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

Caldarone, Barbara J, Harrist, Alexia, Cleary, Muriel A, Beech, Robert D, King, Sarah L and Picciotto, Marina R (2004) High-affinity nicotinic acetylcholine receptors are required for antidepressant effects of amitriptyline on behavior and hippocampal cell proliferation. Biological Psychiatry, 56 (9). pp. 657-664. ISSN 0006-3223

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Abstract

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.

Item Type: Article
Additional Information: Worked with first author to develop protocol and instrumentation to run the behavioural assays.
Schools and Departments: School of Psychology > Psychology
Subjects: B Philosophy. Psychology. Religion > BF Psychology
R Medicine > RM Therapeutics. Pharmacology
Related URLs:
Depositing User: Sarah King - Psychology
Date Deposited: 06 Feb 2012 15:37
Last Modified: 26 Apr 2012 14:20
URI: http://sro.sussex.ac.uk/id/eprint/13610
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