High-affinity nicotinic acetylcholine receptors are required for antidepressant effects of amitriptyline on behavior and hippocampal cell proliferation

Biol Psychiatry. 2004 Nov 1;56(9):657-64. doi: 10.1016/j.biopsych.2004.08.010.


Background: A wide variety of antidepressants act as noncompetitive antagonists of nicotinic acetylcholine receptors (nAChRs), but the relationship between this antagonism and the therapeutic effects of antidepressants is unknown.

Methods: Antidepressant properties of the noncompetitive nAChR antagonist mecamylamine in the forced swim test were tested alone and in combination with the tricyclic antidepressant amitriptyline. Mice lacking high-affinity nAChRs were tested in three behavioral models to determine whether these receptors are required for behavioral effects of amitriptyline in common models of antidepressant action. Finally, the brains of wild-type and knockout animals treated with amitriptyline were examined to determine whether high-affinity nAChRs are required for antidepressant-induced increases in hippocampal cell proliferation.

Results: Inhibition of nAChRs by mecamylamine had antidepressant-like effects in the forced swim test and potentiated the antidepressant activity of amitriptyline when the two drugs were used in combination. Mice lacking high-affinity nAChRs showed no behavioral response to amitriptyline. Finally, after chronic treatment with amitriptyline, nAChR knockout mice did not show the increase in hippocampal cell proliferation seen in wild-type mice.

Conclusions: These data support the hypothesis that antagonism of nAChRs is an essential component of the therapeutic action of antidepressants.

Publication types

  • Comparative Study
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Amitriptyline / administration & dosage*
  • Amitriptyline / blood
  • Analysis of Variance
  • Animals
  • Antidepressive Agents, Tricyclic / administration & dosage*
  • Antidepressive Agents, Tricyclic / blood
  • Behavior, Animal / drug effects*
  • Bromodeoxyuridine / metabolism
  • Cell Count
  • Cell Proliferation / drug effects*
  • Dose-Response Relationship, Drug
  • Drosophila Proteins
  • Drug Interactions
  • Helplessness, Learned
  • Hindlimb Suspension / methods
  • Hippocampus / cytology*
  • Immunohistochemistry / methods
  • Mecamylamine / pharmacology
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Neurons / cytology
  • Neurons / drug effects*
  • Nicotinic Antagonists / pharmacology
  • Nortriptyline / blood
  • Nortriptyline / pharmacology
  • Receptors, Nicotinic / deficiency
  • Receptors, Nicotinic / physiology*
  • Swimming / physiology


  • Antidepressive Agents, Tricyclic
  • Drosophila Proteins
  • Nicotinic Antagonists
  • Receptors, Nicotinic
  • nicotinic acetylcholine receptor alpha-subunits, Drosophila
  • Amitriptyline
  • Mecamylamine
  • Nortriptyline
  • Bromodeoxyuridine