Sex differences in cholinergic systems in the interpeduncular nucleus following nicotine exposure and withdrawal

Neuropharmacology. 2019 Nov 1:158:107714. doi: 10.1016/j.neuropharm.2019.107714. Epub 2019 Jul 17.


The medial habenula-interpeduncular nucleus (MHb-IPN) pathway modulates negative affective states produced by nicotine withdrawal. Sex differences in the contribution of acetylcholine (ACh) systems in this pathway have not been explored. Thus, this study assessed ACh levels and gene expression of α- and β-containing nicotinic acetylcholine receptor (nAChR) subunits in the IPN of female and male rats following nicotine treatment and withdrawal. Rats were prepared with a pump that delivered nicotine for 14 days, and naïve controls received a sham surgery. In Study 1, rats were prepared with a probe in the IPN, and ACh levels were measured following saline and then mecamylamine administration. In Study 2, separate groups of naïve control or nicotine-treated rats received saline or mecamylamine and physical signs and anxiety-like behavior were assessed using elevated plus maze (EPM) procedures. The IPN was then dissected and mRNA levels were assessed using RT-qPCR methods. Nicotine treatment increased ACh levels to a larger extent in females than males. Nicotine withdrawal produced a similar increase in physical signs; however, females displayed greater anxiety-like behavior than males. In females, gene expression of α5 increased following nicotine treatment and withdrawal. In males, α7 increased following nicotine treatment and α2 and α3 increased during nicotine withdrawal. Both females and males displayed an increase in β3 and β4 during nicotine withdrawal. In females, anxiety-like behavior was correlated with α4, α5, and β2 gene expression in the IPN. These results suggest that sex differences in withdrawal are modulated via cholinergic systems in the IPN.

Keywords: Acetylcholine; Female; Male; Rat; Sex differences; nAChR.

Publication types

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

MeSH terms

  • Animals
  • Anxiety / genetics*
  • Behavior, Animal / drug effects
  • Female
  • Gene Expression / drug effects
  • Interpeduncular Nucleus / drug effects*
  • Interpeduncular Nucleus / metabolism
  • Male
  • Mecamylamine / pharmacology
  • Nicotine / pharmacology*
  • Nicotinic Agonists / pharmacology*
  • Nicotinic Antagonists / pharmacology
  • RNA, Messenger / drug effects*
  • RNA, Messenger / metabolism
  • Rats
  • Receptors, Nicotinic / drug effects*
  • Receptors, Nicotinic / genetics
  • Sex Factors
  • Substance Withdrawal Syndrome / genetics*
  • alpha7 Nicotinic Acetylcholine Receptor / drug effects
  • alpha7 Nicotinic Acetylcholine Receptor / genetics


  • Chrna5 protein, rat
  • Chrna7 protein, rat
  • Nicotinic Agonists
  • Nicotinic Antagonists
  • RNA, Messenger
  • Receptors, Nicotinic
  • alpha7 Nicotinic Acetylcholine Receptor
  • nicotinic acetylcholine receptor alpha4 subunit
  • Mecamylamine
  • Nicotine