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

Department of Affective Disorders, Neurosearch A/S, Ballerup, Denmark JTA{at}Neurosearch.dk

GM Olsen

Department of Inflammatory Disease, Neurosearch A/S, Ballerup, Denmark

O Wiborg

Department of Biological Psychiatry, Psychiatric Hospital, Aarhus, Denmark

JP Redrobe

Department of Affective Disorders, Neurosearch A/S, Ballerup, Denmark

Abstract

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 (4β2-selective agonist), PNU-282987 (7-selective agonist), mecamylamine (non-selective antagonist), dihydro-β-erythroidine (DHβE; 4β2-selective antagonist), methyllycaconitine (MLA; 7-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 4β2 or 7 nAChRs with DHβE 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 4β2 and/or 7 nAChRs induced antidepressant-like effects in mice. A strategy involving antagonism of central nAChRs could potentially lead to the development of novel antidepressant therapeutics.

Key Words: nicotinic receptors • agonists • antagonists • depression • mice • forced swim test • tail suspension test

This version was published on September 1, 2009

Journal of Psychopharmacology, Vol. 23, No. 7, 797-804 (2009)
DOI: 10.1177/0269881108091587


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