Cytisine, a partial agonist of high-affinity nicotinic acetylcholine receptors, has antidepressant-like properties in male C57BL/6J mice
Open accessAbstract
The nicotine in tobacco is thought to modulate neuronal systems regulating mood. Moreover, it appears possible that blockade rather than activation of beta2-containing (beta2*) nicotinic acetylcholine receptors (nAChRs) may lead to antidepressant-like effects. We used cytisine, a partial agonist of alpha4/beta2*nAChRs and a full agonist at alpha3/beta4*nAChRs, in several tests of antidepressant efficacy. Further, we used c-fos expression to identify potential neurobiological correlates of the antidepressant-like effects of cytisine. Cytisine had antidepressant-like effects in several animal models of antidepressant efficacy. In addition, immunohistochemical analyses indicated that cytisine could reduce c-fos immunoreactivity in the basolateral amygdala by approximately 50%. These data show that cytisine acts like classical antidepressants in rodent models of antidepressant efficacy. In addition, cytisine's ability to block alpha4/beta2*nAChRs may be responsible for its antidepressant-like properties, and these may be mediated through a reduction of neuronal activity in the basolateral amygdala. These studies also suggest that both antagonists and partial agonists of alpha4/beta2*nAChRs would be interesting targets for the development of novel antidepressant drugs.
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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 Mineur et al., 2007
The Results (page not provided) report significantly reduced immobility after mecamylamine treatment in both the tail suspension and forced swim tests, supporting its antidepressant-like effects in mice. The passages from this paper do not report antidepressant-like effects of DhβE; a search for its full chemical name found no such result. (LLM, conf=0.90)
Experimental — accuracy not yet measuredThe 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 Mineur et al., 2007
The Discussion reports that β2-subunit knockout mice do not show mecamylamine’s antidepressant-like effects, citing Rabenstein et al. (2006). It also says cytisine’s blockade of α4/β2* receptors may be critical to its effect. Those passages support a role for these receptors, but this paper does not demonstrate that the α4/β2* subclass is necessary for nicotinic antagonists’ antidepressant-like effects; its conclusion is hedged, and its knockout evidence is reported from another study. (LLM, conf=0.86)
Experimental — accuracy not yet measuredNicotinic partial agonists are effective in mouse models of antidepressant efficacy.
“nicotinic partial agonists, that would be expected to decrease activity of acetylcholine at endogenous nAChRs when cholinergic tone is high but increase activity of nAChRs when cholinergic tone is low, are effective in mouse models of antidepressant efficacy (Mineur et al. 2007(Mineur et al. , 2009b(Mineur et al. , 2011a;;Rollema et al. 2009;Caldarone et al. 2011)”
From Mechanisms of Nicotine Addiction (2021) · cites this paper as Mineur et al. 2007
The nicotinic partial agonist cytisine results in antidepressant-like effects in several behavioral paradigms in mice.
“the nicotinic partial agonist cytisine results in antidepressant-like effects in several behavioral paradigms in mice (Mineur et al., 2007).”
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 Mineur et al., 2007
Mecamylamine and cytisine decrease c-fos immunoreactivity in the basolateral amygdala, indicating a reduction of neuronal activity in this region.
“Both mecamylamine and cytisine, in agreement with their antidepressant-like properties, decreased c-fos immunoreactivity in the basolateral amydgala, indicating a reduction of neuronal activity in this region (Mineur et al., 2007).”
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 Mineur et al., 2007
Cytisine shows antidepressant-like effects in both FST and TST.
“Cytisine, a nicotinic partial agonist, exhibits antidepressant-like activity in the FST and the TST, two tests sensitive to the effects of antidepressant compounds (Mineur et al., 2007(Mineur et al., , 2009)).”
From Nicotinic Partial Agonists Varenicline and Sazetidine-A Have Differential Effects on Affective Behavior (2010) · cites this paper as Mineur et al., 2007
Chronic, but not acute, cytisine treatment significantly reduced anxiety in the novelty-suppressed feeding paradigm.
“Mineur et al. (2007) found that chronic, but not acute, cytisine treatment significantly reduced anxiety in the NSF paradigm”
From Nicotinic Partial Agonists Varenicline and Sazetidine-A Have Differential Effects on Affective Behavior (2010) · cites this paper as Mineur et al., 2007
Varenicline might have additional potential benefits for cognitive function beyond those specific to nicotine withdrawal.
“Prior evidence for the cognitive enhancing effects of selective nAChR agonists suggests further that varenicline might have additional potential benefits in this area beyond those specific to nicotine withdrawal (52).”
From Varenicline improves mood and cognition during smoking abstinence (2009) · cites this paper as [52]
In rodents, decreasing ACh signaling through nAChRs depresses neuronal activity in the basolateral amygdala as measured by c-fos immunoreactivity.
“In rodents, decreasing ACh signaling through nAChRs depresses neuronal activity in the basolateral amygdala as measured by c-fos immunoreactivity (Mineur et al., 2007).”
From Acetylcholine as a Neuromodulator: Cholinergic Signaling Shapes Nervous System Function and Behavior (2012) · cites this paper as Mineur et al., 2007
Antagonism of mAChRs or nAChRs, or blockade of ACh signaling through nAChRs with partial agonists, can decrease depression-like behavior in rodents.
“Consistent with an increase in ACh leading to symptoms of depression, antagonism of mAChRs or nAChRs, or blockade of ACh signaling through nAChRs with partial agonists, can decrease depression-like behavior in rodents (Caldarone et al., 2004; De Pablo et al., 1991; Mineur et al., 2007; Picciotto et al., 2002; Rabenstein et al., 2006).”
From Acetylcholine as a Neuromodulator: Cholinergic Signaling Shapes Nervous System Function and Behavior (2012) · cites this paper as Mineur et al., 2007
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 [16]
nAChRs in the amygdala could be important for the antidepressant effect of nAChR blockade.
“there is some evidence that nAChRs in the amygdala could be important for the antidepressant effect of nAChR blockade (Mineur et al., 2007)”
From Mood and anxiety regulation by nicotinic acetylcholine receptors: A potential pathway to modulate aggression and related behavioral states (2015) · cites this paper as Mineur et al., 2007
Decreasing amygdala cholinergic activity through α4β2* nAChR blockade could decrease stress reactivity and depression-like symptoms.
“decreasing amygdala cholinergic activity through α4β2* nAChR blockade could decrease stress reactivity and depression-like symptoms (LeDoux, 2003; Mineur et al., 2007)”
From Mood and anxiety regulation by nicotinic acetylcholine receptors: A potential pathway to modulate aggression and related behavioral states (2015) · cites this paper as Mineur et al., 2007
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 Mineur et al., 2007
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 Mineur et al., 2007
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- Authors
- Mineur, Y. S., Somenzi, O., & Picciotto, M. R.
- Affiliations
- Yale University (US)
- Corresponding author
- Picciotto, Marina R.
- Venue
- Neuropharmacology
- Publisher
- Elsevier BV
- Published
- 2007-04
- Volume
- 52
- Issue
- 5
- Pages
- 1256-1262
- ISSN
- 0028-3908 (ISSN-L)
- PMC
- PMC1959230
- OpenAlex
- W2120593159
- Cited by
- 137
- References
- 40
- Citations by year
- 2026: 4 · 2025: 3 · 2024: 4 · 2023: 5 · 2022: 5 · 2021: 4 · 2020: 9 · 2019: 4 · 2018: 5 · 2017: 3 · 2016: 3 · 2015: 5 · 2014: 11 · 2013: 10 · 2012: 14
- FWCI
- 5.16
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Neuropharmacology (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Alliance for Research on Schizophrenia and Depression
- National Institutes of Health
- National Institute on Alcohol Abuse and Alcoholism (P50AA015632, AA15632)
- National Institute of Mental Health (MH77681, R01MH077681)
- National Institute on Drug Abuse (K02DA000436, DA 13334, 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
- cytisine, nicotinic acetylcholine receptors, partial agonists, antidepressant-like effects, Fos expression, basolateral amygdala, nicotine, antidepressant targets, C57BL/6J mice
- MeSH terms
- Quinolizidine Alkaloids, Alkaloids, Animals, Antidepressive Agents, Anxiety, Azocines, Brain, Depression, Feeding Behavior, Immunohistochemistry, Male, Mecamylamine, Mice, Inbred C57BL, Motor Activity, Quinolizines, Receptors, Muscarinic, Swimming, Gene Expression, Genes, fos, Nicotinic Agonists, Hindlimb Suspension, Mice
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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