The nicotinic antagonist mecamylamine has antidepressant-like effects in wild-type but not β2- or α7-nicotinic acetylcholine receptor subunit knockout mice
Abstract
Rationale Increases in cholinergic transmission are linked to depression in human subjects and animal models. We therefore examined the effect of decreasing nicotinic acetylcholine receptor (nAChR) activity in tests of antidepressant efficacy using C57BL/6J mice.Objectives We determined whether the noncompetitive nAChR antagonist mecamylamine had antidepressant-like effects in the forced swim test (FST) and tail suspension test (TST). These experiments were repeated in mice lacking either the beta2- or alpha7-nAChR subunits to identify the nAChR subunits involved in mediating the antidepressant response to mecamylamine.Materials and methods Adult mice on the C57BL/6J background were acutely administered mecamylamine i.p. 30 min before testing in the FST or TST.Results A dose-response study showed that mecamylamine significantly decreased immobility time in the TST at the 1.0-mg/kg dose but did not alter baseline locomotor activity. The competitive nAChR antagonist dihydro-beta-erythroidine, but not the blood-brain barrier impermeant antagonist hexamethonium, also decreased immobility in the TST. One milligram per kilogram of mecamylamine also significantly decreased time immobile in the FST whereas both beta2- and alpha7-knockout mice were insensitive to the effects of mecamylamine in the FST.Conclusions Decreased activity of central nAChRs has antidepressant-like effects in both the TST and FST and these effects are dependent on both beta2 and alpha7 subunits. Therefore, compounds that decrease nAChR activity may be attractive new candidates for development as antidepressants in humans.
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Mice lacking the α7 nAChR subunit are resistant to the antidepressant-like effects of mecamylamine.
“mice lacking the α7 subunit are also resistant to the antidepressant-like effects of mecamylamine (Rabenstein et al. 2006)”
From Mechanisms of Nicotine Addiction (2021) · cites this paper as Rabenstein et al. 2006
Mecamylamine has antidepressant-like effects in mice.
“the nicotinic antagonist mecamylamine has antidepressantlike effects in mice (Caldarone et al. 2004;Rabenstein et al. 2006;Andreasen et al. 2009)”
From Mechanisms of Nicotine Addiction (2021) · cites this paper as Rabenstein et al. 2006
KO mice lacking the α7 subunit do not respond to mecamylamine in mouse models of antidepressant response.
“like mice lacking the β2 nAChR subunit, KO mice lacking the α7 subunit also do not respond to the broad spectrum nAChR antagonist mecamylamine in mouse models of antidepressant response (Rabenstein et al., 2006).”
From It is not “either/or”: Activation and desensitization of nicotinic acetylcholine receptors both contribute to behaviors related to nicotine addiction and mood (2008) · cites this paper as Rabenstein et al., 2006
Mecamylamine and DhβE have antidepressant-like properties in mice.
“Mecamylamine and the competitive nicotinic antagonist DhβE also have antidepressant-like properties in mice (Caldarone et al., 2004; Mineur et al., 2007; Rabenstein et al., 2006).”
From It is not “either/or”: Activation and desensitization of nicotinic acetylcholine receptors both contribute to behaviors related to nicotine addiction and mood (2008) · cites this paper as Rabenstein et al., 2006
The α4/β2* subclass of nAChRs is necessary for the antidepressant-like effects of nicotinic antagonists.
“the α4/β2* subclass of nAChRs is necessary for the antidepressant-like effects of nicotinic antagonists as demonstrated in KO mice and using selective pharmacological agents (Gatto et al., 2004; Mineur et al., 2007; Rabenstein et al., 2006).”
From It is not “either/or”: Activation and desensitization of nicotinic acetylcholine receptors both contribute to behaviors related to nicotine addiction and mood (2008) · cites this paper as Rabenstein et al., 2006
The effect of nAChR antagonism appears to be centrally mediated.
“The effect of nAChR antagonism appears to be centrally mediated since unlike the permeant antagonist mecamylamine, hexamethonium, a nicotinic antagonist that does not cross the blood-brain barrier, did not result in a significant antidepressant-like response in mice (Rabenstein et al., 2006).”
From It is not “either/or”: Activation and desensitization of nicotinic acetylcholine receptors both contribute to behaviors related to nicotine addiction and mood (2008) · cites this paper as Rabenstein et al., 2006
KO mice lacking the β2* subunit show decreased depression-like behavior in the forced swim and tail suspension tests at baseline.
“at baseline, KO mice lacking the β2* subunit show decreased depression-like behavior in the forced swim and tail suspension tests at baseline, supporting the possibility that the β2 KO mimics the effect of nAChR blockade (Caldarone et al., 2004; Rabenstein et al., 2006).”
From It is not “either/or”: Activation and desensitization of nicotinic acetylcholine receptors both contribute to behaviors related to nicotine addiction and mood (2008) · cites this paper as Rabenstein et al., 2006
In FST and TST, acute nicotinic antagonists like mecamylamine, unlike acute nicotine, yield antidepressant-like effects.
“Acute treatment with nicotinic antagonists, such as mecamylamine, but not acute nicotine, results in antidepressant-like effects in the forced swim test (FST) and the tail suspension test (TST) (Caldarone et al., 2004;Rabenstein et al., 2006).”
From Nicotinic Partial Agonists Varenicline and Sazetidine-A Have Differential Effects on Affective Behavior (2010) · cites this paper as Rabenstein et al., 2006
Mice lacking the β2-nAChR subunit are insensitive to the antidepressant-like effects of mecamylamine and amitriptyline.
“However, mice lacking the β2-nAChR subunit are insensitive to the antidepressant-like effects of mecamylamine (15) and amitriptyline (18).”
From Persistent β <sub>2</sub> *-Nicotinic Acetylcholinergic Receptor Dysfunction in Major Depressive Disorder (2012) · cites this paper as [15]
Nicotine binds to neuronal nAChRs and partial agonists and antagonists of nAChRs including nicotine, mecamylamine, DHβE, cytisine and varenicline have antidepressant-like effects in preclinical studies.
“Furthermore, nicotine binds to neuronal nicotinic acetylcholine receptors (nAChRs) and partial agonists and antagonists of nAChRs including nicotine (14), mecamylamine and dihydro-beta-erythroidine (DHβE) (15), cytisine (16) and varenicline (17), have antidepressant-like effects in preclinical studies.”
From Persistent β <sub>2</sub> *-Nicotinic Acetylcholinergic Receptor Dysfunction in Major Depressive Disorder (2012) · cites this paper as [15]
Preclinical studies in the forced swim test and tail suspension test have demonstrated antidepressant-like activity of mecamylamine and the selective α4β2 nicotinic acetylcholine receptor partial agonists cytisine and ispronicline.
“Preclinical studies in the forced swim test and the tail suspension test, established mouse models of antidepressant efficacy, have demonstrated antidepressant-like activity of the non-selective nicotinic acetylcholine receptor antagonist mecamylamine and the selective α4β2 nicotinic acetylcholine receptor partial agonists, cytisine (Caldarone et al., 2004; Rabenstein et al., 2006; Mineur et al.,”
From Varenicline has antidepressant-like activity in the forced swim test and augments sertraline's effect (2009) · cites this paper as Rabenstein et al., 2006
The present results are in agreement with previous reports that both nicotinic acetylcholine receptor antagonists and partial agonists show antidepressant-like efficacy in animal depression models and can also increase antidepressant activity when co-administered with classic antidepressants such as SSRIs or tricyclic antidepressants.
“The present results are in agreement with previous reports that both nicotinic acetylcholine receptor antagonists and partial agonists show antidepressant-like efficacy in animal depression models and can also increase antidepressant activity when co-administered with classic antidepressants such as SSRIs or tricyclic antidepressants (Caldarone et al., 2004; Rabenstein et al., 2006; Mineur et al.,”
From Varenicline has antidepressant-like activity in the forced swim test and augments sertraline's effect (2009) · cites this paper as Rabenstein et al., 2006
The α4β2 selective high-affinity nAChR antagonist DHβE decreases immobility in the forced swim test and tail-suspension test.
“an α4β2 selective high-affinity nAChR antagonist, DHβE, has been found to decrease immobility in the FST and tail-suspension test (Andreasen, Olsen, Wiborg, & Redrobe, 2009; Rabenstein et al., 2006).”
From Nicotine addiction and psychiatric disorders (2015) · cites this paper as Rabenstein et al., 2006
Mecamylamine has antidepressant-like effects in the forced swim test and tail-suspension test in wild-type but not β2 knockout animals.
“mecamylamine, a nonselective nAChR antagonist, has similar antidepressant-like effects in the FST and tail-suspension test in wild-type but not in β2 KO animals (Andreasen, Nielsen, & Redrobe, 2009; Caldarone et al., 2004; Rabenstein, Caldarone, & Picciotto, 2006).”
From Nicotine addiction and psychiatric disorders (2015) · cites this paper as Rabenstein et al., 2006
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- Authors
- Rabenstein, R. L., Caldarone, B. J., & Picciotto, M. R.
- Affiliations
- Yale University (US)
- Corresponding author
- Picciotto, M. R.
- Venue
- Psychopharmacology
- Published
- 2006-10-03
- Volume
- 189
- Issue
- 3
- Pages
- 395-401
- ISSN
- 0033-3158 (ISSN-L)
- 1432-2072
- OpenAlex
- W2043809720
- Cited by
- 129
- References
- 43
- Citations by year
- 2026: 5 · 2025: 1 · 2024: 4 · 2023: 3 · 2022: 2 · 2021: 5 · 2020: 6 · 2019: 3 · 2018: 5 · 2017: 1 · 2016: 5 · 2015: 7 · 2014: 12 · 2013: 7 · 2012: 11
- FWCI
- 3.94
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Psychopharmacology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Alliance for Research on Schizophrenia and Depression
- National Institutes of Health
- National Institute on Alcohol Abuse and Alcoholism (P50AA015632, DA13334/AA15632)
- National Institute of Mental Health (MH77681, R01MH077681)
- National Institute on Drug Abuse (DA 00436, P50DA013334)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Nicotinic Acetylcholine Receptors Study
- Health Sciences › Medicine › Pharmacology › Treatment of Major Depression
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Keywords
- mecamylamine, nicotinic acetylcholine receptors, antidepressant-like effects, knockout mice, forced swim test, tail suspension test, immobility time, dihydro-beta-erythroidine, hexamethonium, cholinergic neurotransmission, depression, nAChR antagonists
- MeSH terms
- Animals, Antidepressive Agents, Female, Male, Mecamylamine, Mice, Inbred C57BL, Motor Activity, Receptors, Nicotinic, Mice, Knockout, Nicotinic Antagonists, Hindlimb Suspension, Mice, alpha7 Nicotinic Acetylcholine Receptor
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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