Differential antagonism and tolerance/cross-tolerance among nicotinic acetylcholine receptor agonists: Scheduled-controlled responding and hypothermia in C57BL/6J mice

Fernando B. De Moura, Lance R. McMahon

Research output: Contribution to journalArticlepeer-review

6 Scopus citations

Abstract

The tobacco-dependence pharmacotherapies varenicline and cytisine act as partial α4β2 nAChR agonists. However, the extent to which α4β2 nicotinic acetylcholine receptors (nAChRs) mediate their in-vivo effects remains unclear. Nicotine, varenicline, cytisine, and epibatidine were studied in male C57BL/6J mice for their effects on rates of fixed ratio responding and rectal temperature alone and in combination with the nonselective nAChR antagonist mecamylamine and the α4β2 nAChR antagonist dihydro-β-erythroidine. The effects of nicotine, varenicline, cytisine, epibatidine, and cocaine were assessed before and during chronic nicotine treatment. The rate-decreasing and hypothermic effects of nicotine, varenicline, cytisine, and epibatidine were antagonized by mecamylamine (1 mg/kg), but only the effects of nicotine and epibatidine were antagonized by dihydro-β-erythroidine (3.2 mg/kg). Chronic nicotine produced 4.7 and 5.1-fold rightward shifts in the nicotine dose-effect functions to decrease response rate and rectal temperature, respectively. Nicotine treatment decreased the potency of epibatidine to decrease response rate and rectal temperature 2.2 and 2.9-fold, respectively, and shifted the varenicline dose-effect functions 2.0 and 1.7-fold rightward, respectively. Cross-tolerance did not develop from nicotine to cytisine. These results suggest that the in-vivo pharmacology of tobacco cessation aids cannot be attributed to a single nAChR subtype; instead, multiple receptor subtypes differentially mediate their effects.

Original languageEnglish (US)
Pages (from-to)240-248
Number of pages9
JournalBehavioural pharmacology
Volume27
Issue number2-3
DOIs
StatePublished - Apr 2016

Keywords

  • Cross-tolerance
  • Cytisine
  • Dihydro-β-erythroidine
  • Epibatidine
  • Hypothermia
  • Mecamylamine
  • Nicotine
  • Simple-schedule responding
  • Tolerance
  • Varenicline

ASJC Scopus subject areas

  • Pharmacology
  • Psychiatry and Mental health

Fingerprint Dive into the research topics of 'Differential antagonism and tolerance/cross-tolerance among nicotinic acetylcholine receptor agonists: Scheduled-controlled responding and hypothermia in C57BL/6J mice'. Together they form a unique fingerprint.

Cite this