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 (α4β2-selective agonist), PNU-282987 (α7-selective agonist), mecamylamine (non-selective antagonist), dihydro-β-erythroidine (DHβE; α4β2-selective antagonist), methyllycaconitine (MLA; α7-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 α4β2 or α7 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 α4β2 and/or α7 nAChRs induced antidepressant-like effects in mice. A strategy involving antagonism of central nAChRs could potentially lead to the development of novel antidepressant therapeutics.
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