Antidepressant-like effects of nicotinic acetylcholine receptor antagonists, but not agonists, in the mouse forced swim and mouse tail suspension tests

J Psychopharmacol. 2009 Sep;23(7):797-804. doi: 10.1177/0269881108091587. Epub 2008 Jun 26.


Current literature suggests involvement of nicotinic acetylcholine receptors (nAChRs) in major depression. However, it is controversial whether the antidepressant-like effect of nAChR modulation is induced by activation, desensitization or inhibition of central nAChRs. In addition, the specific nAChR subtype/s involved remains unknown. In this study, we systematically compared the effects of non-selective and selective nicotinic agonists and antagonists in two different tests for antidepressant effects in mice: the tail suspension test and the forced swim test. Compounds: nicotine, RJR-2403 (alpha4beta2-selective agonist), PNU-282987 (alpha7-selective agonist), mecamylamine (non-selective antagonist), dihydro-beta-erythroidine (DHbetaE; alpha4beta2-selective antagonist), methyllycaconitine (MLA; alpha7-selective antagonist) and hexamethonium (non-brain-penetrant non-selective antagonist). All compounds were tested in a locomotor activity paradigm to rule out non-specific stimulant effects. The data show that blockade of nAChRs with mecamylamine, or selective antagonism of alpha4beta2 or alpha7 nAChRs with DHbetaE or MLA, respectively, has antidepressant-like effects. These effects were not confounded by motor stimulation. Hexamethonium did not show antidepressant-like activity, supporting the involvement of central nAChRs. At the dose levels tested, none of the nAChR agonists displayed antidepressant-like profiles. In conclusion, antagonism of central alpha4beta2 and/or alpha7 nAChRs induced antidepressant-like effects in mice. A strategy involving antagonism of central nAChRs could potentially lead to the development of novel antidepressant therapeutics.

Publication types

  • Comparative Study

MeSH terms

  • Animals
  • Antidepressive Agents / pharmacology*
  • Behavior, Animal / drug effects*
  • Citalopram / pharmacology
  • Depression / drug therapy
  • Disease Models, Animal
  • Female
  • Mice
  • Mice, Inbred Strains
  • Morpholines / pharmacology
  • Motor Activity / drug effects*
  • Nicotinic Agonists / pharmacology*
  • Nicotinic Agonists / therapeutic use
  • Nicotinic Antagonists / pharmacology*
  • Nicotinic Antagonists / therapeutic use
  • Reboxetine


  • Antidepressive Agents
  • Morpholines
  • Nicotinic Agonists
  • Nicotinic Antagonists
  • Citalopram
  • Reboxetine