from continuous non-contingent nicotine exposure led to significant elevations in thresholds and increases in somatic signs in rats, while there was no significant effect of withdrawal from intermittent non-contingent nicotine exposure at the same doses. nAChRs were upregulated during withdrawal from continuous non-contingent nicotine exposure. α4β2* nAChRs were upregulated in the ventral tegmental area and prelimbic cortex during withdrawal from non-contingent intermittent exposure and in the nucleus accumbens during withdrawal from contingent intermittent nicotine exposure to the same dose.

Conclusions: During non-contingent nicotine exposure, the temporal pattern of nicotine delivery differentially affected thresholds and somatic signs of withdrawal. Upregulation of α4β2* nAChRs was brain site-specific and depended on both temporal pattern and contingency of nicotine exposure.

Keywords: Cotinine; Intracranial self-stimulation; Reward thresholds; Somatic signs; α4β2* nicotinic acetylcholine receptors.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Autoantigens
  • Bridged Bicyclo Compounds, Heterocyclic / metabolism
  • Drug Administration Schedule
  • Infusion Pumps, Implantable
  • Iodine Radioisotopes / metabolism
  • Limbic Lobe / metabolism
  • Male
  • Nicotine / administration & dosage
  • Nicotine / adverse effects*
  • Nucleus Accumbens / metabolism
  • Pyridines / metabolism
  • Radioligand Assay
  • Rats
  • Rats, Wistar
  • Receptors, Nicotinic / metabolism*
  • Reward*
  • Substance Withdrawal Syndrome / diagnosis*
  • Substance Withdrawal Syndrome / metabolism*
  • Up-Regulation
  • Ventral Tegmental Area / metabolism


  • Autoantigens
  • Bridged Bicyclo Compounds, Heterocyclic
  • Iodine Radioisotopes
  • Pyridines
  • Receptors, Nicotinic
  • nicotinic receptor alpha4beta2
  • Nicotine
  • epibatidine