The DOI matches its Crossref record; 300 of the 305 references it cites were found in a registry or an index; none of the 310 sources its claims cite is checked for support yet.
Reward, Addiction, Withdrawal to Nicotine
Open accessAbstract
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.
Overview
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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.
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Claims the paper makes
151 Not checked yet · 17 Own interpretation · 2 No basis given
None of the sources cited for this claim have been checked yet.
In the paper
“The epithalamic habenular complex and its targets appear to be critical for the withdrawal syndrome.”
§ Reward, Addiction, Withdrawal to Nicotine > INTRODUCTION AND SUMMARY
What the sources say
- Not checked yetcites Salas et al. 2004b
- Not checked yetcites Salas et al. 2009
hedgedconditional- Asserted: passes — The authors put it forward as true.
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In the paper
“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).”
§ Reward, Addiction, Withdrawal to Nicotine > REWARD AND INITIATION OF ADDICTION
What the sources say
- Not checked yetcites Garris et al. 1999
- Not checked yetcites Gratton et al. 1988
- Not checked yetcites Phillips et al. 1989
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In the paper
“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).”
§ Reward, Addiction, Withdrawal to Nicotine > REWARD AND INITIATION OF ADDICTION
What the sources say
- Not checked yetcites Hodos 1961
- Not checked yetcites Schultz 2006
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A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“The withdrawal syndrome is not mediated exactly by the same mechanisms or by the same neural circuits that initiate addiction or dependency.”
§ Reward, Addiction, Withdrawal to Nicotine > INTRODUCTION AND SUMMARY
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In the paper
“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).”
§ Reward, Addiction, Withdrawal to Nicotine > REWARD AND INITIATION OF ADDICTION
What the sources say
- Not checked yetcites Schultz et al. 1997
- Not checked yetcites Wise 2004
- Not checked yetcites Wise & Rompre 1989
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In the paper
“as exemplified by lesions in the PPT reducing nicotine self-administration (Lanca et al. 2000).”
§ Reward, Addiction, Withdrawal to Nicotine > REWARD AND INITIATION OF ADDICTION
What the sources say
- Not checked yetcites Lanca et al. 2000
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“In addition, the PPT/LDT cholinergic afferents have important endogenous influences over DA neurons by acting via nAChRs (Maskos 2008, 2010).”
§ Reward, Addiction, Withdrawal to Nicotine > REWARD AND INITIATION OF ADDICTION
What the sources say
- Not checked yetcites Maskos 2008 source
- Not checked yetcites Maskos 2010
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“nicotine is the main addictive component (Benowitz 2009, Dani et al. 2009, Dani & Heinemann 1996, Mansvelder & McGehee 2002).”
§ Reward, Addiction, Withdrawal to Nicotine > INTRODUCTION AND SUMMARY
What the sources say
- Not checked yetcites Benowitz 2009
- Not checked yetcites Dani et al. 2009
- Not checked yetcites Dani & Heinemann 1996
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In the paper
“Therefore, reward mechanisms are observed across species, from insects to primates (Hodos 1961, Lau et al. 2006, McClure et al. 2007, Qin & Wheeler 2007, Wise 2006).”
§ Reward, Addiction, Withdrawal to Nicotine > REWARD AND INITIATION OF ADDICTION
What the sources say
- Not checked yetcites Hodos 1961
- Not checked yetcites Lau et al. 2006
- Not checked yetcites McClure et al. 2007
plain- Asserted: passes — The authors put it forward as true.
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- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
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In the paper
“Likewise, this DA system plays a critical role in the acquisition of behaviors that are inappropriately reinforced by psychostimulant drugs, including nicotine (Balfour 2004, Corrigall 1999, Dani et al. 2009, Dani & Heinemann 1996, Di Chiara 2000, Mansvelder & McGehee 2002).”
§ Reward, Addiction, Withdrawal to Nicotine > INTRODUCTION AND SUMMARY
What the sources say
- Not checked yetcites Balfour 2004
- Not checked yetcites Corrigall 1999
- Not checked yetcites Dani et al. 2009
plaindirect- Asserted: passes — The authors put it forward as true.
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- It may state two separate claims as one. 60
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In the paper
“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).”
§ Reward, Addiction, Withdrawal to Nicotine > INTRODUCTION AND SUMMARY
What the sources say
- Not checked yetcites Dani et al. 2009
- Not checked yetcites Dani & Heinemann 1996
- Not checked yetcites De Biasi & Salas 2008
plaindirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“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).”
§ Reward, Addiction, Withdrawal to Nicotine > REWARD AND INITIATION OF ADDICTION
What the sources say
- Not checked yetcites Fouriezos & Wise 1976
- Not checked yetcites Lippa et al. 1973
- Not checked yetcites Stellar & Corbett 1989
plaindirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
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In the paper
“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).”
§ Reward, Addiction, Withdrawal to Nicotine > INTRODUCTION AND SUMMARY
What the sources say
- Not checked yetcites Imperato et al. 1986
- Not checked yetcites Grenhoff et al. 1986
- Not checked yetcites Mameli-Engvall et al. 2006
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Rewarding stimuli promote learning of goal-directed behaviors, generate positive emotions, and subsequently stimulate repetition of those learned behaviors (Schultz 2010, Thorndike 1911).”
§ Reward, Addiction, Withdrawal to Nicotine > REWARD AND INITIATION OF ADDICTION
What the sources say
- Not checked yetcites Schultz 2010
- Not checked yetcites Thorndike 1911
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“In particular, the mesocorticolimbic dopamine (DA) system plays an important role in self-stimulation and in processing environmental reward.”
§ Reward, Addiction, Withdrawal to Nicotine > INTRODUCTION AND SUMMARY
What the sources say
- Not checked yetcites Olds 1958
- Not checked yetcites Olds & Milner 1954
plaincorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“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).”
§ Reward, Addiction, Withdrawal to Nicotine > REWARD AND INITIATION OF ADDICTION
What the sources say
- Not checked yetcites Phillips & Olds 1969
- Not checked yetcites Fibiger 1978
- Not checked yetcites Wise 1978
plaincorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“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).”
§ Reward, Addiction, Withdrawal to Nicotine > INTRODUCTION AND SUMMARY
What the sources say
- Not checked yetcites Salas et al. 2004b
- Not checked yetcites Salas et al. 2009
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“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).”
§ Reward, Addiction, Withdrawal to Nicotine > REWARD AND INITIATION OF ADDICTION
What the sources say
- Not checked yetcites Pidoplichko et al. 2004
- Not checked yetcites Schilstrom et al. 2000
- Not checked yetcites Mansvelder et al. 2002
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“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).”
§ Reward, Addiction, Withdrawal to Nicotine > DOWNSTREAM FROM DOPAMINE NEURON PHASIC BURSTS
What the sources say
- Not checked yetcites Butcher & Woolf 1984
- Not checked yetcites Zhou et al. 2001
- Not checked yetcites Zhou et al. 2002
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“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).”
§ Reward, Addiction, Withdrawal to Nicotine > DOWNSTREAM FROM DOPAMINE NEURON PHASIC BURSTS
What the sources say
- Not checked yetcites Di Chiara 1999
- Not checked yetcites Pidoplichko et al. 2004
- Not checked yetcites Pontieri et al. 1996
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“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.”
§ Reward, Addiction, Withdrawal to Nicotine > DOWNSTREAM FROM DOPAMINE NEURON PHASIC BURSTS
What the sources say
- Not checked yetcites Grenhoff et al. 1986
- Not checked yetcites Pidoplichko et al. 1997
- Not checked yetcites Schilstrom et al. 2003
hedgeddirect- Asserted: passes — The authors put it forward as true.
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In the paper
“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).”
§ Reward, Addiction, Withdrawal to Nicotine > REWARD AND INITIATION OF ADDICTION
What the sources say
- Not checked yetcites Schultz 2007b
- Not checked yetcites Schultz et al. 1997
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“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).”
§ Reward, Addiction, Withdrawal to Nicotine > REWARD AND INITIATION OF ADDICTION
What the sources say
- Not checked yetcites Grace et al. 2007
- Not checked yetcites Grace & Bunney 1983
- Not checked yetcites Hyland et al. 2002
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In the paper
“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.”
§ Reward, Addiction, Withdrawal to Nicotine > REWARD AND INITIATION OF ADDICTION
What the sources say
- Not checked yetcites Avale et al. 2008
boosteddirect- Asserted: passes — The authors put it forward as true.
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In the paper
“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).”
§ Reward, Addiction, Withdrawal to Nicotine > REWARD AND INITIATION OF ADDICTION
What the sources say
- Not checked yetcites Champtiaux et al. 2003
- Not checked yetcites Salminen et al. 2007
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“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).”
§ Reward, Addiction, Withdrawal to Nicotine > REWARD AND INITIATION OF ADDICTION
What the sources say
- Not checked yetcites Grottick & Higgins 2000
- Not checked yetcites Stolerman et al. 2004
- Not checked yetcites Walters et al. 2006
hedged- Asserted: passes — The authors put it forward as true.
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In the paper
“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).”
§ Reward, Addiction, Withdrawal to Nicotine > DOWNSTREAM FROM DOPAMINE NEURON PHASIC BURSTS
What the sources say
- Not checked yetcites Pons et al. 2008
- Not checked yetcites Zhou et al. 2001
- Not checked yetcites Zhou et al. 2003
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“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).”
§ Reward, Addiction, Withdrawal to Nicotine > DOWNSTREAM FROM DOPAMINE NEURON PHASIC BURSTS
What the sources say
- Not checked yetcites Schultz W. 2007b
- Not checked yetcites Laviolette 2007
- Not checked yetcites Seamans & Yang 2004
plaincorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“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).”
§ Reward, Addiction, Withdrawal to Nicotine > REWARD AND INITIATION OF ADDICTION
What the sources say
- Not checked yetcites Schultz 2007b
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“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).”
§ Reward, Addiction, Withdrawal to Nicotine > REWARD AND INITIATION OF ADDICTION
What the sources say
- Not checked yetcites Pons et al. 2008
plaindirect- Asserted: passes — The authors put it forward as true.
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A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ Reward, Addiction, Withdrawal to Nicotine > REWARD AND INITIATION OF ADDICTION
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“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).”
§ Reward, Addiction, Withdrawal to Nicotine > REWARD AND INITIATION OF ADDICTION
What the sources say
- Not checked yetcites Pidoplichko et al. 1997
- Not checked yetcites Mameli-Engvall et al. 2006
- Not checked yetcites Schilstrom et al. 2000
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“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).”
§ Reward, Addiction, Withdrawal to Nicotine > REWARD AND INITIATION OF ADDICTION
What the sources say
- Not checked yetcites Mameli-Engvall et al. 2006
- Not checked yetcites Picciotto et al. 1998
plain- Asserted: passes — The authors put it forward as true.
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The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“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).”
§ Reward, Addiction, Withdrawal to Nicotine > DOWNSTREAM FROM DOPAMINE NEURON PHASIC BURSTS
hedgeddirect- Asserted: passes — The authors put it forward as true.
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In the paper
“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).”
§ Reward, Addiction, Withdrawal to Nicotine > DOWNSTREAM FROM DOPAMINE NEURON PHASIC BURSTS
What the sources say
- Not checked yetcites Zhang et al. 2009b
hedged- Asserted: passes — The authors put it forward as true.
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None of the sources cited for this claim have been checked yet.
In the paper
“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”
§ Reward, Addiction, Withdrawal to Nicotine > DOWNSTREAM FROM DOPAMINE NEURON PHASIC BURSTS
What the sources say
- Not checked yetcites Rice & Cragg 2004
- Not checked yetcites Zhang & Sulzer 2004
- Not checked yetcites Zhou et al. 2001
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“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.”
§ Reward, Addiction, Withdrawal to Nicotine > DOWNSTREAM FROM DOPAMINE NEURON PHASIC BURSTS
What the sources say
- Not checked yetcites Zhang et al. 2009a
- Not checked yetcites Zhang et al. 2009b
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“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.”
§ Reward, Addiction, Withdrawal to Nicotine > AVERSIVE SENSORY SIGNALING IN THE MESOCORTICOLIMBIC SYSTEM
What the sources say
- Not checked yetcites Brischoux et al. 2009
- Not checked yetcites Ungless et al. 2004
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“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.”
§ Reward, Addiction, Withdrawal to Nicotine > DOWNSTREAM FROM DOPAMINE NEURON PHASIC BURSTS
What the sources say
- Not checked yetcites Cragg 2003
- Not checked yetcites Rice & Cragg 2004
- Not checked yetcites Zhang et al. 2009a
hedgeddirect- Asserted: passes — The authors put it forward as true.
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In the paper
“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).”
§ Reward, Addiction, Withdrawal to Nicotine > AVERSIVE SENSORY SIGNALING IN THE MESOCORTICOLIMBIC SYSTEM
What the sources say
- Not checked yetcites Jhou et al. 2009b
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“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).”
§ Reward, Addiction, Withdrawal to Nicotine > AVERSIVE SENSORY SIGNALING IN THE MESOCORTICOLIMBIC SYSTEM
What the sources say
- Not checked yetcites Roitman et al. 2005
plaindirect- Asserted: passes — The authors put it forward as true.
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- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
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In the paper
“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).”
§ Reward, Addiction, Withdrawal to Nicotine > NICOTINE-INDUCED NEUROADAPTATIONS
What the sources say
- Not checked yetcites Novak et al. 2010
- Not checked yetcites Briand et al. 2008
- Not checked yetcites Grigoriadis & Seeman 1986
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“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).”
§ Reward, Addiction, Withdrawal to Nicotine > AVERSIVE SENSORY SIGNALING IN THE MESOCORTICOLIMBIC SYSTEM
What the sources say
- Not checked yetcites Roitman et al. 2008
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“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).”
§ Reward, Addiction, Withdrawal to Nicotine > NICOTINE-INDUCED NEUROADAPTATIONS
What the sources say
- Not checked yetcites Gaimarri et al. 2007
- Not checked yetcites Marks et al. 1983 source
- Not checked yetcites McCallum et al. 2006
plaincorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“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).”
§ Reward, Addiction, Withdrawal to Nicotine > NICOTINE-INDUCED NEUROADAPTATIONS
What the sources say
- Not checked yetcites Dani & Heinemann 1996
- Not checked yetcites Fenster et al. 1999
- Not checked yetcites Picciotto et al. 2008
plaindirect- Asserted: passes — The authors put it forward as true.
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None of the sources cited for this claim have been checked yet.
In the paper
“The RMTg sends GABAergic projections to the VTA and SNc and inhibits DA cells (Ikemoto 2010, Jhou et al. 2009a).”
§ Reward, Addiction, Withdrawal to Nicotine > AVERSIVE SENSORY SIGNALING IN THE MESOCORTICOLIMBIC SYSTEM
What the sources say
- Not checked yetcites Ikemoto 2010
- Not checked yetcites Jhou et al. 2009a
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“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).”
§ Reward, Addiction, Withdrawal to Nicotine > AVERSIVE SENSORY SIGNALING IN THE MESOCORTICOLIMBIC SYSTEM
What the sources say
- Not checked yetcites Groenewegen et al. 1986
- Not checked yetcites Klemm 2004
- Not checked yetcites Montone et al. 1988
plaincorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“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).”
§ Reward, Addiction, Withdrawal to Nicotine > BEHAVIORAL MANIFESTATIONS OF NICOTINE WITHDRAWAL
What the sources say
- Not checked yetcites Koob & Le Moal 2005
- Not checked yetcites Koob & Volkow 2009
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“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).”
§ Reward, Addiction, Withdrawal to Nicotine > BEHAVIORAL MANIFESTATIONS OF NICOTINE WITHDRAWAL
What the sources say
- Not checked yetcites Buchhalter et al. 2008
- Not checked yetcites Koob & Le Moal 2005
plain- Asserted: passes — The authors put it forward as true.
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- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
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In the paper
“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).”
§ Reward, Addiction, Withdrawal to Nicotine > BEHAVIORAL MANIFESTATIONS OF NICOTINE WITHDRAWAL
What the sources say
- Not checked yetcites Dalley & Everitt 2009
- Not checked yetcites Dani & Montague 2007
- Not checked yetcites Shiffman et al. 2002
hedgedconditional- Asserted: passes — The authors put it forward as true.
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- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
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In the paper
“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).”
§ Reward, Addiction, Withdrawal to Nicotine > BEHAVIORAL MANIFESTATIONS OF NICOTINE WITHDRAWAL
What the sources say
- Not checked yetcites Isola et al. 2008
hedgeddirect- Asserted: passes — The authors put it forward as true.
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- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
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It may state two separate claims as one.
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In the paper
“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).”
§ Reward, Addiction, Withdrawal to Nicotine > NICOTINE-INDUCED NEUROADAPTATIONS
What the sources say
- Not checked yetcites Devine et al. 1993 source
- Not checked yetcites Di Chiara & Imperato 1988
- Not checked yetcites Longoni et al. 1991
plaindirect- Asserted: passes — The authors put it forward as true.
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- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
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It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“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).”
§ Reward, Addiction, Withdrawal to Nicotine > NICOTINE-INDUCED NEUROADAPTATIONS
What the sources say
- Not checked yetcites Tang & Dani, 2009
- Not checked yetcites De Biasi & Salas 2008
- Not checked yetcites Hadjiconstantinou & Neff 2010
plaindirect- Asserted: passes — The authors put it forward as true.
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None of the sources cited for this claim have been checked yet.
In the paper
“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).”
§ Reward, Addiction, Withdrawal to Nicotine > NICOTINE-INDUCED NEUROADAPTATIONS
What the sources say
- Not checked yetcites Steiner & Gerfen 1998
- Not checked yetcites Berrendero et al. 2005
- Not checked yetcites Hadjiconstantinou & Neff 2010
plaindirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ Reward, Addiction, Withdrawal to Nicotine > BEHAVIORAL MANIFESTATIONS OF NICOTINE WITHDRAWAL
hedgedconditional- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
In the paper
“During withdrawal, the NAc displays a DA deficit, whereas the PFC has an increase in DA output (Carboni et al. 2000).”
§ Reward, Addiction, Withdrawal to Nicotine > MOLECULAR MECHANISMS OF WITHDRAWAL
What the sources say
- Not checked yetcites Carboni et al. 2000
plaincorrelational- Asserted: passes — The authors put it forward as true.
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- Load-bearing: passes — The paper’s conclusions depend on it.
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It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Withdrawal reflects the abrupt disruption of the equilibrium maintained in the presence of nicotine, and withdrawal triggers new neuroadaptations that counteract the negative state.”
§ Reward, Addiction, Withdrawal to Nicotine > MOLECULAR MECHANISMS OF WITHDRAWAL
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“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).”
§ Reward, Addiction, Withdrawal to Nicotine > BEHAVIORAL MANIFESTATIONS OF NICOTINE WITHDRAWAL
What the sources say
- Not checked yetcites Damaj et al. 2003
plaindirect- Asserted: passes — The authors put it forward as true.
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- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
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It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“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).”
§ Reward, Addiction, Withdrawal to Nicotine > MOLECULAR MECHANISMS OF WITHDRAWAL
What the sources say
- Not checked yetcites Hadjiconstantinou & Neff 2010
- Not checked yetcites Rahman et al. 2004
plaindirect- Asserted: passes — The authors put it forward as true.
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- Load-bearing: passes — The paper’s conclusions depend on it.
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It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Anhedonia, conditioned place aversion, anxiety-related behavior, and conditioned fear are four major affective manifestations of nicotine withdrawal.”
§ Reward, Addiction, Withdrawal to Nicotine > BEHAVIORAL MANIFESTATIONS OF NICOTINE WITHDRAWAL
plaindirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“Because enhanced DA transmission in the PFC occurs during stressful and aversive stimuli and is implicated in anxiety”
§ Reward, Addiction, Withdrawal to Nicotine > MOLECULAR MECHANISMS OF WITHDRAWAL
What the sources say
- Not checked yetcites Bradberry et al. 1991
- Not checked yetcites Broersen et al. 2000
- Not checked yetcites Inglis & Moghaddam 1999
plaincorrelational- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“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).”
§ Reward, Addiction, Withdrawal to Nicotine > MOLECULAR MECHANISMS OF WITHDRAWAL
What the sources say
- Not checked yetcites Cryan et al. 2003
- Not checked yetcites Paterson & Markou 2007
hedgedconditional- Asserted: passes — The authors put it forward as true.
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- Load-bearing: passes — The paper’s conclusions depend on it.
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It may state two separate claims as one.
- Rests on an assumption: Bupropion inhibits nAChRs and is mainly a norepinephrine/dopamine reuptake blocker.
In the paper
“as nicotine withdrawal produces deficits in contextual fear conditioning and affects the acquisition of learned responses (Portugal et al. 2008).”
§ Reward, Addiction, Withdrawal to Nicotine > BEHAVIORAL MANIFESTATIONS OF NICOTINE WITHDRAWAL
What the sources say
- Not checked yetcites Portugal et al. 2008
plaindirect- Asserted: passes — The authors put it forward as true.
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- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
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It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“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.”
§ Reward, Addiction, Withdrawal to Nicotine > BEHAVIORAL MANIFESTATIONS OF NICOTINE WITHDRAWAL
What the sources say
- Not checked yetcites Epping-Jordan et al. 1998
- Not checked yetcites Harrison et al. 2001
- Not checked yetcites Watkins et al. 2000 source
plaindirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
In the paper
“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).”
§ Reward, Addiction, Withdrawal to Nicotine > DISTINCT NICOTINIC RECEPTOR SUBTYPES MEDIATE WITHDRAWAL
What the sources say
- Not checked yetcites Salas et al. 2004b
plaindirect- Asserted: passes — The authors put it forward as true.
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- Load-bearing: passes — The paper’s conclusions depend on it.
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None of the sources cited for this claim have been checked yet.
In the paper
“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).”
§ Reward, Addiction, Withdrawal to Nicotine > DISTINCT NICOTINIC RECEPTOR SUBTYPES MEDIATE WITHDRAWAL
What the sources say
- Not checked yetcites Glick et al. 2002
- Not checked yetcites Maisonneuve & Glick 2003
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
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It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ Reward, Addiction, Withdrawal to Nicotine > DISTINCT NICOTINIC RECEPTOR SUBTYPES MEDIATE WITHDRAWAL
plaindirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
- 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.
In the paper
“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).”
§ Reward, Addiction, Withdrawal to Nicotine > DISTINCT NICOTINIC RECEPTOR SUBTYPES MEDIATE WITHDRAWAL
What the sources say
- Not checked yetcites Maisonneuve & Glick 2003
plaindirect- Asserted: passes — The authors put it forward as true.
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- Load-bearing: passes — The paper’s conclusions depend on it.
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It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“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).”
§ Reward, Addiction, Withdrawal to Nicotine > DISTINCT NICOTINIC RECEPTOR SUBTYPES MEDIATE WITHDRAWAL
What the sources say
- Not checked yetcites Boulter et al. 1990 source
- Not checked yetcites Salas et al. 2004a
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
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It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“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,”
§ Reward, Addiction, Withdrawal to Nicotine > DISTINCT NICOTINIC RECEPTOR SUBTYPES MEDIATE WITHDRAWAL
What the sources say
- Not checked yetcites Berrettini et al. 2008
- Not checked yetcites Bierut et al. 2008
- Not checked yetcites Saccone et al. 2007
hedgedcorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
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.”
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 source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“Therefore, during the withdrawal period, phasic DA neuron activity of the kind induced by nicotine (9, 30) re-exposure induces DA signals that may make smokers in the withdrawal period more vulnerable to the reinforcing influence of nicotine (2).”
From Withdrawal from Chronic Nicotine Exposure Alters Dopamine Signaling Dynamics in the Nucleus Accumbens (2012) · cites this paper as [2]
Experimental — accuracy not yet measuredThe cited source says what the claim attributes to it.
In the citing paper
“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]
In the citing paper
“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]
In the citing paper
“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]
In the citing paper
“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
In the citing paper
“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.
Rated minor: it would not touch a result — a value no result rests on, a p-value that stays on the same side of the significance level, or a conflict that is clerical, resolved elsewhere in the paper, or outside its own findings.
In the paper
§ Reward, Addiction, Withdrawal to Nicotine > DISTINCT NICOTINIC RECEPTOR SUBTYPES MEDIATE WITHDRAWAL
“Because the nAChR subunits comprised in the CHRNA5-CHRNA3-CHRNB4 reduce the aversive effects of nicotine and drive its consumption”
§ Reward, Addiction, Withdrawal to Nicotine > DISTINCT NICOTINIC RECEPTOR SUBTYPES MEDIATE WITHDRAWAL
“people with SNP rs16969968 smoke more and become addicted at a younger age because they lack sufficient functional α5* nAChRs. The presence of fewer aversive effects (even at higher nicotine doses) during the initial contact with the drug would promote the hedonic drive”
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Lee, B. G., Anastasía, A., Hempstead, B. L., Lee, F. S., & Blendy, J. A. (2015) · Nicotine & Tobacco Research · doi:10.1093/ntr/ntv047 · Cited by 13
Cole, R. D., Zimmerman, M., Matchanova, A., Kutlu, M. G., Gould, T. J., & Parikh, V. (2019) · Neuropsychopharmacology · doi:10.1038/s41386-019-0574-6 · Cited by 15
Saravia, R., Ten-Blanco, M., Pereda-Pérez, I., & Berrendero, F. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms222413316 · Cited by 14
“Since regular smokers maintain levels of circulating nicotine over the course of the day, nAChRs remain longer in a desensitized state [54,55].”
BackgroundThe effect of nicotine patches on craving in the brain
Liberman, K., Schuerbeek, P. V., Herremans, S. C., Meysman, M., Mey, J. D., & Buls, N. (2018) · Medicine · doi:10.1097/md.0000000000012415 · Cited by 11
Yang, K., McLaughlin, I., Shaw, J. K., Cardé, N. A. Q., Dani, J. A., & Biasi, M. D. (2023) · Neuropharmacology · doi:10.1016/j.neuropharm.2023.109547 · Cited by 12
Self-citationA qualitative study of smokers’ views on brain-based explanations of tobacco dependence
Morphett, K., Carter, A., Hall, W., & GARTNER, C. E. (2015) · International Journal of Drug Policy · doi:10.1016/j.drugpo.2015.12.011 · Cited by 12
Magnesium and Zinc Involvement in Tobacco Addiction
Nechifor, M. (2012) · Journal of Addiction Research & Therapy · doi:10.4172/2155-6105.s2-005 · Cited by 10
“The nicotine increases the firing rate and the phasic burst of midbrain dopaminergic neurons [23].”
BackgroundEadaim, A., Hahm, E.-T., Justice, E. D., & Tsunoda, S. (2020) · Cell Reports · doi:10.1016/j.celrep.2020.108119 · Cited by 11
Ding, Z., Li, X., Chen, H., Hou, H., & Hu, Q. (2022) · Frontiers in Molecular Neuroscience · doi:10.3389/fnmol.2022.925272 · Cited by 11
Lee, A. M., Arreola, A. C., Kimmey, B. A., & Schmidt, H. D. (2014) · Behavioural Brain Research · doi:10.1016/j.bbr.2014.08.016 · Cited by 13
Yong, Z., Yan, L., Gao, X., Gong, Z., & Su, R. (2014) · Neuroscience · doi:10.1016/j.neuroscience.2014.05.026 · Cited by 12
“Of these nuclei, the NAc plays a vital role in the cognitive, hedonic and motor effects of drugs of abuse, and in the transition to addiction (De Biasi and Dani, 2011).”
BackgroundUnburned Tobacco Smoke Affects Neuroinflammation-Related Pathways in the Rat Mesolimbic System
Morosini, C., Vivarelli, F., Rullo, L., Volino, E., Losapio, L. M., Paolini, M., Romualdi, P., Canistro, D., & Candeletti, S. (2024) · International Journal of Molecular Sciences · doi:10.3390/ijms25105259 · Cited by 12
“In particular, in the central nervous system (CNS), nicotine stimulates the cortical and limbic brain structures, which mediate rewarding motivational effects, including the ventral tegmental area (VTA) and the nucleus accumbens (NAc) [3].”
BackgroundMoyen, N. E., Anderson, H. M., Burchfield, J. M., et al. (2015) · American Journal of Physiology-Regulatory, Integrative and Comparative Physiology · doi:10.1152/ajpregu.00079.2015 · Cited by 11
“, decreased heart rate and hypothalamic pituitary adrenal axis dysregulation; (11)].”
BackgroundSmoking addiction in chronic obstructive pulmonary disease
Klinke, M. E., & Jónsdóttir, H. (2014) · Chronic Respiratory Disease · doi:10.1177/1479972314546764 · Cited by 14
“An abundance of research has proved the addictive nature of smoking, by both describing the addictive behavior of smoking and confirming the addiction by means of functional brain image studies.(14,15) The diagnostic criteria for (nicotine) dependence have been indexed and fulfill the criteria defined by the American…”
BackgroundMethodInfluentialComparison of color discrimination in chronic heavy smokers and healthy subjects
Fernandes, T. P., & dos Santos, N. A. (2017) · F1000Research · doi:10.12688/f1000research.10714.1 · Cited by 11
Comparison of color discrimination in chronic heavy smokers and healthy subjects
Fernandes, T. P., de Almeida, N. L. P., & dos Santos, N. A. (2017) · F1000Research · doi:10.12688/f1000research.10714.3 · Cited by 11
Bade, A. N., Gendelman, H. E., Boska, M. D., & Liu, Y. (2017) · Europe PMC (PubMed Central) · Cited by 10
Giromini, L., Viglione, D. J., Vitolo, E., et al. (2019) · Scandinavian Journal of Psychology · doi:10.1111/sjop.12585 · Cited by 11
Bağdaş, D., Rupprecht, L. E., Nunes, E. J., Schillinger, E. S., Immanuel, J. J., & Addy, N. (2021) · Nicotine & Tobacco Research · doi:10.1093/ntr/ntab241 · Cited by 11
Brain CYP2B induction can decrease nicotine levels in the brain
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“Chronic nicotine exposure in rats and in smoking leads to adaptive changes, such as nAchR upregulation (Benwell et al. 1988; Lapchak et al. 1989), which is thought to be compensatory mechanisms in response to the continued presence of nicotine in the brain (De Biasi & Dani 2011).”
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Jensen, K. P., DeVito, E. E., & Sofuoglu, M. (2016) · Tobacco Regulatory Science · doi:10.18001/trs.2.4.14 · Cited by 11
Exploring the association between melatonin and nicotine dependence (Review)
Georgakopoulou, V., Sklapani, P., Τράκας, Ν., Reiter, R. J., & Spandidos, D. A. (2024) · International Journal of Molecular Medicine · doi:10.3892/ijmm.2024.5406 · Cited by 12
“Chronic nicotine exposure leads to neuro‑ adaptations, altering the reward circuitry of the brain and perpetuating addiction (37).”
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Jones, J. D., Arout, C. A., Luba, R. R., Murugesan, D., Madera, G., Gorsuch, L., Schusterman, R., & Martinez, S. (2024) · Pharmacology Biochemistry and Behavior · doi:10.1016/j.pbb.2024.173771 · Cited by 12
Leach, P. T., Holliday, E. D., Kutlu, M. G., & Gould, T. J. (2014) · Nicotine & Tobacco Research · doi:10.1093/ntr/ntu229 · Cited by 12
Rose, J. E., & Dehkordi, O. (2016) · Journal of Addiction Research & Therapy · doi:10.4172/2155-6105.1000274 · Cited by 10
“The direct effects of nicotine on CNS neurons are critical for its reward and addiction properties [5-9].”
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Hoek, J. A., Waa, A. M., Edwards, R., Gregan, M.-J., & Graham‐DeMello, A. (2025) · Journal of the Royal Society of New Zealand · doi:10.1080/03036758.2025.2455498 · Cited by 13
“Yet despite knowledge of factors that foster smoking uptake and complicate cessation (De Biasi and Dani 2011; Chaiton et al. 2016), no government introduced a co-ordinated strategy to realise the Smokefree 2025 goal.”
Animal Models to Investigate the Impact of Flavors on Nicotine Addiction and Dependence
Bağdaş, D., Kebede, N., Zepei, A. M., Harris, L., Minanov, K., Picciotto, M. R., & Addy, N. (2022) · Current Neuropharmacology · doi:10.2174/1570159x20666220524120231 · Cited by 8
“Nicotine, the primary addictive substance in tobacco and alternative tobacco products [10], binds to nicotinic acetylcholine receptors (nAChRs) and can activate brain reward circuits [11].”
Smith, M. L., Mignogna, K. M., Rokita, J. L., Macleod, L. C., Damaj, M. I., & Miles, M. F. (2023) · Genes Brain & Behavior · doi:10.1111/gbb.12844 · Cited by 9
“documented to show modulation in dopamine signaling during nicotine withdrawal.(19) Therefore, to further enhance candidate gene analysis for the Nic_ssw1 and Nic_ptow1 QTLs, we con-”
BackgroundMethodInfluentialHan, P., Jing, X., Han, S., Wang, X., Li, Q., Zhang, Y., Yu, P., Liu, X.-A., Wu, P., Chen, H., et al. (2023) · Frontiers in Neuroscience · doi:10.3389/fnins.2023.1288102 · Cited by 8
Liu, Y., Harding, M., Doré, J. J. E., & Chen, X. (2017) · Progress in Neuro-Psychopharmacology and Biological Psychiatry · doi:10.1016/j.pnpbp.2017.02.004 · Cited by 8
“2 LTCCs mediate burst firing in the VTA (Liu et al., 2007,2014), thus increasing dopamine transmission in the terminals (Chergui et al., 1994; Sulzer et al., 2016) sufficient for place preference conditioning in vivo (Tsai et al., 2009) and mediate nicotine reinforcement (De Biasi and Dani, 2011).”
Smokers with insomnia symptoms are less likely to stop smoking
Hägg, S. A., Ljunggren, M. E., Janson, C., Holm, M., Franklin, K. A., Gíslason, Þ., Johannessen, A., Jögi, R., Olin, A., Schlünssen, V., et al. (2020) · Respiratory Medicine · doi:10.1016/j.rmed.2020.106069 · Cited by 9
Patel, D. G., Vishwakarma, P. K., Patel, R., & Jain, N. S. (2020) · Behavioural Brain Research · doi:10.1016/j.bbr.2020.112997 · Cited by 7
Bidwell, L. C., Balestrieri, S. G., Colby, S. M., Knopik, V. S., & Tidey, J. W. (2017) · Psychopharmacology · doi:10.1007/s00213-017-4753-z · Cited by 9
“…ADHD have increased sensitivity to nicotine, in part by highlighting alterations in dopamine and other catecholamine function in brain regions and neurotransmitter systems (Brennan and Arnsten 2008) that are also modulated by both chronic and acute nicotine administration (De Biasi and Dani 2011).”
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“This relationship may be pronounced in heavy smokers; nicotine, as the predominant addictive constituent and reinforcing property in tobacco products, is the primary driver of repeated cigarette smoking secondary to the neurological rewarding effects [83], especially with chronic nicotine exposure [84].”
BackgroundNicotine Motivated Behavior in C. elegans
Salim, C., Batsaikhan, E., Kan, A. K., Chen, H., & Jee, C. (2024) · International Journal of Molecular Sciences · doi:10.3390/ijms25031634 · Cited by 10
“…increases the fi ring rate of midbrain neurons by mammals, nicotine increases the firing rate of midbrain dopamine neurons by stimulating α 4 β 2nAChRs, promoting nicotine dependence via the dopamine receptor [36]. stimulating α 4 β 2nAChRs, promoting nicotine dependence via the receptor [36].”
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“In alignment with the findings of this study, previous research conducted by our team and other researchers has consistently reported anxiogenic effects linked to withdrawal from tobacco smoking or nicotine [35,39,46,53,54].”
ResultFlavonoids: a natural remedy in the prevention and management of diverse diseases
Yu, B., Zhang, J. C., Zhu, M.-X., Li, Z., Ren, L., Zhang, F., Liu, C., & Zhang, L. (2025) · Frontiers in Medicine · doi:10.3389/fmed.2025.1713869 · Cited by 11
Neurobiological Considerations for Tobacco Use Disorder
Chawla, M., & Garrison, K. A. (2018) · Current Behavioral Neuroscience Reports · doi:10.1007/s40473-018-0168-3 · Cited by 9
Du, X. M., Choa, F., Chiappelli, J., Bruce, H. A., Kvarta, M. D., Summerfelt, A. T., Ma, Y., Regenold, W. T., Walton, K. M., Wittenberg, G. F., et al. (2024) · Brain stimulation · doi:10.1016/j.brs.2024.02.020 · Cited by 9
“Nicotine addiction has long been associated with aberrant reward signaling [60,61] and abstinence from smoking is strongly associated with stress and anxiety [62,63].”
BackgroundBeliefs modulate the effects of drugs on the human brain
Volkow, N. D., & Baler, R. (2015) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1500552112 · Cited by 7
Cotinine Conundrum--A Step Forward but Questions Remain
Spitz, M. R., Amos, C. I., Bierut, L. J., & Caporaso, N. E. (2012) · JNCI Journal of the National Cancer Institute · doi:10.1093/jnci/djs211 · Cited by 8
Zhang, K.-M., Zhao, G.-Y., Zhang, B.-B., Xu, Q. K., Chu, C., Jin, H., & Qiu, D. (2016) · Neuroscience Letters · doi:10.1016/j.neulet.2016.12.005 · Cited by 8
Exploring the interoceptive stimulus effects of nicotine and varenicline
Thompson, B. M., Barrett, S. T., & Bevins, R. A. (2019) · Pharmacology Biochemistry and Behavior · doi:10.1016/j.pbb.2019.04.001 · Cited by 8
Scientific overview: 2013 BBC plenary symposium on tobacco addiction
Biasi, M. D., McLaughlin, I., Perez, E. E., Crooks, P. A., Dwoskin, L. P., Bardo, M. T., Pentel, P. R., & Hatsukami, D. K. (2014) · Drug and Alcohol Dependence · doi:10.1016/j.drugalcdep.2014.05.013 · Cited by 7
“Second, smoking is also motivated by the urge to alleviate affective, cognitive, and physical symptoms of withdrawal that emerge during periods of abstinence (De Biasi and Dani, 2011).”
BackgroundSelf-citationC. elegansand mutants with chronic nicotine exposure as a novel model of cancer phenotype
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Interactions between the Nicotinic and Endocannabinoid Receptors at the Plasma Membrane
Vallés, A. S., & Barrantes, F. J. (2022) · Membranes · doi:10.3390/membranes12080812 · Cited by 7
Varani, A. P., Antonelli, M. C., & Balerio, G. N. (2013) · Progress in Neuro-Psychopharmacology and Biological Psychiatry · doi:10.1016/j.pnpbp.2013.02.016 · Cited by 7
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The Effects of Nicotine and Cannabinoids on Cytokines
Miller, G., Pareek, O., Penman, S. L., & Thanos, P. K. (2024) · Current Pharmaceutical Design · doi:10.2174/0113816128293077240529111824 · Cited by 6
Unraveling the Role of CHRNA6, the Neuronal α6 Nicotinic Acetylcholine Receptor Subunit
Heydary, Y. H., Castro, E. M., Lotfipour, S., & Leslie, F. M. (2025) · Receptors · doi:10.3390/receptors4010001 · Cited by 8
Momentary Associations Between Reported Craving and Valuing Health in Daily Smokers
MacLean, R. R., Martino, S., Carroll, K. M., Smyth, J. M., Pincus, A. L., & Wilson, S. J. (2016) · Nicotine & Tobacco Research · doi:10.1093/ntr/ntw253 · Cited by 6
Tan, X., Neslund, E. M., & Ding, Z. (2023) · Neuropharmacology · doi:10.1016/j.neuropharm.2023.109495 · Cited by 7
Riggs, N. R., Anthenien, A. M., & Leventhal, A. M. (2016) · Substance Use & Misuse · doi:10.3109/10826084.2015.1126742 · Cited by 7
“For example, although nicotinic acetylcholine receptors are expressed throughout the brain, they are more densely expressed in the mesolimbic dopaminergic system of the brain (i.e., ventral tegmental area), responsible for reward sensitivity and motivation (De Biasi & Dani, 2011).”
BackgroundZamboni, L., Marchetti, P., Congiu, A., Giordano, R., Fusina, F., Carli, S., Centoni, F., Verlato, G., & Lugoboni, F. (2021) · International Journal of Environmental Research and Public Health · doi:10.3390/ijerph18062920 · Cited by 6
“This particular process could be explained with an alteration in dopamine and other catecholaminergic functions in the brain regions and neuro-transmitter systems that are also modulated by both chronic and acute nicotine administration [34,35].”
BackgroundAdministration of Nicotine Can Inhibit Myopic Growth in Animal Models
Thomson, K., Karouta, C., & Ashby, R. (2024) · Investigative Ophthalmology & Visual Science · doi:10.1167/iovs.65.11.29 · Cited by 5
Liu, M., Wang, H., Fu, Y., Li, X., Wu, P., Liu, G., Wang, R., Zhang, Y., Chen, H., Hou, H., et al. (2024) · Molecular Neurobiology · doi:10.1007/s12035-024-04040-8 · Cited by 5
Qiu, L., Liang, C., Kochunov, P. V., Hutchison, K. E., Jing Sui （Beijing Normal University）， my correct affiliation is beijing normal university, N. Q. U. O. S. A. T., Jiang, R., Zhi, D., Vergara, V. M., Yang, X., Zhang, D., et al. (2024) · Translational Psychiatry · doi:10.1038/s41398-024-03035-2 · Cited by 5
“Nicotine modulates affect by increasing the concentration of dopamine in the FLN [41], which involves the mesocorticolimbic dopamine system, contributing to the processing of rewarding sensory stimuli during the overall shaping of successful behaviors [42, 43].”
BackgroundWang, Y., Yang, Z., Shi, X., Han, H., Li, A. N., Zhang, B., Yuan, W., Sun, Y., Li, X., Lian, H., et al. (2025) · Communications Biology · doi:10.1038/s42003-025-07837-y · Cited by 8
Nicotina y modelos animales: ¿qué nos aporta el paradigma de enriquecimiento ambiental?
Mesa‐Gresa, P., Pérez‐Martinez, A., & Redolat, R. (2012) · Adicciones · doi:10.20882/adicciones.100 · Cited by 5
Lacidipine Attenuates Symptoms of Nicotine Withdrawal in Mice
Khurana, K., Kumar, M., & Bansal, N. (2021) · Neurotoxicity Research · doi:10.1007/s12640-021-00421-2 · Cited by 5
Devi, S., Goyal, S., Rathor, B. S., Kumar, P., & Singla, S. (2023) · International Journal of Science and Research Archive · doi:10.30574/ijsra.2023.9.1.0352 · Cited by 5
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Kollins, S. H., Schoenfelder, E. N., English, J. S., McClernon, F. J., Dew, R. E., & Lane, S. D. (2013) · Experimental and Clinical Psychopharmacology · doi:10.1037/a0033851 · Cited by 5
“First, at a neuropharmacological level, nicotine facilitates dopamine release in relevant pathways in a manner similar to psychostimulants that are commonly used in the clinical treatment of ADHD (Rush et al., 2002; Brody et al., 2004; De Biasi & Dani, 2011; Grace, 2001; Volkow et al., 2012).”
BackgroundDao, D. Q., Salas, R., & Biasi, M. D. (2014) · The Receptors · doi:10.1007/978-1-4939-1167-7_18 · Cited by 5
Self-citationToyoda, H. (2019) · Synapse · doi:10.1002/syn.22094 · Cited by 5
“Particularly, it is considered that dopamine systems are essential components for rewarding and dependence properties of nicotine (De Biasi & Dani, 2011).”
BackgroundVarenicline rescues nicotine-induced decrease in motivation for sucrose reinforcement
Hart, E. E., Hertia, D., Barrett, S. T., & Charntikov, S. (2020) · Behavioural Brain Research · doi:10.1016/j.bbr.2020.112887 · Cited by 3
The link between tobacco smoking and susceptibility to misinformation
Piksa, M., Zaniewska, M., Cieslik-Starkiewicz, A., Kunst, J. R., Morzy, M., Piasecki, J., & Ryguła, R. (2025) · Psychopharmacology · doi:10.1007/s00213-025-06802-1 · Cited by 4
The Pharmacogenetics of Nicotine Dependence and Smoking Cessation Therapies
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Preclinical Aspects of Nicotinic Acetylcholine Receptor Imaging
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Haibach, J. P., Homish, G. G., Collins, R. L., Ambrosone, C. B., & Giovino, G. A. (2014) · Nicotine & Tobacco Research · doi:10.1093/ntr/ntu215 · Cited by 4
The involvement of mesolimbic dopamine system in cotinine self-administration in rats
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“As nicotine stimulates brain activity of the reward-signaling neurotransmitter, dopamine (De Biasi and Dani 2011; Jasinska et al. 2013), tobacco smoking might contribute to calm smokers (Nichter et al. 2007).”
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“Nicotine, the primary psychoactive ingredient in tobacco, is highly addictive and a key determinant of the continuation of tobacco use (Benowitz, 2010; De Biasi & Dani, 2011).”
BackgroundMousavi, S., Rezayof, A., Alijanpour, S., Delphi, L., & Sahafi, O. H. (2023) · Pharmacology, Biochemistry and Behavior · doi:10.1016/j.pbb.2023.173650 · Cited by 3
Effects of Tobacco Use on the Macrostructure and Microstructure of Sleep in Patients with OSA
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Preclinical and Clinical Aspects of Nicotinic Acetylcholine Receptor Imaging
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A medial habenula neural circuit controlling anxiety-like behaviors in response to acute stress
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“Nicotine regulates various neurobiological processes underlying reward, learning and memory, stress response, anxiety, food intake, and metabolism (13, 32, 42, 51).”
BackgroundMMM – The molecular model of memory
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Uncovering the basis of nicotine addiction
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Peroxisome Proliferator-Activated Nuclear Receptors and Drug Addiction
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Reward Circuitry and Drug Addiction
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Metadata
- 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
- 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
- green
- www.ncbi.nlm.nih.gov
- 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 › Public Health, Environmental and Occupational Health › 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.
A language model drew the claims from the paper on 2026-10-08, under version 3 of the claim definition (model deepseek-v4.1-flash, prompt extract-v3).
A second model labelled each claim on 2026-10-08 (model jev-1.13-20260917, definition revision gold-guideline-v0.2).
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