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

Jesper Andreasen T.; G M Olsen; O Wiborg; J P Redrobe

doi:10.1177/0269881108091587

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

Jesper Andreasen T., G M Olsen, O Wiborg, J P Redrobe

82 Citations (Scopus)

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.

Original language	English
Journal	Journal of Psychopharmacology
Volume	23
Issue number	7
Pages (from-to)	797-804
Number of pages	8
ISSN	0269-8811
DOIs	https://doi.org/10.1177/0269881108091587
Publication status	Published - 1 Sept 2009

Keywords

Animals
Antidepressive Agents
Behavior, Animal
Citalopram
Depression
Disease Models, Animal
Female
Mice
Mice, Inbred Strains
Morpholines
Motor Activity
Nicotinic Agonists
Nicotinic Antagonists

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10.1177/0269881108091587

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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.",

keywords = "Animals, Antidepressive Agents, Behavior, Animal, Citalopram, Depression, Disease Models, Animal, Female, Mice, Mice, Inbred Strains, Morpholines, Motor Activity, Nicotinic Agonists, Nicotinic Antagonists",

author = "{Andreasen T.}, Jesper and Olsen, {G M} and O Wiborg and Redrobe, {J P}",

year = "2009",

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volume = "23",

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TY - JOUR

T1 - Antidepressant-like effects of nicotinic acetylcholine receptor antagonists, but not agonists, in the mouse forced swim and mouse tail suspension tests

AU - Andreasen T., Jesper

AU - Olsen, G M

AU - Wiborg, O

AU - Redrobe, J P

PY - 2009/9/1

Y1 - 2009/9/1

N2 - 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.

AB - 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.

KW - Animals

KW - Antidepressive Agents

KW - Behavior, Animal

KW - Citalopram

KW - Depression

KW - Disease Models, Animal

KW - Female

KW - Mice

KW - Mice, Inbred Strains

KW - Morpholines

KW - Motor Activity

KW - Nicotinic Agonists

KW - Nicotinic Antagonists

U2 - 10.1177/0269881108091587

DO - 10.1177/0269881108091587

M3 - Journal article

C2 - 18583432

SN - 0269-8811

VL - 23

SP - 797

EP - 804

JO - Journal of Psychopharmacology

JF - Journal of Psychopharmacology

IS - 7

ER -

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

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Keywords

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