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Cited by 371Nicotinic Acetylcholine Receptors StudySmoking Behavior and CessationNeurotransmitter Receptor Influence on Behavior

Reward, addiction, withdrawal to nicotine

Open access
De Biasi, Mariella, Dani, John A.·2011·Annual Review of Neuroscience
DOI 10.1146/annurev-neuro-061010-113734PMC PMC3137256
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Abstract

Nicotine is the principal addictive component that drives continued tobacco use despite users' knowledge of the harmful consequences. The initiation of addiction involves the mesocorticolimbic dopamine system, which contributes to the processing of rewarding sensory stimuli during the overall shaping of successful behaviors. Acting mainly through nicotinic receptors containing the α4 and β2 subunits, often in combination with the α6 subunit, nicotine increases the firing rate and the phasic bursts by midbrain dopamine neurons. Neuroadaptations arise during chronic exposure to nicotine, producing an altered brain condition that requires the continued presence of nicotine to be maintained. When nicotine is removed, a withdrawal syndrome develops. The expression of somatic withdrawal symptoms depends mainly on the α5, α2, and β4 (and likely α3) nicotinic subunits involving the epithalamic habenular complex and its targets. Thus, nicotine taps into diverse neural systems and an array of nicotinic acetylcholine receptor (nAChR) subtypes to influence reward, addiction, and withdrawal.

AI snapshot

Written from the paper’s full text.

TL;DR

Nicotine drives reward and addiction mainly by acting on β2-containing nAChRs in the mesocorticolimbic dopamine system, increasing midbrain dopamine neuron firing and phasic bursts. Withdrawal depends on distinct nAChR subunits—especially α5, α2, and β4—in the habenulo-interpeduncular axis, so reward, addiction, and withdrawal are mediated by partially separate neural circuits.

Key findings

  • Nicotine increases dopamine neuron firing and phasic burst activity, with tonic firing roughly 4 Hz and phasic bursts roughly 20–80 Hz; β2* nAChRs, often with α4 and/or α6, are essential for nicotine reinforcement and dopamine release.
  • In mice lacking β2, nicotine does not induce phasic bursts, dopamine release, or self-administration; re-expression of β2 in the VTA, but not SNc, reinstates self-administration, and either α4 or α6 re-expression also reinstates it.
  • Somatic withdrawal signs depend on α5, α2, and β4 nAChR subunits in the medial habenula/interpeduncular nucleus (MHb/IPN); mecamylamine injected into Hb/IPN precipitates withdrawal, whereas injection into VTA, hippocampus, or cortex does not.
  • Withdrawal is associated with decreased extracellular dopamine in the NAc and increased dopamine output in the PFC; symptoms appear within a few hours and include irritability, anxiety, anger, difficulty concentrating, sleep disturbance, increased appetite, and weight gain.

Methods

  • Narrative review synthesizing published literature on nicotinic acetylcholine receptors, mesocorticolimbic dopamine circuitry, nicotine reward, neuroadaptations, and withdrawal.
  • Draws on animal models (especially mouse knockout and re-expression studies, rat electrophysiology, microdialysis, fast-scan cyclic voltammetry) and human genetic/imaging findings.
  • Main analysis is qualitative integration of cited studies rather than a systematic review, meta-analysis, or new primary data.

Limitations

  • Not stated in the paper: the review does not include a formal limitations section.
  • Evident from the text: it is a narrative review without described systematic search criteria, inclusion/exclusion rules, or quantitative synthesis.
  • Evident from the text: some conclusions are explicitly speculative, such as the proposed interpretation of SNP rs16969968 in CHRNA5 and its possible link to smoking behavior and addiction risk.

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

Integrity signals

Registry

Crossref · 10.1146/annurev-neuro-061010-113734

Cites

300 of 300 references verified0 citation errors · 0 not checkable

Statistics

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Claims the paper makes

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  • Premisecitation

    The epithalamic habenular complex and its targets are critical for the withdrawal syndrome.

    “The epithalamic habenular complex and its targets appear to be critical for the withdrawal syndrome.”
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    Self-stimulation of the medial forebrain bundle facilitates DA release.

    “Self-stimulation of the medial forebrain bundle facilitates DA release (Garris et al. 1999, Gratton et al. 1988, Phillips et al. 1989), and DA receptor antagonists or DA neuron lesions inhibit brain self-stimulation (Fouriezos & Wise 1976, Lippa et al. 1973, Stellar & Corbett 1989).”
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    The effectiveness or value of rewards can be estimated by measuring the effort a subject expends on behaviors that achieve the rewarded goal.

    “The effectiveness or value of rewards can be estimated by measuring the effort a subject expends on behaviors that achieve the rewarded goal (Hodos 1961, Schultz 2006).”
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  • Interpretationnone given

    The withdrawal syndrome is not mediated by exactly the same mechanisms or neural circuits that initiate addiction or dependency.

    “The withdrawal syndrome is not mediated exactly by the same mechanisms or by the same neural circuits that initiate addiction or dependency.”
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    DA efferents from the midbrain VTA that target the PFC and NAc are recognized as paramount neural structures shaping reward-related behavior.

    “The DA efferents originating from the midbrain VTA and particularly targeting the PFC and NAc became recognized as paramount neural structures shaping reward-related behavior (Schultz et al. 1997; Wise 2004, 2009; Wise & Rompre 1989).”
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    Premisecitation

    After chronic nicotine use, removing nicotine produces a withdrawal syndrome that nicotine replacement therapy can relieve.

    “After chronic use of nicotine, removal of nicotine produces a withdrawal syndrome that can be relieved by nicotine replacement therapy (Dani et al. 2009, Dani & Heinemann 1996, De Biasi & Salas 2008, Di Chiara 2000, Mansvelder & McGehee 2002, Stolerman & Shoaib 1991).”
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    DA receptor antagonists or DA neuron lesions inhibit brain self-stimulation.

    “Self-stimulation of the medial forebrain bundle facilitates DA release (Garris et al. 1999, Gratton et al. 1988, Phillips et al. 1989), and DA receptor antagonists or DA neuron lesions inhibit brain self-stimulation (Fouriezos & Wise 1976, Lippa et al. 1973, Stellar & Corbett 1989).”
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    Premisecitation

    Nicotine acts mainly through midbrain nAChRs containing β2 with α4 and/or α6 to raise firing rate and phasic bursts of midbrain DA neurons and to elevate DA in PFC, NAc, and other targets.

    “Acting mainly via midbrain nAChRs composed of the β2 subunit in combination with the α4 and/or α6 subunits, nicotine increases the firing rate and phasic burst activity of midbrain DA neurons and elevates DA in the PFC, NAc, and other targets (Imperato et al. 1986, Grenhoff et al. 1986, Mameli-Engvall et al. 2006, Pons et al. 2008, Zhang et al. 2009b).”
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    Rewarding stimuli promote learning of goal-directed behaviors, generate positive emotions, and stimulate repetition of those behaviors.

    “Rewarding stimuli promote learning of goal-directed behaviors, generate positive emotions, and subsequently stimulate repetition of those learned behaviors (Schultz 2010, Thorndike 1911).”
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    The mesocorticolimbic dopamine system is important for self-stimulation and for processing environmental reward.

    “In particular, the mesocorticolimbic dopamine (DA) system plays an important role in self-stimulation and in processing environmental reward.”
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    The midbrain DA systems have an important role in the response to salient stimuli and to brain self-stimulation.

    “Early investigations showed that the midbrain dopamine (DA) systems have an important role in the response to salient stimuli and to brain self-stimulation (Phillips & Olds 1969; Fibiger 1978, Wise 1978).”
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    The MHb and IPN richly express β4 and α5 nAChR subunits, and α2 only in rodent IPN, and these subunits are necessary for neuroadaptations that lead to somatic withdrawal symptoms during nicotine abstinence.

    “The medial habenula (MHb) and one of its primary targets, the interpeduncular nucleus (IPN), richly express β4 and α5 nAChR subunits (and α2 only in the rodent IPN), which are necessary for the neuroadaptations that lead to somatic withdrawal symptoms during nicotine abstinence (Salas et al. 2004b, 2009).”
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    PPT/LDT cholinergic afferents boost glutamate afferent transmission via presynaptic nAChRs and provide excitatory drive to GABA projection neurons and interneurons mainly via β2* nAChRs.

    “The PPT/LDT cholinergic afferents boost glutamate afferent transmission via presynaptic nAChRs (Pidoplichko et al. 2004, Schilstrom et al. 2000) and provide some excitatory drive to GABA projection neurons and interneurons, mainly via β2-containing (β2*) nAChRs (Mansvelder et al. 2002, Pidoplichko et al. 2004, Pons et al. 2008).”
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    Only about 2% of striatal neurons are cholinergic, but they have extremely dense axonal arbors that provide denser cholinergic innervation than is seen anywhere else in the brain.

    “Although only ~2% of the striatal neurons are cholinergic, they have extremely dense axonal arbors that provide denser cholinergic innervation than is seen anywhere else in the brain (Butcher & Woolf 1984, Zhou et al. 2001, 2002).”
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    Addictive drugs including nicotine increase basal DA concentration in the NAc shell as measured by microdialysis, but that background increase is smaller or not detected in the dorsolateral striatum.

    “Addictive drugs (including nicotine) increase the basal DA concentration in the NAc shell as measured by microdialysis, but that background increase is smaller or not detected in the dorsolateral striatum (Di Chiara 1999, Pidoplichko et al. 2004, Pontieri et al. 1996, Zhang et al. 2009b).”
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    Nicotine at the concentration obtained from tobacco induces phasic bursts from VTA/SNc DA neurons that innervate much of the dorsal to ventral striatum, suggesting that the DA signal should be comparable throughout the striatum.

    “Nicotine, at the concentration obtained from tobacco, induces phasic bursts from VTA/SNc DA neurons (Figure 1b) that innervate much of the dorsal to ventral extent of the striatum (Grenhoff et al. 1986, Pidoplichko et al. 1997, Schilstrom et al. 2003, Zhang et al. 2009b), suggesting that the DA signal should be comparable throughout the striatum.”
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    Phasic burst firing is induced by unpredicted reward or by unanticipated cues conditioned to a known reward.

    “For example, phasic burst firing is induced by unpredicted reward or unanticipated cues that have been conditioned to a known reward (Schultz 2007b, Schultz et al. 1997).”
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    DA neurons have tonic firing at roughly 4 Hz of individual action potentials and phasic firing at higher average frequency with bursts roughly 20-80 Hz.

    “Tonic firing is at a relatively low frequency (roughly 4 Hz) that generally consists of individual action potentials. Phasic firing is usually at a higher average frequency, and it includes high-frequency burst discharges (roughly 20–80 Hz) (Grace et al. 2007; Grace & Bunney 1983, 1984; Hyland et al. 2002; Robinson et al. 2004).”
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    Nicotine self-administration is reinstated by re-expression of the β2 subunit in the VTA but not in the neighboring SNc, confirming the specific role of the VTA in reward.

    “Nicotine self-administration is reinstated by re-expression of the β2 subunit in the VTA but not in the neighboring SNc (Avale et al. 2008), confirming the specific role of the VTA in reward.”
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    Interpretationcitation

    β2* nAChRs with both α4 and α6 are important for nicotine's reinforcing properties, and α4 and α6 cannot completely substitute for each other.

    “Thus, β2* nAChRs in combinations with both α4 and α6 subunits are important for the reinforcing properties of nicotine, and the α4 and α6 subunits cannot completely substitute for each other even though they are abundantly expressed in VTA neurons (Champtiaux et al. 2003, Salminen et al. 2007).”
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    Pharmacological evidence indicates that the α7 subunit does not influence chronic nicotine self-administration in trained rats or nicotine-induced conditioned place preference.

    “Interestingly, local re-expression of α7 in the VTA did not reinstate self-administration in α7 −/− mice (Pons et al. 2008), consistent with the pharmacological evidence indicating that the α7 subunit does not influence chronic nicotine self-administration in trained rats (Grottick & Higgins 2000) nor nicotine-induced conditioned place preference (Stolerman et al. 2004, Walters et al. 2006).”
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    Premisecitation

    Nicotinic receptors are expressed on DA neuron fibers and terminals, and the activity of those nAChRs, particularly those containing β2, α4, and α6, is highly regulated by ongoing striatal cholinergic interneuron discharges and dense AChE activity.

    “Nicotinic receptors are expressed on DA neuron fibers and terminals, and the activity of those nAChRs, particularly containing the β2, α4, and α6 subunits (Pons et al. 2008), is highly regulated by ongoing striatal cholinergic interneuron discharges and dense acetylcholine esterase activity (Zhou et al. 2001, 2003).”
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    Premisecitation

    DA projection target areas are involved in reinforcement (ventral striatum), learning and declarative memory (hippocampus), emotional memory (amygdala), habit formation (dorsal striatum), and executive functions and working memory (PFC and orbitofrontal cortex).

    “Those DA projection target areas are involved in reinforcement (ventral striatum), learning and declarative memory (hippocampus), emotional memory (amygdala), and habit formation (dorsal striatum), as well as executive functions and working memory (PFC and orbitofrontal cortex) (Schultz W. 2007b, Laviolette 2007, Seamans & Yang 2004).”
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    Premisecitation

    Disrupting phasic bursts impairs conditioned behavioral responses, diminishes learning of cues about reward and salience, and disrupts reward processing.

    “Disrupting those bursts impairs conditioned behavioral responses, diminishes the ability to learn cues about reward and salience, and disrupts the overall processing of reward (Schultz 2007b).”
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    Premisecitation

    Nicotine self-administration is reinstated by re-expression of either the α4 or the α6 nAChR subunit, consistent with expression of α4β2 and α4α6β2 nAChRs in the VTA.

    “Nicotine self-administration is also reinstated by the re-expression of either the α4 or the α6 nAChR subunit, consistent with the expression of α4β2 and α4α6β2 nAChRs in the VTA (Pons et al. 2008).”
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    Interpretationreasoning

    Phasic burst firing by DA neurons and downstream phasic DA signals are vital for processing reward-related information and important for the initial phase of addiction.

    “Phasic burst firing by DA neurons and the consequent downstream phasic DA signals are vital for processing reward-related information and, thus, are important for the initial phase of addiction.”
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    Premisecitation

    Nicotine directly activates DA neurons via nAChR subtypes and modifies their firing modes and frequency through excitatory and inhibitory inputs and synaptic plasticity.

    “Nicotine directly activates DA neurons via those and other nAChR subtypes (Pidoplichko et al. 1997), and nicotine modifies the firing modes and firing frequency of DA neurons through excitatory and inhibitory inputs and synaptic plasticity (Mameli-Engvall et al. 2006; Schilstrom et al. 2000, 2003; Zhang et al. 2009b).”
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    Premisecitation

    In mice lacking the β2 nAChR subunit, nicotine does not induce phasic bursts by DA neurons, does not induce DA release, and does not support self-administration.

    “In mice lacking the β2 nAChR subunit (β2 −/−), nicotine does not induce phasic bursts by DA neurons (Mameli-Engvall et al. 2006), nicotine does not induce DA release, and nicotine does not support self-administration (Picciotto et al. 1998).”
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    Premisenone given

    Measured in vivo from the VTA, nicotine administration to a rat causes some DA neurons to fire at a higher rate and to fire more and longer bursts.

    “Measured in vivo from the VTA, nicotine administration to a rat causes (some) DA neurons to fire at a higher rate and to fire more and longer bursts (Figure 1).”
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    Interpretationcitation

    The data suggest that background DA concentration would increase in the NAc shell and not in the dorsal striatum.

    “The details of the DA signaling change in both anatomical areas, but as judged by the area under the curves (Figure 3a,b), the data suggest that the background DA concentration would increase in the NAc shell and not the dorsal striatum (Zhang et al. 2009b).”
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    Premisecitation

    When nicotine is added to striatal brain slices, a significant proportion of presynaptic and axonal nAChRs is desensitized, inhibiting low-frequency tonic DA release, while phasic bursts induce large DA signals.

    “However, when nicotine is added to striatal brain slices, a significant proportion of presynaptic and axonal nAChRs is desensitized. As a consequence, low-frequency, tonic DA release is inhibited (Rice & Cragg 2004, Zhang & Sulzer 2004, Zhou et al. 2001), but phasic DA release is regulated differently, such that phasic bursts induce large DA signals (Cragg 2003; Rice & Cragg 2004; Zhang et al. 200”
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    Premisereasoning

    In the NAc shell, phasic burst discharges produce a greater increase in DA release than in the dorsal striatum, where DA release from a single-pulse stimulus is comparable to release from a phasic-burst stimulus.

    “In the NAc shell, phasic burst discharges produce a greater increase in DA release than in the dorsal striatum, where the DA release from a single-pulse stimulus is comparable to the release from a phasic-burst stimulus.”
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    Premisecitation

    Aversive stimuli excite ventral VTA neurons and inhibit dorsal VTA neurons.

    “Reward omission induces phasic inhibition of VTA neurons (Schultz 2007a,b), and aversive stimuli excite ventral (Brischoux et al. 2009) and inhibit dorsal (Ungless et al. 2004) VTA neurons.”
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    Interpretationcitation

    DA axon terminals in the dorsolateral striatum and NAc shell respond differently to incoming action potentials, consistent with phasic bursts inducing a greater increase of DA release in the NAc shell, which has a more important role in mediating the rewarding properties of nicotine that drive early addiction.

    “DA axon terminals in the dorsolateral striatum and NAc shell respond differently to incoming action potentials, consistent with phasic bursts inducing a greater increase of DA release in the NAc shell (Cragg 2003; Rice & Cragg 2004; Zhang et al. 2009a,b; Zhang & Sulzer 2004), which has a more important role in mediating the rewarding properties of nicotine that drive the early phases of addiction.”
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    Premisecitation

    RMTg neurons are phasically activated by aversive stimuli and inhibited by natural rewards or reward-predictive stimuli.

    “As in the LHb, RMTg neurons are phasically activated by aversive stimuli and inhibited by natural rewards such as food or reward-predictive stimuli, and conversely, RMTg neurons are stimulated by aversive stimuli (Jhou et al. 2009b).”
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    Premisecitation

    NAc neurons decrease their firing to appetitive stimuli and increase their firing to aversive stimuli.

    “Owing to afferents mediating sensory input, NAc neurons decrease their firing to appetitive stimuli and increase their firing to aversive stimuli (Roitman et al. 2005).”
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    Premisecitation

    Nicotine exposure increases high-affinity DA D2 receptors in the NAc, an effect also produced by cocaine, causing DA hypersensitivity.

    “Nicotine exposure also increases high-affinity DA D2 receptors in the NAc (Novak et al. 2010), an effect, also produced by cocaine, that causes DA hypersensitivity (Briand et al. 2008, Grigoriadis & Seeman 1986).”
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    Premisecitation

    In the NAc of rats, intraoral sucrose increased DA levels, whereas quinine decreased DA levels.

    “In the NAc of rats, intraoral sucrose (i.e., rewarding) infusion increased DA levels, whereas quinine (i.e., aversive) infusion decreased DA levels (Roitman et al. 2008).”
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    Nicotinic receptor upregulation differs among subtypes, varies among brain regions for the same subtype, and depends on the contingency of nicotine administration.

    “Nicotinic receptor upregulation differs among the diverse subtypes, varies among brain regions for the same nAChR subtype, and depends on the contingency of nicotine administration (Gaimarri et al. 2007, Marks et al. 1983, McCallum et al. 2006, Metaxas et al. 2010, Nguyen et al. 2004, Pauly et al. 1996, Schwartz & Kellar 1983).”
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    Because nicotine is not hydrolyzed by AChE, its long-lasting presence favors excessive nAChR desensitization, and the homeostatic response to desensitized receptors is upregulation.

    “Because nicotine is not hydrolyzed by acetylcholine esterase, as ACh is, nicotine’s long-lasting presence favors excessive nAChR desensitization. The homeostatic response to desensitized (turned-off) receptors is upregulation (Dani & Heinemann 1996, Fenster et al. 1999, Picciotto et al. 2008).”
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    Premisecitation

    The RMTg sends GABAergic projections to the VTA and SNc and inhibits DA cells.

    “The RMTg sends GABAergic projections to the VTA and SNc and inhibits DA cells (Ikemoto 2010, Jhou et al. 2009a).”
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    Premisecitation

    The IPN sends projections to the serotonergic raphé nuclei and to the dopaminergic VTA.

    “The IPN, in turn, sends projections to the serotonergic raphé nuclei and to the dopaminergic VTA (Groenewegen et al. 1986, Klemm 2004, Montone et al. 1988).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites Groenewegen et al. 1986

      Not checked in the free run.

    • cites Klemm 2004

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    • cites Montone et al. 1988

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  • May combine two claims.

    Premisecitation

    Negative affective symptoms such as dysphoria, anxiety, and irritability, and to a lesser extent somatic withdrawal signs, signal dependency and underlie drug-seeking behavior.

    “The emergence of negative affective symptoms such as dysphoria, anxiety, and irritability (Koob & Le Moal 2001) and, to a lesser extent, the somatic manifestations of withdrawal, signal dependency and underlie drug-seeking behavior (Koob & Le Moal 2005, Koob & Volkow 2009).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites Koob & Le Moal 2005

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    • cites Koob & Volkow 2009

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  • May combine two claims.

    Premisecitation

    Other measurable withdrawal manifestations include reduced heart rate, altered neurohormonal profiles, disrupted electroencephalographic theta power, and perturbations of learned behaviors.

    “Other quantifiable manifestations include reduced heart rates, altered neurohormonal profiles, disrupted electroencephalographic theta power, and perturbations of learned behaviors (Buchhalter et al. 2008, Koob & Le Moal 2005).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Buchhalter et al. 2008

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    • cites Koob & Le Moal 2005

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  • May combine two claims.

    Premisecitation

    Powerful cravings accompany withdrawal and can be triggered by drug-reinforced memories such as seeing a cigarette or a smoking-associated place.

    “Powerful cravings also accompany withdrawal, and they may be precipitated by drug-reinforced memories, such as the sight of a cigarette and the place associated with smoking (Dalley & Everitt 2009, Dani & Montague 2007, Shiffman et al. 2002, Smolka et al. 2005, Volkow et al. 2002).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites Dalley & Everitt 2009

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    • cites Dani & Montague 2007

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    • cites Shiffman et al. 2002

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  • May combine two claims.

    Premisecitation

    Nicotine cessation increases prodynorphin mRNA levels in nucleus accumbens dynorphinergic neurons, possibly as compensation for increased dynorphinergic tone.

    “Nicotine cessation increases the levels of prodynorphin mRNA in NAc dynorphinergic neurons, possibly as a compensatory mechanism to increased dynorphinergic tone (Isola et al. 2008).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Isola et al. 2008

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  • May combine two claims.

    Premisecitation

    Dynorphins decrease and enkephalins increase the release of DA.

    “In particular, dynorphins decrease and enkephalins increase the release of DA (Devine et al. 1993; Di Chiara & Imperato 1988; Longoni et al. 1991; Pentney & Gratton 1991; Spanagel et al. 1990a,b, 1992).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites Devine et al. 1993 source

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    • cites Di Chiara & Imperato 1988

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    • cites Longoni et al. 1991

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    The overall neuroadaptations contribute to mechanisms that maintain nicotine consumption, including associative learning, and also participate in the nicotine-withdrawal syndrome.

    “The overall neuroadaptations contribute to the mechanisms that maintain nicotine consumption, including mechanisms underlying associative learning (Tang & Dani, 2009), and they also participate in the nicotine-withdrawal syndrome (De Biasi & Salas 2008, Hadjiconstantinou & Neff 2010).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites Tang & Dani, 2009

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    • cites De Biasi & Salas 2008

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    • cites Hadjiconstantinou & Neff 2010

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  • May combine two claims.

    Premisecitation

    The endogenous opioid system influences positive and negative motivational and affective states and participates in the behavioral effects of several addictive drugs, including nicotine.

    “The endogenous opioid system influences positive and negative motivational and affective states (Steiner & Gerfen 1998) and participates in the behavioral effects of several addictive drugs, including nicotine (Berrendero et al. 2005, Hadjiconstantinou & Neff 2010, Trigo et al. 2009).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites Steiner & Gerfen 1998

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    • cites Berrendero et al. 2005

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    • cites Hadjiconstantinou & Neff 2010

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  • May combine two claims.

    Interpretationreasoning

    The anxiety-like behavior in rodents resembles human nicotine-abstinence anxiety and suggests that anxiety sensitivity affects withdrawal severity.

    “This phenomenon is similar to the anxiety reported by humans experiencing nicotine abstinence and suggests that the sensitivity to anxiety influences the degree of withdrawal signs.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    During withdrawal, the nucleus accumbens shows a dopamine deficit while the prefrontal cortex shows increased dopamine output.

    “During withdrawal, the NAc displays a DA deficit, whereas the PFC has an increase in DA output (Carboni et al. 2000).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Carboni et al. 2000

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  • May combine two claims.

    Interpretationnone given

    Withdrawal reflects abrupt disruption of the equilibrium maintained by nicotine and triggers new neuroadaptations that counteract the negative state.

    “Withdrawal reflects the abrupt disruption of the equilibrium maintained in the presence of nicotine, and withdrawal triggers new neuroadaptations that counteract the negative state.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Mecamylamine is the best antagonist for precipitating nicotine withdrawal, with slightly higher affinity for α3β4* than β2* nAChRs.

    “Mecamylamine, which has a slightly higher affinity for α3β4* nAChRs than for β2* receptors, is the best antagonist at precipitating nicotine withdrawal (Damaj et al. 2003).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Damaj et al. 2003

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  • May combine two claims.

    Premisecitation

    Nicotine abstinence increases dopamine uptake into synaptosomes and elevates dopamine transporters in the substantia nigra/ventral tegmental area.

    “Nicotine abstinence is accompanied by increased DA uptake into synaptosomes and elevated DA transporters (DATs) in the SNc/VTA (Hadjiconstantinou & Neff 2010, Rahman et al. 2004).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites Hadjiconstantinou & Neff 2010

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    • cites Rahman et al. 2004

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  • May combine two claims.

    Interpretationnone given

    Anhedonia, conditioned place aversion, anxiety-related behavior, and conditioned fear are four major affective manifestations of nicotine withdrawal.

    “Anhedonia, conditioned place aversion, anxiety-related behavior, and conditioned fear are four major affective manifestations of nicotine withdrawal.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Enhanced prefrontal cortex dopamine transmission occurs during stressful and aversive stimuli and is implicated in anxiety.

    “Because enhanced DA transmission in the PFC occurs during stressful and aversive stimuli and is implicated in anxiety”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites Bradberry et al. 1991

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    • cites Broersen et al. 2000

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    • cites Inglis & Moghaddam 1999

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  • May combine two claims.

    Interpretationcitation

    Bupropion may aid smoking cessation partly by normalizing nucleus accumbens dopamine levels, which may attenuate anhedonia and somatic withdrawal signs.

    “Buproprion may aid smoking cessation, in part, by normalizing NAc DA levels, and those DA levels may in turn attenuate anhedonia and somatic withdrawal signs (Cryan et al. 2003, Paterson & Markou 2007).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites Cryan et al. 2003

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    • cites Paterson & Markou 2007

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    • Rests on an assumption: Bupropion inhibits nAChRs and is mainly a norepinephrine/dopamine reuptake blocker.

  • May combine two claims.

    Premisecitation

    Nicotine withdrawal produces deficits in contextual fear conditioning and affects acquisition of learned responses.

    “as nicotine withdrawal produces deficits in contextual fear conditioning and affects the acquisition of learned responses (Portugal et al. 2008).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Portugal et al. 2008

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Both spontaneous and mecamylamine-precipitated nicotine withdrawal increase self-stimulation thresholds.

    “Both spontaneous (Epping-Jordan et al. 1998, Harrison et al. 2001) and mecamylamine-precipitated (Watkins et al. 2000) nicotine withdrawal induce increases in self-stimulation thresholds.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites Epping-Jordan et al. 1998

      Not checked in the free run.

    • cites Harrison et al. 2001

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    • cites Watkins et al. 2000 source

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  • May combine two claims.

    Premisecitation

    Absence of β4 abolishes mecamylamine-precipitated somatic withdrawal signs and prevents withdrawal-induced hyperalgesia.

    “Absence of β4 abolishes the somatic signs of withdrawal precipitated by systemic injection of mecamylamine (Salas et al. 2004b) and prevents withdrawal-induced hyperalgesia (Salas et al. 2004b).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Salas et al. 2004b

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    18-Methoxycoronaridine is a potent antagonist of β4* nAChRs with significant antiaddictive properties.

    “Third, a derivative of the alkaloid ibogaine, 18-methoxycoronaridine (18-MC) (Vastag 2005), is a potent antagonist of β4* nAChRs (Glick et al. 2002) with significant antiaddictive properties (Maisonneuve & Glick 2003).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites Glick et al. 2002

      Not checked in the free run.

    • cites Maisonneuve & Glick 2003

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  • May combine two claims.

    Interpretationreasoning

    The main circuits for regulated nicotine dosing are the mesocorticolimbic dopamine system and epithalamic habenular circuits, with one supporting the rising arm and the other the falling arm of the inverted U dose-response curve.

    “The primary circuits underlying this exquisitely regulated dosing are mainly the mesocorticolimbic DA system and the epithalamic habenular circuits: One supports the rising arm, the other the falling arm of the inverted U dose-response curve.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Smokers regulate puffing and inhalation depth to achieve the most desirable nicotine dose at the top of the inverted U dose-response curve.

  • May combine two claims.

    Premisecitation

    In animal models, 18-MC reduces self-administration of nicotine, morphine, cocaine, and methamphetamine; reduces oral intake of alcohol and nicotine; and decreases opioid withdrawal signs.

    “In animal models, 18-MC reduced self-administration of nicotine, morphine, cocaine, and methamphetamine; reduced oral intake of alcohol and nicotine; and decreased signs of opioid withdrawal (Maisonneuve & Glick 2003).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Maisonneuve & Glick 2003

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Mice heterozygous for the α3 subunit show attenuated nicotine-induced seizures, and α3 lies in the same gene cluster as α5 and β4.

    “Attenuation of nicotine-induced seizure is also present in mice heterozygous for the α3 subunit, which is found in the same gene cluster that contains α5 and β4 (Boulter et al. 1990, Salas et al. 2004a).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Boulter et al. 1990 source

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    • cites Salas et al. 2004a

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  • May combine two claims.

    Premisecitation

    The SNP rs16969968 within CHRNA5 correlates with nicotine dependency risk, heavy smoking, and the pleasurable sensation produced by a cigarette.

    “Recent findings on the influence of gene variants in the CHRNA5-CHRNA3-CHRNB4 gene cluster on nicotine addiction (Bierut et al. 2008, Thorgeirsson et al. 2008) show that a single nucleotide polymorphism (SNP) within CHRNA5, rs16969968, seems to correlate with nicotine dependency risk, heavy smoking, and the pleasurable sensation produced by a cigarette (Berrettini et al. 2008, Bierut et al. 2008,”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites Berrettini et al. 2008

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    • cites Bierut et al. 2008

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    • cites Saccone et al. 2007

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60 of 60

  • The paper relies on this without support.

    No mRNA encoding nAChR subunits can be detected in the lateral habenula by in situ hybridization.

    “and no mRNA encoding for nAChR subunits can be detected in the LHb by in situ hybridization techniques.”

  • The paper relies on this without support.

    Smokers regulate puffing and inhalation depth to achieve the most desirable nicotine dose at the top of the inverted U dose-response curve.

    “Smokers finely control nicotine intake by regulating how they puff on a cigarette and how deeply they inhale. In that way, they achieve the most desirable nicotine dose, at the top of the inverted U dose-response curve.”

  • The paper relies on this without support.

    Bupropion inhibits nAChRs and is mainly a norepinephrine/dopamine reuptake blocker.

    “Although buproprion inhibits nAChRs, it is mainly a norepinephrine/DA re-uptake blocker.”
3 of 3

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • The DAergic system, particularly the mesocorticolimbic pathway, is involved in drug addiction because DA modulates limbic and cortical sites for goal-directed behavior.

    “The role of the DAergic system (in particular the mesocorticolimbic pathway) in drug addiction derives from DA’s ability to modulate many of the limbic and cortical sites involved in goal-directed behavior (Fig. 1) [18, 28–31].”

    From Mechanistic insights into nicotine withdrawal (2011) · cites this paper as [18]

  • The LHb is a source of anti-reward signals that influences reward-related DA neuron activity.

    “Studies conducted in recent years have identified the LHb as a source of anti-reward signals that plays an important role in determining the reward-related activity of DA neurons [18, 30, 68–70].”

    From Mechanistic insights into nicotine withdrawal (2011) · cites this paper as [18]

  • Nicotine follows an inverted U-shaped dose-response curve, and smokers titrate intake to get rewarding effects while avoiding aversive effects of high doses.

    “Nicotine follows an inverted U-shaped dose-response curve [18, 60], and smokers titrate their nicotine intake to experience the rewarding while avoiding the aversive effects produced by high nicotine doses [61–64].”

    From Mechanistic insights into nicotine withdrawal (2011) · cites this paper as [18]

  • The habenulo-interpeduncular pathway has been implicated in the addictive effects of smoking.

    “as well as the habenulo-interpeduncular pathway, which has been implicated in the addictive effects of smoking (Dani and Bertrand, 2007;De Biasi and Dani, 2011).”

    From Varenicline Is a Potent Partial Agonist at α6β2* Nicotinic Acetylcholine Receptors in Rat and Monkey Striatum (2012) · cites this paper as De Biasi and Dani, 2011

  • The mesolimbic dopamine system is a major contributor to reward function and addiction.

    “Another critical site of action would be the mesolimbic dopamine system, which is a major contributor to reward function and addiction”

    From Varenicline Is a Potent Partial Agonist at α6β2* Nicotinic Acetylcholine Receptors in Rat and Monkey Striatum (2012) · cites this paper as De Biasi and Dani, 2011

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

  • Gene-cluster receptors are assigned opposite effects on nicotine aversion

    Minor

    The paper says subunits in this gene cluster reduce nicotine's aversive effects, but then argues that insufficient functional α5 receptors-one of those subunits-would result in fewer aversive effects. These statements assign opposite effects to α5 receptor function.

1 of 1

Cites

Flagged first, then by citations

5 of the 305 references couldn’t be matched to a known paper.

Research works printed but not linked: 8

  1. Am. Psychiatr. Assoc. (APA), 2000, American Psychiatric Association, Diagnostic and Statistical Manual—IVTR
  2. Benowitz NL., 2001, Risks Associated with Smoking Cigarettes with Low Machine-Measured Yields of Tar and Nicotine, 39
  3. Corringer PJ, 2006, J. Physiol., 99, 162
  4. Ellison G, 1996, NIDA Res. Monogr., 163, 117
  5. Klemm WR., 2004, Med. Sci. Monit., 10, RA261
  6. Salas R, 2010, Front. Hum. Neurosci., 4, 36
  7. Smolka MN, 2005, Psychopharmacology, 184, 1
  8. Thorndike EL, 1911, Animal Intelligence

Cited by

Sorted by citations

Related

Authors
De Biasi, M., & Dani, J. A.
Affiliations
Baylor College of Medicine (US)
ORCID
Dani, John A.
Venue
Annual Review of Neuroscience
Publisher
Annual Reviews
Published
2011-07-21
Volume
34
Issue
1
Pages
105-130
ISSN
  • 0147-006X (ISSN-L)
  • 1545-4126
DOI
10.1146/annurev-neuro-061010-113734
PMC
PMC3137256
OpenAlex
W2165425515
Semantic Scholar
c6462f78d05c8073c59243cb5544623aa43f3c33
Cited by
366
References
305
Citations by year
2026: 12 · 2025: 17 · 2024: 20 · 2023: 13 · 2022: 13 · 2021: 14 · 2020: 32 · 2019: 23 · 2018: 22 · 2017: 36 · 2016: 28 · 2015: 29 · 2014: 42 · 2013: 27 · 2012: 33
FWCI
3.13
Type
journal article
Language
en
Open access
Locations
  • Annual Review of Neuroscience (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • Cancer Research Institute
  • Cancer Prevention and Research Institute of Texas
  • National Institutes of Health
  • National Institute on Drug Abuse (R21DA029157, DA09411, DA017173, R01DA017173, R01DA009411, DA029157)
  • National Cancer Institute (U19CA148127)
  • National Institute of Neurological Disorders and Stroke (NS 21229, R37NS021229, R01NS021229)
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 › Neurotransmitter Receptor Influence on Behavior
Keywords
nicotine, nicotine dependence, nicotine withdrawal, reward, mesocorticolimbic dopamine system, nicotinic acetylcholine receptors, nicotinic receptor subunits, dopaminergic neurons, neural adaptation, habenula, tobacco use
MeSH terms
Animals, Cerebral Cortex, Dopamine, Humans, Limbic System, Neuronal Plasticity, Neurons, Nicotine, Receptors, Nicotinic, Reward, Substance Withdrawal Syndrome, Behavior, Addictive

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.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-08.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-08.

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