title: Antidepressant-like effects of nicotinic acetylcholine receptor antagonists, but not agonists, in the mouse forced swim and mouse tail suspension tests.
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 (alpha4beta2-selective agonist), PNU-282987 (alpha7-selective agonist), mecamylamine (non-selective antagonist), dihydro-beta-erythroidine (DHbetaE; alpha4beta2-selective antagonist), methyllycaconitine (MLA; alpha7-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 alpha4beta2 or alpha7 nAChRs with DHbetaE 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 alpha4beta2 and/or alpha7 nAChRs induced antidepressant-like effects in mice. A strategy involving antagonism of central nAChRs could potentially lead to the development of novel antidepressant therapeutics.
authors.affiliation: Department of Affective Disorders, Neurosearch A/S, Ballerup, Denmark. JTA@Neurosearch.dk
authors.forename: J T
authors.initials: JT
authors.lastname: Andreasen
authors.forename: G M
authors.initials: GM
authors.lastname: Olsen
authors.forename: O
authors.initials: O
authors.lastname: Wiborg
authors.forename: J P
authors.initials: JP
authors.lastname: Redrobe
mesh_terms: D000818:Animals; D000928:Antidepressive Agents / Q000494:pharmacology*; D001522:Behavior, Animal / Q000187:drug effects*; D015283:Citalopram / Q000494:pharmacology; D003863:Depression / Q000188:drug therapy; D004195:Disease Models, Animal; D005260:Female; D051379:Mice; D008815:Mice, Inbred Strains; D009025:Morpholines / Q000494:pharmacology; D009043:Motor Activity / Q000187:drug effects*; D018722:Nicotinic Agonists / Q000494:pharmacology* / Q000627:therapeutic use; D018733:Nicotinic Antagonists / Q000494:pharmacology* / Q000627:therapeutic use; D000077593:Reboxetine
chemical_list: D000928:Antidepressive Agents; D009025:Morpholines; D018722:Nicotinic Agonists; D018733:Nicotinic Antagonists; D015283:Citalopram; D000077593:Reboxetine