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.
Key words
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Article info
Publication history
Accepted:
August 19,
2004
Received in revised form:
August 12,
2004
Received:
April 26,
2004
Identification
Copyright
© 2004 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.
