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Cited by 157Nicotinic Acetylcholine Receptors StudySmoking Behavior and CessationNeuroscience and Neuropharmacology Research

Mood and anxiety regulation by nicotinic acetylcholine receptors: A potential pathway to modulate aggression and related behavioral states

Open access
Picciotto, Marina R., Lewis, Alan S., van Schalkwyk, Gerrit I., Mineur, Yann S.·2015·Neuropharmacology
DOI 10.1016/j.neuropharm.2014.12.028PMC PMC4486625
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Abstract

The co-morbidity between smoking and mood disorders is striking. Preclinical and clinical studies of nicotinic effects on mood, anxiety, aggression, and related behaviors, such as irritability and agitation, suggest that smokers may use the nicotine in tobacco products as an attempt to self-medicate symptoms of affective disorders. The role of nicotinic acetylcholine receptors (nAChRs) in circuits regulating mood and anxiety are beginning to be elucidated in animal models, but the mechanisms underlying the effects of nicotine on aggression-related behavioral states (ARBS) are still not understood. Clinical trials of nicotine or nicotinic medications for neurological and psychiatric disorders have often found effects of nicotinic medications on ARBS, but few trials have studied these outcomes systematically. Similarly, the increase in ARBS resulting from smoking cessation can be resolved by nicotinic agents, but the effects of nicotinic medications on these types of mental states and behaviors in non-smokers are less well understood. Here we review the literature on the role of nAChRs in regulating mood and anxiety, and subsequently on the closely related construct of ARBS. We suggest avenues for future study to identify how nAChRs and nicotinic agents may play a role in these clinically important areas.

AI snapshot

Written from the paper’s full text.

TL;DR

This review synthesizes preclinical and clinical evidence that nicotinic acetylcholine receptors (nAChRs) regulate mood and anxiety and the closely related construct of aggression-related behavioral states (ARBS), suggesting smokers may use nicotine to self-medicate affective symptoms. It argues nicotinic agents may reduce ARBS across diagnoses, but mechanisms and whether agonists or antagonists are optimal remain unresolved.

Key findings

  • Preclinical work indicates that decreasing α4β2* nAChR signaling can improve depression-like behaviors, that nAChR antagonists or partial agonists can potentiate SSRI/NRI effects, and that β2* nAChRs are required for antidepressant efficacy of at least one antidepressant; nicotine reduces aggression in many rat paradigms, with effects blocked by mecamylamine but not peripheral blockade by hexamethonium, while mouse results vary by strain and paradigm.
  • Clinical imaging shows β2* nAChR availability is greatly decreased in actively depressed patients and intermediate in remitted subjects, suggesting a possible depression biomarker; nicotine can improve depressive symptoms even in non-smokers, and withdrawal is associated with anxiety, irritability, and aggression.
  • In a double-blind, placebo-controlled trial of transdermal nicotine in adult smokers with schizophrenia, agitation decreased 33% on the Agitated Behavior Scale versus 23% for placebo, with greater reductions on the PANSS excited component; in ADHD, a small study (n = 17) found no effect on agitation/aggression subscales, while a larger study (n = 40) found post-hoc significant improvement in irritability only.
  • A mecamylamine trial in Tourette’s syndrome (n = 61) found no overall symptom difference from placebo but a significant decrease in “sudden mood changes”; in an ICU prospective trial (n = 144), smokers had an almost doubled rate of agitation versus controls when nicotine replacement was not permitted.

Methods

  • Narrative review of preclinical and clinical literature on nAChRs in mood, anxiety, and ARBS; no primary data collection.
  • Evidence includes animal models (rodent and cat aggression paradigms, knockout mice, pharmacological studies) and human studies (clinical trials, case series, imaging, post-mortem, and nicotine withdrawal studies).
  • Main analysis is qualitative synthesis; no systematic search strategy, meta-analysis, or formal risk-of-bias assessment is described.

Limitations

  • The paper states that mechanisms underlying nicotine’s effects on ARBS are still not understood, that few clinical trials have studied ARBS outcomes systematically, that effects in non-smokers are less well understood, and that current clinical literature does little to clarify whether nicotinic agonists or antagonists are most helpful.
  • The paper notes that many supporting clinical studies are small and uncontrolled case series, and some findings are secondary, post-hoc, or anecdotal.
  • Evident from the text: as a narrative review, it cannot quantify pooled effects or systematically appraise study quality; species, strain, and sex differences complicate interpretation, as the paper itself states.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1016/j.neuropharm.2014.12.028

Cites

151 of 151 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

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  • Premisecitation

    Smoking and mood disorders are highly co-morbid.

    “Nicotine consumption through tobacco products is highly co-morbid with mood disorders, including depression, anxiety and irritability”
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    • cites Moylan et al., 2012 source

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    • cites Glassman et al., 1990 source

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    • cites Covey et al., 1998 source

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  • Premisecitation

    Low dose chronic nicotine has a comparable effect to an antagonist of high affinity β2* nAChRs in a conditioned emotional response task in mice.

    “low dose chronic nicotine has a comparable effect to an antagonist of high affinity β2 subunit-containing (β2*) nAChRs in a conditioned emotional response task in mice (Anderson and Brunzell, 2012)”
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    • cites Anderson and Brunzell, 2012

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  • Interpretationreasoning

    A partial agonist, or a mix of agents with differing effects at heteromeric and homomeric nAChRs, may be the most promising for developing nicotinic-based antidepressants.

    “These data suggest that a partial agonist, or a mix of agents with differing effects at heteromeric and homomeric nAChRs may be the most promising for developing nicotinic-based antidepressants”
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    • cites Picciotto et al., 2008 source

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    • cites Picciotto et al., 2012 source

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    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)”
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    • cites Mineur et al., 2007 source

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  • Interpretationreasoning

    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)”
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    • cites LeDoux, 2003 source

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    Premisecitation

    The overall incidence of smoking in depressed patients is twice as high as in the general population.

    “the overall incidence of smoking in depressed patients is twice as high as in the general population (Glassman et al., 1990)”
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    • cites Glassman et al., 1990 source

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    Interpretationcitation

    This phenomenon could underlie the cyclical mood dysregulation experienced by smokers between smoking episodes and could perpetuate smoking behavior.

    “This phenomenon could also underlie the cyclical mood dysregulation experienced by smokers between smoking episodes, and could therefore perpetuate smoking behavior (Watkins et al., 2000).”
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    • cites Watkins et al., 2000 source

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    Interpretationreasoning

    The net effect of nicotine on mood depends on the integration of multiple nicotinic signals because nicotine can both activate and desensitize different nAChR subtypes.

    “because nicotine can both activate and desensitize different nAChR subtypes, resulting in differential modulation of many brain circuits, the net effect of nicotine on mood will depend on the integration of multiple nicotinic signals”
    Quote in the paperSubstantial claim

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    Premisecitation

    α4β2* nAChRs can be rapidly and persistently desensitized in the presence of nicotine, whereas α7 nAChRs can maintain their activity.

    “α4β2* nAChRs can be rapidly and persistently desensitized in the presence of nicotine, whereas α7 nAChRs can maintain their activity (Mansvelder et al., 2002)”
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    • cites Mansvelder et al., 2002 source

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    Premisecitation

    nAChRs are expressed on many cell types throughout the central nervous system and modulate multiple neurotransmitter systems.

    “nAChRs are expressed on many cell types throughout the central nervous system (Han et al., 2000), and modulate multiple neurotransmitter systems”
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    • cites Han et al., 2000 source

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    Premisecitation

    Chronic nicotine exposure induces up-regulation of nAChRs and profound desensitization of these receptors in vitro.

    “Chronic nicotine exposure induces up-regulation of nAChRs, but also profound desensitization of these receptors in vitro (Fenster et al., 1997; Grady et al., 1994).”
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    Interpretationcitation

    Limiting nAChR signaling through α4β2* nAChRs can lead to positive effects on mood symptoms, but other nAChRs also appear important for antidepressant responses.

    “These studies suggest that limiting nAChR signaling through α4β2* nAChRs can lead to positive effects on mood symptoms, however other nAChRs also appear to be important for antidepressant responses.”
    Quote in the paperSubstantial claim

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    Interpretationcitation

    During ongoing smoking, there is decreased ACh signaling through some nAChR subtypes, but signaling is likely restored and potentially increased over time as nicotine is cleared during withdrawal because high affinity nAChRs are upregulated by chronic nicotine use.

    “These data suggest there is decreased ACh signaling through some nAChR subtypes during ongoing smoking, but likely to be restored and potentially increased over time (because high affinity nAChRs are upregulated by chronic nicotine use as experienced by smokers (Fenster et al., 1999) as nicotine is cleared during withdrawal.”
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    Premisecitation

    Smoking cessation and nicotine withdrawal can be accompanied by depressive episodes, stress-induced anger, and increased tension.

    “smoking cessation and nicotine withdrawal can be accompanied by depressive episodes, stress-induced anger, and increased tension (al'Absi et al., 2007; Hatsukami et al., 1985)”
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    Premisecitation

    Both nicotine and the nicotinic antagonist mecamylamine can increase serotonin release in the hippocampus.

    “both nicotine and the nicotinic antagonist mecamylamine can increase serotonin release in the hippocampus (Kenny et al., 2000)”
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    • cites Kenny et al., 2000 source

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    Interpretationreasoning

    Increased ACh transmission can increase behaviors related to depression in humans and rodents, but the type of circuits/cell types modulated by ACh or nAChRs can have opposite effects on mood regulation, and the outcome depends on the sum of these effects.

    “while increased ACh transmission can increase behaviors related to depression in humans (Risch et al., 1980) and rodents (Mineur et al., 2013), the type of circuits/cell types that are modulated by ACh or nAChRs can have opposite effects on mood regulation, and the outcome on behavior depends on the sum of these effects.”
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    • cites Risch et al., 1980 source

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    • cites Mineur et al., 2013 source

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    Premisecitation

    At baseline, β2−/− mice exhibit increased levels of norepinephrine, dopamine, serotonin, and acetylcholine within the prelimbic region of the PFC, yet display similar levels of aggression compared to control mice both before and after global norepinephrine depletion.

    “At baseline, β2−/− mice exhibit increased levels of norepinephrine, dopamine, serotonin, and acetylcholine within the prelimbic region of the PFC, yet display similar levels of aggression compared to control mice both before and after global norepinephrine depletion.”
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    • cites Coura et al., 2013 source

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    Premisecitation

    Increasing doses of nicotine reduced the proportion of fighting episodes in rats after footshock and replaced that behavior with posturing.

    “increasing doses of nicotine not only reduced the proportion of fighting episodes in rats after footshock, but also replaced that behavior with posturing (an intermediate aggressive behavior)”
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    • cites Driscoll and Baettig, 1981

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    Premisecitation

    In cats, nicotine reduced aggression in a dose-dependent manner in a rat-biting assay, and doses highly effective at reducing aggression did not cause changes in food intake.

    “In cats, nicotine reduced aggression in a dose-dependent manner in a rat-biting assay, and doses that were highly effective at reducing aggression did not cause changes in food intake, suggesting a specific effect on aggression (Berntson et al., 1976).”
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    Premisecitation

    Serotonin depletion could prevent antidepressant-like effects induced by cytisine in the forced swim and social defeat tests, while effects of serotonergic drugs could be potentiated by cytisine.

    “We recently found that serotonin depletion could prevent antidepressant-like effects induced by the nicotinic partial agonist cytisine in the forced swim and the social defeat tests, while the effects of serotonergic drugs could be potentiated by this nicotinic compound (Mineur et al., 2014).”
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    • cites Mineur et al., 2014

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    Premisecitation

    A single nicotine injection reduced aggression from baseline, and four days of repeated daily injection reduced aggression even further.

    “a single nicotine injection reduced aggression from baseline, and four days of repeated daily injection reduced aggression even further”
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    • cites Silverman, 1971 source

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    Premisecitation

    In rats, a hypothalamic aggression area has been implicated in aggressive behavior by stimulation paradigms, and efferents from this region have been mapped with substantial connection throughout the brain.

    “In rats, a hypothalamic “aggression area” (HAA) has been implicated in aggressive behavior by stimulation paradigms, and efferents from this region have been mapped, with substantial connection throughout the brain, including thalamic nuclei, septal nuclei, and the periaqueductal gray (Roeling et al., 1994).”
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    Premisecitation

    Strain differences in the antidepressant effects of nicotinic agonists and antagonists have been identified, and strains of mice can show profoundly different behavioral responses to nicotine administration.

    “Strain differences in the antidepressant effects of nicotinic agonists and antagonists have been identified (Andreasen and Redrobe, 2009) and strains of mice can show profoundly different behavioral responses to nicotine administration (Marks et al., 1983; Marks et al., 1986)”
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    • cites Andreasen and Redrobe, 2009

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    Interpretationreasoning

    Decreasing nAChR activity can facilitate monoamine transmission and this may mediate the ability of nicotinic drugs to alter depression-like behaviors.

    “changes in nAChR signaling, and more specifically, decreasing nAChR activity, can facilitate monoamine transmission and this may mediate the ability of nicotinic drugs to alter depression-like behaviors”
    Quote in the paperSubstantial claim

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    Premisecitation

    Mecamylamine can have antidepressant-like properties in mouse models, but antidepressant effects of this drug are not observed in assays of rats.

    “while the nicotinic antagonist mecamylamine can have antidepressant-like properties in mouse models (Picciotto et al., 2008; Picciotto et al., 2012), antidepressant effects of this drug are not observed in assays of rats (Tizabi et al., 2000)”
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    • cites Picciotto et al., 2008 source

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    • cites Picciotto et al., 2012 source

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    • cites Tizabi et al., 2000 source

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    Premisecitation

    Cats specifically reduced biting, an aggressive behavior, while pawing and cuffing, non-aggressive behaviors, remained stable or increased.

    “Cats specifically reduced biting, an aggressive behavior, while pawing and cuffing, non-aggressive behaviors, remained stable or increased, supporting the idea that nicotine had specific effects on behaviors related to aggression.”
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    • cites Berntson et al., 1976 source

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    Premisecitation

    The ventrolateral subdivision of the ventromedial hypothalamic nucleus (VMHvl) is necessary and sufficient for offensive aggression in mice.

    “a distinct region within the HAA, the ventrolateral subdivision of the ventromedial hypothalamic nucleus (VMHvl), was recently shown to be necessary and sufficient for offensive aggression in mice (Lin et al., 2011)”
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    Premisecitation

    Mice lacking β2* nAChRs in dopamine neurons of the VTA lack anxiolytic responses to nicotine and are insensitive to nicotine reward.

    “mice lacking β2* nAChRs in dopamine neurons of the VTA lack anxiolytic responses to nicotine and are insensitive to nicotine reward (McGranahan et al., 2011)”
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    • cites McGranahan et al., 2011 source

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    Interpretationcitation

    Aggression was modulated by the balance of monoamines and acetylcholine in the prelimbic cortex, and requires functional β2 nAChRs.

    “a finding that suggests aggression was modulated by the balance of monoamines and acetylcholine in the prelimbic cortex, and requires functional β2 nAChRs (Coura et al., 2013)”
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    • cites Coura et al., 2013 source

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    Premisecitation

    In an isolation-induced aggression model, one study found no effect of acute nicotine on aggression but an anti-aggressive effect of lobeline.

    “in an isolation-induced aggression model, one study found no effect of acute nicotine on aggression but an anti-aggressive effect of lobeline, an agent with complex pharmacological properties at nAChRs (Redolat et al., 2000)”
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    Premisecitation

    Both chronic nicotine and mecamylamine can facilitate serotonin transmission in the hippocampus, while monoamine depletion effects can be partially reversed by nicotine administration and can lead to changes in anxiety-like behavior in the elevated plus maze.

    “both chronic nicotine and the nicotinic antagonist mecamylamine can facilitate serotonin transmission in the hippocampus, while the effects of monoamine depletion can be partially reversed by nicotine administration and can lead to changes in anxiety-like behavior in the elevated plus maze (File et al., 2000a; File et al., 2000b; Fu et al., 1998; Kenny et al., 2000)”
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    Premisecitation

    Effects of nicotine in the muricide study did not stem from a general sedating effect, were not affected by peripheral nAChR blockade with hexamethonium, and were blocked by mecamylamine.

    “effects of nicotine in the muricide study did not stem from a general sedating effect, were not affected by peripheral nAChR blockade with hexamethonium, and were blocked by mecamylamine (Waldbillig, 1980)”
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    • cites Waldbillig, 1980 source

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    Premisecitation

    Nicotine influences the rate of dorsal raphe nucleus (DRN) neuron firing, and can increase serotonin release in rat midbrain slices, an effect largely mediated by presynaptic enhancement of both norepinephrine and glutamate release.

    “Nicotine influences the rate of dorsal raphe nucleus (DRN) neuron firing, and can increase serotonin release in rat midbrain slices (Mihailescu et al., 1998), an effect that appears to be largely mediated by presynaptic enhancement of both norepinephrine (Li et al., 1998) and glutamate release (Garduno et al., 2012).”
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    Premisecitation

    ARBS are observed across numerous neuropsychiatric disorders, including depressive, bipolar, psychotic, neurocognitive, neurodevelopmental, stress-related, substance use and personality disorders.

    “ARBS are observed across numerous neuropsychiatric disorders, including depressive, bipolar, psychotic, neurocognitive, neurodevelopmental, stress-related, substance use and personality disorders (American Psychiatric Association, 2013).”
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    • cites American Psychiatric Association, 2013

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    Premisecitation

    ARBS are prominent in the context of nicotine withdrawal, and these symptoms tend to resolve following administration of nicotine.

    “A second line of evidence comes from a number of studies describing the prominence of ARBS in the context of nicotine withdrawal (Lucidarme et al., 2010), and the tendency for these symptoms to resolve following administration of nicotine (Schechter, 2011).”
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    Premisecitation

    Serotonin disruption is involved in aggressive states and traits in humans, but dopaminergic, norepinephrinergic, and GABAergic neurotransmission have all been implicated in aggression.

    “including evidence of involvement of serotonin disruption in humans in aggressive states and traits, but dopaminergic, norepinephrinergic, and GABAergic neurotransmission have all been implicated in aggression (Nelson and Trainor, 2007; Takahashi et al., 2012b; Yanowitch and Coccaro, 2011)”
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    • cites Takahashi et al., 2012b

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    • cites Yanowitch and Coccaro, 2011

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    Premisecitation

    Clinical data on the role of nicotine in anxiety is more complex, with the most consistent findings being the development of anxiety symptoms in the context of withdrawal, and the observation that these symptoms may improve with nicotine replacement.

    “Clinical data on the role of nicotine in anxiety is more complex, with the most consistent findings being the development of anxiety symptoms in the context of withdrawal, and the observation that these symptoms may improve with nicotine replacement (Picciotto et al., 2002).”
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    Interpretationreasoning

    More selective antagonists or partial agonists may decrease signaling through specific nAChR subtypes while sparing others, and may be more effective or well-tolerated.

    “more selective antagonists or partial agonists may decrease signaling through specific nAChR subtypes while sparing others, and may be more effective or well-tolerated”
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    Premisecitation

    Nicotine delivered through skin patches can improve mood in non-smokers, potentially through sustained desensitization of nAChRs.

    “Nicotine delivered through skin patches can also improve mood in non-smokers (Salin-Pascual et al., 1995; Salin-Pascual et al., 1996), potentially through sustained desensitization of nAChRs (Mineur and Picciotto, 2010; Picciotto et al., 2008).”
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    • cites Mineur and Picciotto, 2010

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    Interpretationreasoning

    β2* nAChR availability could be a biomarker of depression, correlated with severity of the symptoms.

    “raise the possibility that β2* nAChR availability could be a biomarker of depression, correlated with severity of the symptoms”
    Quote in the paperSubstantial claim

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    Premisecitation

    In patients with schizophrenia, the construct of urgency correlated strongly with aggression, and was inversely correlated with functional connectivity in a cortical circuit believed to modulate impulsivity.

    “in patients with schizophrenia, in whom the construct of “urgency”, defined as the tendency to act rashly in the context of positive or negative emotion, correlated strongly with aggression, and was inversely correlated with functional connectivity in a cortical circuit believed to modulate impulsivity (Hoptman et al., 2014)”
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    • cites Hoptman et al., 2014 source

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    Premisecitation

    Clinical studies have demonstrated an increased rate of smoking in individuals with depression, a tendency for depressive symptoms to develop in the context of smoking cessation, and the capacity for nicotine to improve depressive symptoms, even in non-smokers.

    “Clinical studies have demonstrated an increased rate of smoking in individuals with depression (Diwan et al., 1998), a tendency for depressive symptoms to develop in the context of smoking cessation (Laje et al., 2001), and the capacity for nicotine to improve depressive symptoms, even in non-smokers (McClernon et al., 2006; Salin-Pascual et al., 1996).”
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    Premisecitation

    Availability of β2* nAChRs for tracer binding was greatly decreased in actively depressed patients but was intermediate in remitted subjects.

    “Recent imaging studies have shown that availability of β2* nAChRs for tracer binding was greatly decreased in actively depressed patients but was intermediate in remitted subjects (Saricicek et al., 2012).”
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    • cites Saricicek et al., 2012 source

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    Premisecitation

    Similar compounds have shown promising effects in smaller clinical trials, and enhanced the effects of SSRIs in human depressed subjects.

    “similar compounds have shown promising effects in smaller clinical trials, and enhanced the effects of SSRIs in human depressed subjects (George et al., 2008; Philip et al., 2009)”
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    Interpretationreasoning

    A subset of patients may be more responsive to these medications or have an underlying alteration of cholinergic signaling.

    “suggesting that a subset of patients may be more responsive to these medications or have an underlying alteration of cholinergic signaling”
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    Premisenone given

    Current clinical literature does little to clarify whether nicotinic agonists or antagonists are most helpful for treating ARBS.

    “Current clinical literature does little to clarify whether nicotinic agonists or antagonists are most helpful for treating ARBS.”
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    Premisenone given

    These studies have occurred across a variety of diagnostic categories.

    “Notably, these studies have occurred across a variety of diagnostic categories.”
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    Premisecitation

    The reports of decreased irritability in those cases were spontaneously reported by parents, and treatment was continued in these cases.

    “This was spontaneously reported by parents, and was sufficiently convincing that treatment was continued in these cases.”
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    Premisecitation

    In a larger study (n = 40), post-hoc analysis found patients in the treatment arm experienced a statistically significant improvement in irritability with no improvement in any of the other 12 measures on the POMS.

    “More recently, a larger study (n = 40) found on post-hoc analysis that patients in the treatment arm experienced a statistically significant improvement in irritability with no improvement in any of the other 12 measures on the POMS.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationnone given

    Changes in nAChRs may help with the diagnosis and characterization of the pathophysiology of depression.

    “However, changes in nAChRs could provide relevant biomarkers for at least a subset of depressive symptoms, and may help with the diagnosis and characterization of the pathophysiology of depression.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Nicotine withdrawal and its affective consequences have been studied extensively.

    “Nicotine withdrawal and its affective consequences have been studied extensively (Stoker and Markou, 2013), yet the effects of nicotine withdrawal on aggressive behavior needs further exploration both in animal models and in humans.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Stoker and Markou, 2013

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    In that trial, there was anecdotal evidence of decreased irritability in four cases.

    “but provided anecdotal evidence of decreased irritability in four cases.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Arnold et al., 2012 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S1 (asserted).

    Interpretationreasoning

    The ability of nicotinic agents to modulate mood and anxiety might be one mechanism underlying their effects on ARBS.

    “and we hypothesize that the ability of these agents to modulate mood and anxiety might be one mechanism underlying these effects.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Study design and conductreasoning

    These studies were both small and uncontrolled.

    “These studies were both small and uncontrolled, but contribute to an increasing base of clinical data justifying further exploration of nicotinic agents for management of ARBS across a variety of diagnostic categories.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Rosin et al., 2001 source

      Not checked in the free run.

    • cites Carmel and Sheitman, 2007

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S4 (based).

    Interpretationnone given

    Changes in nAChRs could provide relevant biomarkers for at least a subset of depressive symptoms.

    “However, changes in nAChRs could provide relevant biomarkers for at least a subset of depressive symptoms, and may help with the diagnosis and characterization of the pathophysiology of depression.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    In a small study (n = 17), although nicotine was effective for overall symptoms, it had no effect on subscales associated with agitation or aggression.

    “The first small study (n = 17) found that although nicotine was effective for overall symptoms, it had no effect on subscales associated with agitation or aggression (Conners et al., 1996).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Conners et al., 1996

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    The concept of nicotine withdrawal has been codified in the DSM-5 and irritability is described as a characteristic symptom.

    “The concept of nicotine withdrawal has been codified in the DSM-5 and irritability is described as a characteristic symptom (American Psychiatric Association, 2013).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites American Psychiatric Association, 2013

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Interpretationreasoning

    Nicotinic agents may reduce ARBS not by influencing the core symptoms of schizophrenia, but via a parallel mechanism that only becomes apparent in individuals with suprathreshold levels of aggression.

    “At least one way to interpret these findings is to suggest that nicotinic agents may reduce ARBS not by influencing the core symptoms of schizophrenia, but via a parallel mechanism that only becomes apparent in individuals with suprathreshold levels of aggression.”
    Quote in the paperSubstantial claim
53 of 53

  • The authors state this as an assumption.

    The mechanisms mediating the connection between smoking and mood alterations are not yet understood.

    “The underlying mechanisms mediating the connection between smoking and mood alterations are not yet understood, however.”

  • The authors state this as an assumption.

    The mechanisms underlying the effects of nicotine on aggression-related behavioral states are still not understood.

    “but the mechanisms underlying the effects of nicotine on aggression-related behavioral states (ARBS) are still not understood”

  • The authors state this as an assumption.

    The effects of nicotinic medications on ARBS in non-smokers are less well understood.

    “but the effects of nicotinic medications on these types of mental states and behaviors in non-smokers are less well understood”

  • The paper relies on this without support.

    Many conditions involving impulsive aggression are chronic disorders that require long-term treatment.

    “In addition, many conditions involving impulsive aggression are chronic disorders that require long-term treatment, such as neurodevelopmental or neurodegenerative disorders.”

  • The paper relies on this without support.

    There is a lack of currently available agents to effectively treat aggression, irritability, and agitation without significant side effects.

    “Despite the complexity, the lack of currently available agents to effectively treat aggression, irritability, and agitation without significant side effects means that further study in this promising area is strongly indicated.”
5 of 5

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Related

Authors
Picciotto, M. R., Lewis, A. S., van Schalkwyk, G. I., & Mineur, Y. S.
Affiliations
Yale University (US)
Corresponding author
Picciotto, Marina R.
ORCID
Venue
Neuropharmacology
Publisher
Elsevier BV
Published
2015-09
Volume
96
Issue
Pt B
Pages
235-243
ISSN
0028-3908 (ISSN-L)
DOI
10.1016/j.neuropharm.2014.12.028
PMC
PMC4486625
OpenAlex
W1969972941
Semantic Scholar
32f08831c6a19ce6d7602ffbde36908f6094129b
Cited by
157
References
154
Citations by year
2026: 11 · 2025: 13 · 2024: 10 · 2023: 15 · 2022: 17 · 2021: 11 · 2020: 17 · 2019: 18 · 2018: 14 · 2017: 16 · 2016: 7 · 2015: 8
FWCI
1.45
Type
journal article
Language
en
Open access
Licence
www.elsevier.com/tdm/userlicense/1.0/ (tdm)
Locations
  • Neuropharmacology (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
Funders
National Institutes of Health (MH077681, MH19961, MH014276, DA033945, DA14241)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Nicotinic Acetylcholine Receptors Study
  • Health Sciences › Medicine › Physiology › Smoking Behavior and Cessation
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
Keywords
nicotinic acetylcholine receptors, nicotine, mood regulation, anxiety regulation, irritability, agitation, self-medication, smoking cessation, nicotinic agonists, psychiatric comorbidity
MeSH terms
Affect, Aggression, Animals, Anxiety, Clinical Trials as Topic, Humans, Nicotine, Receptors, Nicotinic, Substance Withdrawal Syndrome, Tobacco Use Disorder, Nicotinic Agonists

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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.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-10.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-10.

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