Self-administration of cotinine in Wistar rats: Comparisons to nicotine

Nicotine is the major addictive component in tobacco. Cotinine is the major metabolite of nicotine and a weak agonist for nicotinic acetylcholine receptors (nAChRs). Nicotine supports self-administration in rodents. However, it remains undetermined whether cotinine can be self-administered. This study aimed to characterize cotinine self-administration in rats, to compare effects of cotinine to those of nicotine, and to determine potential involvement of nAChRs in cotinine's effects. Adult Wistar rats were trained to self-administer cotinine or nicotine (0.0075, 0.015, 0.03, or 0.06 mg/kg per infusion) under fixed-ratio (FR) and progressive-ratio (PR) schedules. Blood nicotine and cotinine levels were determined after the last FR session. Effects of mecamylamine, a nonselective nAChR antagonist, and varenicline, a partial agonist for a4b2* nAChRs, on cotinine and nicotine self-administration were determined. Rats readily acquired cotinine self-administration, responded more on active lever, and increased motivation to self-administer cotinine when the reinforcement requirement increased. Blood cotinine levels ranged from 77 to 792 ng/ml. Nicotine induced more infusions at lower doses during FR schedules and greater breakpoints at higher doses during the PR schedule than cotinine. There was no difference in cotinine self-administration between male and female rats. Mecamylamine and varenicline attenuated nicotine but not cotinine self-administration. These results indicate that cotinine was self-administered by rats. These effects of cotinine were less robust than nicotine and exhibited no sex difference. nAChRs appeared to be differentially involved in self-administration of nicotine and cotinine. These results suggest cotinine may play a role in the development of nicotine use and misuse.



Work Title Self-administration of cotinine in Wistar rats: Comparisons to nicotine
Open Access
  1. Zheng Ming Ding
  2. Yong Gao
  3. Alena M. Sentir
  4. Xiaoying Tan
License In Copyright (Rights Reserved)
Work Type Article
  1. Journal of Pharmacology and Experimental Therapeutics
Publication Date March 1, 2021
Publisher Identifier (DOI)
Deposited November 16, 2021




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Work History

Version 1

  • Created
  • Added Ding-COT_IVSA.pdf
  • Added Creator Zheng Ming Ding
  • Added Creator Yong Gao
  • Added Creator Alena M. Sentir
  • Added Creator Xiaoying Tan
  • Published
  • Updated
  • Updated
  • Updated