Withdrawal from Chronic Nicotine Exposure Alters Dopamine Signaling Dynamics in the Nucleus Accumbens
Open accessAbstract
Background Unaided attempts to quit smoking commonly fail during the first two weeks of the nicotine withdrawal syndrome. Alterations in dopamine (DA) signaling correlate with withdrawal from chronic nicotine exposure, but those changes have not been well characterized. Methods Mice were administered nicotine in their drinking water for 4 or 12 weeks. Then nicotine was withheld for 1 to 10 days while DA signaling was characterized using in vivo microdialysis or fast-scan cyclic voltammetry. Results Upon withdrawal of nicotine, the basal DA concentration in the nucleus accumbens decreased as measured by microdialysis. The length of time that the low basal DA state lasted depended on the length of the chronic nicotine treatment. Microdialysis indicated that acute re-exposure to nicotine during withdrawal temporarily reversed this hypodopaminergic state. Voltammetry measurements supported the microdialysis results by showing that nicotine withdrawal decreased tonic and phasic DA release. The basal DA concentration and tonic DA signals, however, were disproportionately lower than the phasic DA signals. Therefore, the phasic/tonic DA signaling ratio was increased during the withdrawal period. Conclusions The relative increase in the sensitivity of DA release to phasic stimulation suggests an increase in the signal-to-noise relationship of DA signaling during the withdrawal period. Therefore, the DA signal produced by acute nicotine re-exposure produces a DA response that may reinforce relapse to drug use (i.e., smoking). Because the basal DA concentration is low during withdrawal, therapies aimed at elevating the background DA signal represent a reasonable treatment strategy for nicotine dependent individuals attempting to quit.
AI snapshot
Written from the paper’s full text.
TL;DR
Withdrawal from chronic nicotine in mice lowered basal nucleus accumbens dopamine and disproportionately reduced tonic versus phasic dopamine release, increasing the phasic/tonic dopamine signaling ratio. Acute nicotine re-exposure temporarily restored dopamine levels, which the authors suggest may enhance relapse-related reinforcement during abstinence.
Key findings
- One day after withdrawal, basal DA in the medial NAc was significantly lower after 4 weeks (0.22 ± 0.03 nM, n = 7) and 12 weeks (0.24 ± 0.01 nM, n = 7) of nicotine than in controls (0.31 ± 0.02 nM, n = 9; p < 0.05).
- Acute nicotine (1 mg/kg, i.p.) during withdrawal increased absolute DA to similar levels within 20 min across groups, but the relative nicotine-induced DA response was significantly higher in both 4-week and 12-week withdrawal groups than in controls.
- Voltammetry showed lower evoked DA after withdrawal: single-pulse DA was 0.13 ± 0.01 μM × s vs. control 0.21 ± 0.02 μM × s, and 5-pulse phasic DA was 0.54 ± 0.05 vs. control 0.70 ± 0.06 (p < 0.01); the phasic-to-tonic ratio increased to 4.2 ± 0.15 from 3.4 ± 0.13 (p < 0.05).
- The paired-pulse P2/P1 ratio was higher after withdrawal (0.89 ± 0.12) than in controls (0.59 ± 0.05; p < 0.001), and DHβE reduced single-pulse DA by only 19 ± 8% after withdrawal vs. 57 ± 5% in controls (p < 0.01).
Methods
- Wild-type C57BL/6J mice aged 2–3 months received nicotine hydrogen tartrate (300 μg/ml) in drinking water with 2% saccharin for 4 or 12 weeks, then nicotine was withdrawn for 1, 5, or 10 days; controls received saccharin water.
- DA signaling was measured using in vivo microdialysis in the medial NAc and fast-scan cyclic voltammetry in NAc shell brain slices with tonic (≈3 Hz) and phasic (≈20 Hz) stimulation protocols.
- Dialysate DA was quantified by HPLC and analyzed with repeated-measures ANOVA on log-transformed concentrations; voltammetric DA signals were analyzed by paired t test or one-way ANOVA, with significance at p < 0.05.
Limitations
- Stated: the authors note that their results contrast with a previous rat study (Rahman et al., 2004) and suggest species-related quantitative differences between rats and mice may account for the difference.
- Stated: DHβE may not block all high-affinity nAChRs with equal efficacy, and upregulation of less common β2* nAChRs or changes in subunit composition could contribute to altered DA release during withdrawal.
- Evident: the study focuses on DA and nAChR mechanisms while noting that nicotine also modulates GABA, glutamate, cholinergic, serotonin, and opioid systems; these other systems were not directly tested here.
Model-written summary. Check it against the paper before relying on it.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
0 of 8 cited sources checked · 0 supported · 0 flagged
- Findingown data
In slices from mice treated with nicotine for 12 weeks, dopamine release evoked by tonic and phasic stimulation was generally reduced after 1 day of withdrawal compared with controls.
“In brain slices from mice chronically treated with nicotine (12 wks), there was a general reduction in DA release evoked by tonic and phasic stimulation after withdrawal (1 day) compared to the controls (Figure 3B).”
Quote in the paperSubstantial claim - Findingown data
After single-stimulus dopamine release returned to control levels, the phasic-to-tonic ratio also returned to normal.
“After DA release to a single stimulus (1p) returned to control levels, then the phasic/tonic ratio also returned to normal (Figure 6B, C).”
Quote in the paperSubstantial claim - Findingown data
In control nucleus accumbens slices, a single pulse evoked a smaller dopamine signal than phasic stimulation with 5 pulses at 20 Hz.
“In control NAc slices (Figure 4A), a single pulse (1p) stimulation evoked a smaller DA signal (0.21 ± 0.02 μM × s, n = 51) compared to phasic stimulation (0.70 ± 0.06 μM × s, n = 51).”
Quote in the paperSubstantial claim - Findingown data
Baseline dopamine concentration was inversely related to the percent increase in dopamine concentration produced by the nicotine challenge.
“Interestingly, the baseline DA concentration (Figure 5C) was inversely related to the percent increase in DA concentration produced by the nicotine challenge (Figure 5D).”
Quote in the paperNot a substantial claim - Findingown data
Voltammetric recordings showed a disproportionate inhibition of tonic release compared with release evoked by phasic bursts.
“Coupled with this hypothesized decrease in DA neuron firing, our voltammetric recordings showed a disproportionate inhibition of tonic release compared to release evoked by phasic bursts.”
Quote in the paperSubstantial claim
- Findingown data
One day and 5 days after withdrawal from 12 weeks of nicotine, dopamine signals were lower across all stimulation frequencies tested.
“Voltammetric recordings further confirmed that 1 day and 5 days after withdrawal (from 12 wks of nicotine) DA signals were lower across all stimulation frequencies (1p, and 5p at 5–20 Hz) (Figure 6A).”
Quote in the paperSubstantial claim - Findingown data
After 1 day of withdrawal, basal dopamine concentration in the medial nucleus accumbens was significantly lower after 4 weeks and 12 weeks of nicotine treatment than in controls.
“The mean basal DA concentration (Figure 2B,C) was significantly lower (p < 0.05) after 4 weeks (0.22 ± 0.03 nM, n = 7) and 12 weeks (0.24 ± 0.01 nM, n = 7) of nicotine treatment compared to the control (0.31 ± 0.02 nM, n = 9).”
Quote in the paperSubstantial claim - Findingown data
Paired pulses evoked smaller dopamine signals in the 12-week group after 1 day of withdrawal than in the control group.
“Paired pulses evoked smaller DA signals (0.18 ± 0.03, n = 17) in the 12-week group after withdrawal (1 day) compared to the control group (0.32 ± 0.03, n = 45, p < 0.05).”
Quote in the paperSubstantial claim - Findingown data
When dopamine signals were normalized to the tonic plateau response, the percent change in phasic dopamine signaling was enhanced after nicotine withdrawal compared with controls.
“However, by normalizing the DA signals to the tonic plateau response, we found that the percent change in phasic DA signaling was enhanced after nicotine withdrawal compared to the controls (Figure 3C).”
Quote in the paperSubstantial claim - Findingown data
Nicotine withdrawal increased the slope of the relationship between dopamine signal and number of pulses.
“Nicotine withdrawal increased the slope of this relationship (Figure 4D, black data), indicating an increased sensitivity to phasic burst length.”
Quote in the paperSubstantial claim - Findingown data
After 12 weeks of nicotine treatment, baseline dopamine levels did not return to normal until 10 days after withdrawal.
“In contrast, after 12 wks of nicotine treatment, the baseline DA levels did not return to normal until 10 days after withdrawal (Figure 5B).”
Quote in the paperSubstantial claim - Findingown data
The ratio of phasic-to-tonic dopamine release in control mice was 3.4 ± 0.13.
“The ratio between these two measurements (i.e., the ratio of phasic-to-tonic DA release) was 3.4 ± 0.13 in control mice, indicating a potentiation of phasic evoked DA responses.”
Quote in the paperSubstantial claim - Findingown data
Both the 4-week and 12-week withdrawal groups had a significantly larger relative nicotine-induced dopamine response than control mice.
“Both the 4-week and 12-week withdrawal groups showed a significantly higher relative nicotine-induced DA response compared to the control mice (Figure 2E,F).”
Quote in the paperSubstantial claim - Findingown data
There was no difference in basal dopamine levels between the 4-week and 12-week nicotine treatment groups after 1 day of withdrawal.
“There was no difference in basal DA levels between the 4-week and 12-week nicotine treatments after 1 day of withdrawal: F(1,12) = 0.73, p > 0.05.”
Quote in the paperNot a substantial claim - Findingown data
The decrease in dopamine concentration measured by microdialysis lasted longer after 12 weeks of nicotine treatment than after 4 weeks.
“The DA concentration decrease measured by microdialysis lasted longer after 12 weeks of nicotine treatment than after 4 weeks of treatment.”
Quote in the paperSubstantial claim - Findingown data
In control slices, DHβE at 100 nM decreased the single-pulse evoked dopamine signal by 57 ± 5%.
“Inhibition of high-affinity nAChRs with DHβE (100 nM) in control slices decreased the single-pulse evoked DA signal by 57 ± 5 %, n = 16 (Figure 7A, B).”
Quote in the paperSubstantial claim - Findingown data
The t90% measure of dopamine signal decay was not significantly different before and after chronic nicotine treatment.
“We found that this measure (t90%) was not significantly different before (control, 0.63 ± 0.44 s) and after chronic nicotine treatment (0.71 ± 0.36 s), which is consistent with the work of others (33).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [33] Perez, 2009, Prominent role of alpha3/alpha6beta2* nAChRs in regulating evoked dopamine release in primate putamen: Effect of long-term nicotine treatment, Mol Pharmacol source
Not checked in the free run.
- Findingown data
Acute nicotine re-exposure during withdrawal normalized dopamine concentration to control levels for a short time.
“Re-exposure to acute nicotine during the withdrawal period normalized the DA concentration to control levels for a short time.”
Quote in the paperSubstantial claim - Findingown data
Acute nicotine at 1 mg/kg i.p. after 1 day of withdrawal raised absolute dopamine concentrations to similar levels across all treatment groups within 20 minutes.
“Acute administration of nicotine (1 mg/kg, i.p.) after 1-day of withdrawal increased the absolute DA concentrations to similar levels within 20 min of the injection across all treatments (Figure 2B,D).”
Quote in the paperSubstantial claim - Findingown data
In the nucleus accumbens shell, the control dopamine signal was linearly dependent on the number of pulses during a 20 Hz stimulus train.
“In the NAc shell, the DA signal in the control was linearly dependent on the number of pulses given during a 20 Hz stimulus train (Figure 4D, gray data).”
Quote in the paperSubstantial claim - Findingown data
By day 10, dopamine signals had returned near control levels.
“By day 10, the DA signals returned near to control levels (Figure 6B).”
Quote in the paperSubstantial claim - Findingown data
Voltammetric measurements in the nucleus accumbens shell showed that tonic dopamine release was more strongly inhibited than phasic release during withdrawal.
“Voltammetric measurements in the NAc shell supported this finding by showing that tonic DA release was more strongly inhibited than phasic release during the withdrawal period.”
Quote in the paperSubstantial claim - Findingown data
During periods when tonic single-pulse dopamine signals were inhibited, the phasic-to-tonic dopamine release ratio was higher than in controls.
“During those periods when tonic (1p) DA signals were inhibited, there was a higher ratio of phasic-to-tonic DA release compared to the control (Figure 6B, C).”
Quote in the paperSubstantial claim - Findingown data
The paired-pulse P2/P1 ratio was higher after nicotine withdrawal (0.89 ± 0.12) than in controls (0.59 ± 0.05).
“However, the paired pulse (P2/P1) ratio was higher after nicotine withdrawal (0.89 ± 0.12) compared to the control (0.59 ± 0.05; p < 0.001) (Figure 4C)”
Quote in the paperSubstantial claim - Findingown data
After 4 weeks of nicotine treatment, baseline dopamine levels returned to control levels by day 5 of withdrawal.
“After 4 wks of nicotine treatment, the baseline DA levels returned to control levels by day 5 of withdrawal (Figure 5A).”
Quote in the paperSubstantial claim - Findingown data
Long-term nicotine exposure especially decreased tonic dopamine signals.
“In the present study, we found that long-term nicotine exposure especially decreased the tonic DA signals.”
Quote in the paperSubstantial claim - Findingown data
The positive correlation between evoked dopamine concentration and the number of pulses within a burst was amplified during the withdrawal period.
“That is, the positive correlation between the evoked DA concentration and the number of pulses within a burst was amplified during the withdrawal period.”
Quote in the paperSubstantial claim - Findingown data
There was a steeper increase in dopamine release associated with burst length.
“However, there was a steeper increase in DA release associated with the burst length.”
Quote in the paperSubstantial claim - Interpretationcitation
The general decrease in dopamine function may contribute to motivational deficits such as anhedonia.
“This general decrease in DA function may contribute to motivational deficits such as anhedonia (39).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [39] Volkow, 2002, Role of dopamine, the frontal cortex and memory circuits in drug addiction: Insight from imaging studies, Neurobiol Learn Mem source
Not checked in the free run.
- Interpretationown data
The influence of high-affinity nicotinic acetylcholine receptors over nucleus accumbens dopamine release decreased after chronic nicotine.
“These findings indicate that the influence of high-affinity nAChRs over NAc DA release decreased after chronic nicotine.”
Quote in the paperSubstantial claim- Rests on an assumption: Dopamine release measured by fast-scan cyclic voltammetry in nucleus accumbens slices and by microdialysis reflects the in vivo dopamine signaling that governs nicotine reinforcement.
- Interpretationcitation
The estimated nicotine exposure level in the mice is comparable to that experienced by a chronic smoker.
“This estimated level of nicotine exposure is comparable to what a chronic smoker might experience (26).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [26] Pietila, 2000, Chronic nicotine administration in the drinking water affects the striatal dopamine in mice, Pharmacol Biochem Behav source
Not checked in the free run.
- Interpretationreasoning
Despite deficits in basal dopamine function, the salience of the drug experience upon re-exposure may be greater.
“Therefore, despite these deficits in basal DA function, the salience of the drug experience upon re-exposure may be greater.”
Quote in the paperSubstantial claim- Rests on an assumption: The dopamine signaling changes observed in mice after nicotine withdrawal can be generalized to human smokers and to smoking relapse.
- Rests on an assumption: Dopamine release measured by fast-scan cyclic voltammetry in nucleus accumbens slices and by microdialysis reflects the in vivo dopamine signaling that governs nicotine reinforcement.
- Interpretationreasoning
β2* nicotinic acetylcholine receptors have less influence over phasic dopamine release during the withdrawal period.
“Together these findings suggest that β2* nAChRs have less influence over phasic DA release during the withdrawal period.”
Quote in the paperSubstantial claim- Rests on an assumption: Dopamine release measured by fast-scan cyclic voltammetry in nucleus accumbens slices and by microdialysis reflects the in vivo dopamine signaling that governs nicotine reinforcement.
- Interpretationown data
The increased slope indicates increased sensitivity of dopamine release to phasic burst length.
“That is, phasic bursts induced relatively more DA release during the withdrawal period, and the longer the burst the greater the enhancement of DA release.”
Quote in the paperSubstantial claim - Interpretationreasoning
The alterations in dopamine function after nicotine withdrawal were partly due to a decrease in the influence of high-affinity nicotinic acetylcholine receptors over dopamine release in the nucleus accumbens.
“The alterations in DA function after nicotine withdrawal was partly due to a decrease in the influence of the high-affinity (mainly β2*) nAChRs over DA release in the NAc.”
Quote in the paperSubstantial claim- Rests on an assumption: Dopamine release measured by fast-scan cyclic voltammetry in nucleus accumbens slices and by microdialysis reflects the in vivo dopamine signaling that governs nicotine reinforcement.
- Interpretationreasoning
Because background dopamine levels are lower during withdrawal, dopamine target areas such as the nucleus accumbens shell experience a greater relative change in dopamine concentration.
“Due to lower background DA levels during withdrawal, the DA target areas, such as the NAc shell, experience a greater relative change in DA concentration.”
Quote in the paperSubstantial claim- Rests on an assumption: Dopamine release measured by fast-scan cyclic voltammetry in nucleus accumbens slices and by microdialysis reflects the in vivo dopamine signaling that governs nicotine reinforcement.
- Interpretationreasoning
Increased GABA inhibition would decrease the basal spontaneous firing of dopamine neurons, particularly reducing tonic release.
“Increased GABA inhibition would result in an overall decrease in the basal spontaneous firing of DA neurons: i.e., tonic release would particularly decrease.”
Quote in the paperSubstantial claim - Interpretationreasoning
During withdrawal, phasic dopamine neuron activity of the kind induced by nicotine re-exposure produces dopamine signals that may make smokers more vulnerable to nicotine reinforcement.
“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).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [2] De Biasi, 2011, Reward, addiction, withdrawal to nicotine, Annu Rev Neurosci source
Not checked in the free run.
- Rests on an assumption: The dopamine signaling changes observed in mice after nicotine withdrawal can be generalized to human smokers and to smoking relapse.
- Rests on an assumption: Dopamine release measured by fast-scan cyclic voltammetry in nucleus accumbens slices and by microdialysis reflects the in vivo dopamine signaling that governs nicotine reinforcement.
- Interpretationcitation
Blockade of β2* nicotinic acetylcholine receptors caused less inhibition of phasic dopamine signals than of tonic signals.
“The present study and others indicate that blockade of β2* nAChRs caused less inhibition of phasic DA signals than tonic signals (12).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [12] Zhang, 2009, Controls of tonic and phasic dopamine transmission in the dorsal and ventral striatum, Mol Pharmacol source
Not checked in the free run.
- Rests on an assumption: Dopamine release measured by fast-scan cyclic voltammetry in nucleus accumbens slices and by microdialysis reflects the in vivo dopamine signaling that governs nicotine reinforcement.
- Interpretationown data
After chronic nicotine, stronger inhibition of tonic dopamine release enhanced the contrast between tonic and phasic dopamine signaling.
“After chronic nicotine, the stronger inhibition of tonic DA release enhanced the contrast between tonic and phasic DA signaling.”
Quote in the paperSubstantial claim- Rests on an assumption: Dopamine release measured by fast-scan cyclic voltammetry in nucleus accumbens slices and by microdialysis reflects the in vivo dopamine signaling that governs nicotine reinforcement.
- Interpretationreasoning
Chronic nicotine switched the pattern of dopamine release so that it became more dependent on the number of spikes within a burst.
“It also switched the pattern of DA release so that it was more highly dependent on the number of spikes within a burst.”
Quote in the paperSubstantial claim- Rests on an assumption: Dopamine release measured by fast-scan cyclic voltammetry in nucleus accumbens slices and by microdialysis reflects the in vivo dopamine signaling that governs nicotine reinforcement.
- Interpretationown data
The background dopamine signal indicates the sensitivity of dopamine release to phasic burst firing.
“This result suggests that the background DA signal indicates the sensitivity of DA release to phasic burst firing.”
Quote in the paperSubstantial claim- Rests on an assumption: Dopamine release measured by fast-scan cyclic voltammetry in nucleus accumbens slices and by microdialysis reflects the in vivo dopamine signaling that governs nicotine reinforcement.
- Interpretationreasoning
The signal-to-noise relationship of the dopamine signal is higher after nicotine withdrawal than in controls.
“Thus, the signal-to-noise relationship of the DA signal is higher after nicotine withdrawal than in the controls.”
Quote in the paperSubstantial claim- Rests on an assumption: Dopamine release measured by fast-scan cyclic voltammetry in nucleus accumbens slices and by microdialysis reflects the in vivo dopamine signaling that governs nicotine reinforcement.
- Interpretationreasoning
The reinforcing effects of nicotine during abstinence are particularly strong because nicotine burst firing causes an even stronger relative response than usual.
“Thus, the reinforcing effects of nicotine during abstinence are particularly strong because nicotine burst firing causes an even stronger relative response than usual.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [41] Caille, 2009, Voluntary nicotine consumption triggers in vivo potentiation of cortical excitatory drives to midbrain dopaminergic neurons, J Neurosci source
Not checked in the free run.
- Rests on an assumption: The dopamine signaling changes observed in mice after nicotine withdrawal can be generalized to human smokers and to smoking relapse.
- Rests on an assumption: Dopamine release measured by fast-scan cyclic voltammetry in nucleus accumbens slices and by microdialysis reflects the in vivo dopamine signaling that governs nicotine reinforcement.
- Interpretationreasoning
This may explain why the low basal dopamine signal could rapidly increase in response to nicotine re-exposure.
“This result may explain why the low basal DA signal could rapidly increase in response to nicotine re-exposure.”
Quote in the paperSubstantial claim- Rests on an assumption: Dopamine release measured by fast-scan cyclic voltammetry in nucleus accumbens slices and by microdialysis reflects the in vivo dopamine signaling that governs nicotine reinforcement.
- May combine two claims. 11
- The quote only partly states this claim. 1
- Classified as probably not a substantial claim. 4
May combine two claims.
Findingown dataIn slices from nicotine-withdrawn mice, DHβE reduced the single-pulse evoked dopamine signal by only 19 ± 8%, significantly less than in controls.
“By contrast, in slices from nicotine withdrawn mice, DHβE only reduced the single-pulse evoked signal by 19 ± 8 %, n = 17 (Figure 7A, B), which was significantly less than the control response (p < 0.01).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataAfter chronic nicotine treatment, dopamine signals evoked by a single pulse and by a 5-pulse train were both smaller than control responses.
“After chronic nicotine treatment, the DA signals evoked by the single-pulse stimulus (0.13 ± 0.01 μM × s, n = 51) and the 5-pulse stimulus train (0.54 ± 0.05, n = 51) were both smaller than the control response (p < 0.01) (Figure 4A).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataAn acute nicotine challenge during withdrawal produced a relatively large dopamine response that returned dopamine levels to near control values for a short time.
“However, an acute nicotine challenge during the withdrawal period produced a DA response that was relatively large, returning DA levels to near control values for a short time.”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataIn control brain slices, tonic stimulation produced regular dopamine responses that raised the baseline, while phasic stimulation evoked a larger response that merged into a single transient.
“In control brain slices, tonic stimulation produced regular DA responses that elevated the baseline DA concentration, and phasic stimulation evoked a larger DA response that merged into a single transient (control, Figure 3A).”
Quote in the paperSubstantial claimThe quote only partly states this claim.
Findingown dataAfter chronic nicotine treatment, the ratio of phasic-to-tonic dopamine release increased to 4.2 ± 0.15.
“as well as an increase in the ratio of phasic-to-tonic DA release (4.2 ± 0.15, p < 0.05).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataThe urinary cotinine-to-creatinine ratio reached about 24 μg/mg after 3 weeks of nicotine treatment and stayed stable thereafter.
“The cotinine/creatinine ratio reached peak values (≈24 μg/mg) after 3 wks of nicotine treatment and remained stable thereafter (Figure 1B).”
Quote in the paperNot a substantial claimMay combine two claims.
Findingown dataDHβE reduced the phasic evoked dopamine signal by 29 ± 7% in controls but had almost no effect (1 ± 10%) after nicotine withdrawal.
“Blockade of the high-affinity (mainly β2*) nAChRs only reduced the phasic evoked DA signal by 29 ± 7 % (Figure 7C, D) in the controls, but had almost no effect on phasic DA signals (1 ± 10 %) after nicotine withdrawal.”
Quote in the paperSubstantial claimMay combine two claims.
InterpretationreasoningThe early period after nicotine withdrawal is a critical time for relapse and potentially for intervention.
“suggesting that the early period following nicotine withdrawal is a critical time for relapse and, potentially, for intervention.”
Quote in the paperSubstantial claimMay combine two claims.
Interpretationown dataThe higher paired-pulse ratio after withdrawal suggests a lower initial probability of release and greater facilitation of release.
“suggesting lower initial probability of release and greater facilitation of release after withdrawal.”
Quote in the paperSubstantial claimClassified as probably not a substantial claim.
InterpretationcitationA low dopamine state may drive drug seeking in order to reverse nicotine-induced dopamine deficiencies.
“These studies support the hypothesis that a low DA state may induce drug seeking to reverse the nicotine-induced DA deficiencies.”
Quote in the paperSubstantial claim- Rests on an assumption: The dopamine signaling changes observed in mice after nicotine withdrawal can be generalized to human smokers and to smoking relapse.
May combine two claims.
InterpretationreasoningAdaptations in dopamine signaling caused by chronic nicotine exposure alter responses to nicotine and possibly to nicotine-related stimuli.
“Adaptations in DA signaling caused by chronic nicotine exposure alter the responses to nicotine (the drug) and possibly to nicotine-related stimuli.”
Quote in the paperSubstantial claim- Rests on an assumption: Dopamine release measured by fast-scan cyclic voltammetry in nucleus accumbens slices and by microdialysis reflects the in vivo dopamine signaling that governs nicotine reinforcement.
Probably not a substantial claim: may not pass S3 (load-bearing).
InterpretationcitationSpecies-related quantitative differences in dopamine function between rats and mice may account for differences in results.
“Species related quantitative differences in DA function between rats and mice may account for the differences in the results (42, 43).”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites [42] Ford, 2006, Properties and opioid inhibition of mesolimbic dopamine neurons vary according to target location, J Neurosci source
Not checked in the free run.
- cites [43] Lammel, 2008, Unique properties of mesoprefrontal neurons within a dual mesocorticolimbic dopamine system, Neuron source
Not checked in the free run.
May combine two claims.
InterpretationreasoningBehavioral reinforcement and withdrawal effects induced by nicotine arise from complex interactions between neurotransmitter systems, with dopamine having a key role.
“Thus, the behavioral reinforcement and withdrawal effects induced by nicotine arise from complex interactions between neurotransmitter systems, with DA having a key role.”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing), S4 (based).
Interpretationnone givenAlterations in GABAergic and glutamatergic drive during nicotine withdrawal likely contribute to changes in tonic versus phasic dopamine neuron firing.
“Alterations in GABAergic and glutamatergic drive during nicotine withdrawal likely contribute to changes in tonic versus phasic DA neuron firing.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S2 (checkable).
InterpretationreasoningThese findings have implications for understanding how exposure to drug-associated cues or drug relapse may exploit existing pathological changes in dopamine function arising from long-term nicotine use.
“These findings have implications for understanding how exposure to drug-associated cues or drug relapse may act upon and exploit existing pathological changes in DA function arising from long-term nicotine use.”
Quote in the paperNot a substantial claim- Rests on an assumption: The dopamine signaling changes observed in mice after nicotine withdrawal can be generalized to human smokers and to smoking relapse.
May combine two claims.
InterpretationreasoningDuring nicotine withdrawal, acute nicotine-induced bursts will produce a significant dopamine signal because the release process is more responsive to facilitation produced by burst firing.
“During the nicotine withdrawal period, the acute nicotine-induced bursts will produce a significant DA signal because the release process is more responsive to facilitation produced by burst firing.”
Quote in the paperSubstantial claim- Rests on an assumption: Dopamine release measured by fast-scan cyclic voltammetry in nucleus accumbens slices and by microdialysis reflects the in vivo dopamine signaling that governs nicotine reinforcement.
The paper relies on this without support.
The dopamine signaling changes observed in mice after nicotine withdrawal can be generalized to human smokers and to smoking relapse.
“Therefore, the DA signal produced by acute nicotine re-exposure produces a DA response that may reinforce relapse to drug use (i.e., smoking).”
“may make smokers in the withdrawal period more vulnerable to the reinforcing influence of nicotine (2).”
The paper relies on this without support.
Dopamine release measured by fast-scan cyclic voltammetry in nucleus accumbens slices and by microdialysis reflects the in vivo dopamine signaling that governs nicotine reinforcement.
“Voltammetric recordings in the nucleus accumbens (NAc) showed that tonic DA signals were inhibited to a greater degree than phasic DA signals after nicotine withdrawal, increasing the relative phasic-to-tonic response during the withdrawal period.”
“To mimic tonic firing (≈3 Hz) and phasic burst firing (≈20 Hz) of DA neurons in vivo, we applied a stimulus train using a combination of tonic (7 pulses delivered at 3 Hz) and phasic (5 pulses delivered at 20 Hz) stimulation.”
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?
Deficiencies in accumbal dopaminergic transmission are believed to contribute to the aversive anhedonic or dysphoric state during nicotine abstinence.
“Such deficiencies in accumbal dopaminergic transmission are believed to contribute to the aversive anhedonic or dysphoric state experienced during nicotine abstinence (Koob and Le Moal 2008; Zhang et al. 2012).”
From Nicotine Withdrawal (2015) · cites this paper as Zhang et al. 2012
The change in dopamine activity during withdrawal correlated with reduced modulatory influence of β2* nAChRs over dopamine release in the nucleus accumbens.
“This change in DA activity during withdrawal was correlated with a reduced modulatory influence by β2* nAChRs over DA release in the NAcc.”
From Nicotine Withdrawal (2015) · cites this paper as Zhang et al. 2012
A reduction in basal dopamine levels persisted for at least 5 days in mice after 12 weeks of chronic nicotine treatment.
“A reduction in basal DA levels was observed to linger for at least 5 days in mice following 12 weeks of chronic nicotine treatment (Zhang et al. 2012).”
From Nicotine Withdrawal (2015) · cites this paper as Zhang et al. 2012
Statistics recomputed
Every reported test result, recomputed from its test statistic and degrees of freedom. A result shows as not adding up only once an independent check has confirmed it.
- ConsistentF(1, 12) = 0.73reported p > .05 · recomputed p = .410
“F(1,12) = 0.73, p > .05”
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
Self-check results appear here once an independent check has confirmed them.
Cites
Koob, G. F., & Volkow, N. D. (2010) · Neuropsychopharmacology · doi:10.1038/npp.2009.110 · Cited by 5,340 · cited 1× · see citing works
“Altered DA transmission after nicotine withdrawal might contribute to changes in motivation and in sensitivity to drug-associated stimuli, thus promoting relapse (3).”
BackgroundUnique properties of mesoprefrontal neurons within a dual mesocorticolimbic dopamine system
Lammel, S., Hetzel, A., Häckel, O., Jones, I., Liss, B., & Roeper, J. (2008) · Neuron · doi:10.1016/j.neuron.2008.01.022 · Cited by 976 · see citing works
Corrigall, W. A., Coen, K. M., & Adamson, K. L. (1994) · Brain Research · doi:10.1016/0006-8993(94)90401-4 · Cited by 740 · cited 4× · see citing works
“The baseline DA concentration returned to ontrol (ctrl) levels by d 5 [F(1,14) .”
BackgroundInfluentialLong-term potentiation of excitatory inputs to brain reward areas by nicotine
Mansvelder, H. D., & McGehee, D. S. (2000) · Neuron · doi:10.1016/s0896-6273(00)00042-8 · Cited by 720 · cited 1× · see citing works
“For example, increased glutamate transmission onto VTA DA neurons is an important component of the action of nicotine that mediates enhanced firing activity and synaptic plasticity in DA neurons (4,6,7,45,46).”
BackgroundDramatic decreases in brain reward function during nicotine withdrawal
Epping-Jordan, M. P., Watkins, S. S., Koob, G. F., & Markou, A. (1998) · Nature · doi:10.1038/30001 · Cited by 674 · see citing works
Nicotine amplifies reward-related dopamine signals in striatum
Rice, M. E., & Cragg, S. J. (2004) · Nature Neuroscience · doi:10.1038/nn1244 · Cited by 594 · see citing works
Endogenous nicotinic cholinergic activity regulates dopamine release in the striatum
Zhou, F.-M., Liang, Y., & Dani, J. A. (2001) · Nature Neuroscience · doi:10.1038/nn769 · Cited by 585 · see citing works
Self-citationHow Addictive Drugs Disrupt Presynaptic Dopamine Neurotransmission
Sulzer, D. (2011) · Neuron · doi:10.1016/j.neuron.2011.02.010 · Cited by 574 · see citing works
Volkow, N. (2002) · Neurobiology of Learning and Memory · doi:10.1006/nlme.2002.4099 · Cited by 514 · see citing works
Weiss, F., Parsons, L. H., Schulteis, G., Hyytiä, P., Lorang, M. T., Bloom, F. E., & Koob, G. F. (1996) · The Journal of Neuroscience · doi:10.1523/jneurosci.16-10-03474.1996 · Cited by 457 · see citing works
PICCIOTTO, M., ADDY, N., MINEUR, Y., & BRUNZELL, D. (2008) · Progress in Neurobiology · doi:10.1016/j.pneurobio.2007.12.005 · Cited by 451 · see citing works
Cellular and synaptic mechanisms of nicotine addiction
Mansvelder, H. D., & McGehee, D. S. (2002) · Journal of Neurobiology · doi:10.1002/neu.10148 · Cited by 438 · cited 1× · see citing works
“For example, increased glutamate transmission onto VTA DA neurons is an important component of the action of nicotine that mediates enhanced firing activity and synaptic plasticity in DA neurons (4,6,7,45,46).”
BackgroundReward, addiction, withdrawal to nicotine
De Biasi, M., & Dani, J. A. (2011) · Annual Review of Neuroscience · doi:10.1146/annurev-neuro-061010-113734 · Cited by 366 · cited 3× · see citing works
“herefore, during the withdrawal period, phasic DA neuron activity f the kind induced by nicotine (9,30) re-exposure induces DA sigals that might make smokers in the withdrawal period more vulerable to the reinforcing influence of nicotine (2).”
BackgroundSelf-citationFrequency-dependent modulation of dopamine release by nicotine
Zhang, H., & Sulzer, D. (2004) · Nature Neuroscience · doi:10.1038/nn1243 · Cited by 361 · see citing works
Properties and opioid inhibition of mesolimbic dopamine neurons vary according to target location
Ford, C. P., Mark, G. P., & Williams, J. T. (2006) · The Journal of Neuroscience · doi:10.1523/jneurosci.4331-05.2006 · Cited by 339 · see citing works
Hierarchical Control of Dopamine Neuron-Firing Patterns by Nicotinic Receptors
Mameli-Engvall, M., Evrard, A., Pons, S., Maskos, U., Svensson, T. H., Changeux, J.-P., & Faure, P. (2006) · Neuron · doi:10.1016/j.neuron.2006.05.007 · Cited by 296 · cited 2× · see citing works
“Through this action nicotine induces phasic burst firing from VTA DA neurons (8,9).”
BackgroundJones, I. W., & Wonnacott, S. (2004) · Journal of Neuroscience · doi:10.1523/jneurosci.3009-04.2004 · Cited by 274 · see citing works
Nashmi, R., Xiao, C., Deshpande, P., McKinney, S., Grady, S. R., Whiteaker, P., Huang, Q., McClure-Begley, T., Lindstrom, J. M., Labarca, C., et al. (2007) · The Journal of Neuroscience · doi:10.1523/jneurosci.2199-07.2007 · Cited by 274 · see citing works
The subtypes of nicotinic acetylcholine receptors on dopaminergic terminals of mouse striatum
Grady, S. R., Salminen, O., Laverty, D. C., Whiteaker, P., McIntosh, J. M., Collins, A. C., & Marks, M. J. (2007) · Biochemical Pharmacology · doi:10.1016/j.bcp.2007.07.032 · Cited by 252 · see citing works
Exley, R. A., & Cragg, S. J. (2007) · British Journal of Pharmacology · doi:10.1038/sj.bjp.0707510 · Cited by 249 · see citing works
Exley, R., Clements, M. A., Hartung, H., McIntosh, J. M., & Cragg, S. J. (2008) · Neuropsychopharmacology · doi:10.1038/sj.npp.1301617 · Cited by 242 · see citing works
Chronic Nicotine Exposure Upregulates Nicotinic Receptors by a Novel Mechanism
Vallejo, Y. F. (2005) · Journal of Neuroscience · doi:10.1523/jneurosci.5240-04.2005 · Cited by 201 · see citing works
Pidoplichko, V. I., Noguchi, J., Areola, O. O., Liang, Y., Peterson, J., Zhang, T., & Dani, J. A. (2004) · Learning & Memory · doi:10.1101/lm.70004 · Cited by 196 · cited 1× · see citing works
“For example, increased glutamate transmission onto VTA DA neurons is an important component of the action of nicotine that mediates enhanced firing activity and synaptic plasticity in DA neurons (4,6,7,45,46).”
BackgroundSelf-citationGender differences in the outcome of an unaided smoking cessation attempt
Ward, K. D., Klesges, R. C., Zbikowski, S. M., Bliss, R. E., & Garvey, A. J. (1997) · Addictive Behaviors · doi:10.1016/s0306-4603(96)00063-9 · Cited by 180 · see citing works
Brunzell, D. H., Russell, D. S., & Picciotto, M. R. (2003) · Journal of Neurochemistry · doi:10.1046/j.1471-4159.2003.01640.x · Cited by 176 · see citing works
Dopamine Signaling Differences in the Nucleus Accumbens and Dorsal Striatum Exploited by Nicotine
Zhang, T., Zhang, L., Liang, Y., Siapas, A. G., Zhou, F.-M., & Dani, J. A. (2009) · Journal of Neuroscience · doi:10.1523/jneurosci.0261-09.2009 · Cited by 165 · cited 2× · see citing works
“Through this action nicotine induces phasic burst firing from VTA DA neurons (8,9).”
BackgroundSelf-citationControls of tonic and phasic dopamine transmission in the dorsal and ventral striatum
Zhang, L., Doyon, W. M., Clark, J. J., Phillips, P. E. M., & Dani, J. A. (2009) · Molecular Pharmacology · doi:10.1124/mol.109.056317 · Cited by 161 · see citing works
Exley, R., Maubourguet, N., David, V., Eddine, R., Evrard, A., Pons, S., Marti, F., Threlfell, S., Cazala, P., McIntosh, J. M., et al. (2011) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1103000108 · Cited by 159 · see citing works
Ikemoto, S., Qin, M., & Liu, Z.-H. (2006) · The Journal of Neuroscience · doi:10.1523/jneurosci.4542-05.2006 · Cited by 151 · see citing works
Nicotinic–serotonergic interactions in brain and behaviour
Seth, P., Cheeta, S., Tucci, S., & File, S. E. (2002) · Pharmacology Biochemistry and Behavior · doi:10.1016/s0091-3057(01)00715-8 · Cited by 145 · see citing works
Measures of Maternal Tobacco Exposure and Infant Birth Weight at Term
England, L. J. (2001) · American Journal of Epidemiology · doi:10.1093/aje/153.10.954 · Cited by 139 · see citing works
Maskos, U. (2008) · British Journal of Pharmacology · doi:10.1038/bjp.2008.5 · Cited by 139 · see citing works
Dhar, P. (2004) · Journal of Pharmaceutical and Biomedical Analysis · doi:10.1016/j.jpba.2004.01.009 · Cited by 126 · see citing works
Rahman, S., Zhang, J., Engleman, E. A., & Corrigall, W. A. (2004) · Neuroscience · doi:10.1016/j.neuroscience.2004.08.010 · Cited by 110 · see citing works
How should urinary cotinine concentrations be adjusted for urinary creatinine concentration?
Thompson, S. G., Barlow, R. D., Wald, N., & Vunakis, H. V. (1990) · Clinica Chimica Acta · doi:10.1016/0009-8981(90)90114-8 · Cited by 100 · see citing works
Nicotine physical dependence and tolerance in the mouse following chronic oral administration
Grabus, S. D., Martin, B. R., Batman, A. M., Tyndale, R. F., Sellers, E. M., & Damaj, M. I. (2004) · Psychopharmacology · doi:10.1007/s00213-004-2007-3 · Cited by 97 · see citing works
Up-regulation of Nicotinic Receptors by Nicotine Varies with Receptor Subtype
Walsh, H., Govind, A. P., Mastro, R., Hoda, J. C., Bertrand, D., Vallejo, Y., & Green, W. N. (2008) · Journal of Biological Chemistry · doi:10.1074/jbc.m703432200 · Cited by 87 · see citing works
King, S. L., Caldarone, B. J., & Picciotto, M. R. (2004) · Neuropharmacology · doi:10.1016/j.neuropharm.2004.06.024 · Cited by 70 · see citing works
Reflections on smoking relapse research
Shiffman, S. S. (2006) · Drug and Alcohol Review · doi:10.1080/09595230500459479 · Cited by 69 · see citing works
Modulation of alcohol and nicotine responses through the endogenous opioid system
Drews, E., & Zimmer, A. (2009) · Progress in Neurobiology · doi:10.1016/j.pneurobio.2009.09.004 · Cited by 64 · see citing works
Chapkis, W. (2013) · doi:10.4324/9781315811512-6 · Cited by 63 · see citing works
Shen, R. (2003) · Journal of Pharmacology and Experimental Therapeutics · doi:10.1124/jpet.103.053371 · Cited by 59 · see citing works
Middleton, L. S., Cass, W. A., & Dwoskin, L. P. (2004) · Journal of Pharmacology and Experimental Therapeutics · doi:10.1124/jpet.103.055335 · Cited by 55 · see citing works
Khiroug, S. S., Khiroug, L. S., & Yakel, J. L. (2004) · Neuroscience · doi:10.1016/j.neuroscience.2004.01.017 · Cited by 53 · see citing works
Chronic nicotine administration in the drinking water affects the striatal dopamine in mice
Pietilä, K., & Ahtee, L. (2000) · Pharmacology Biochemistry and Behavior · doi:10.1016/s0091-3057(00)00235-5 · Cited by 50 · see citing works
Tan, H., Bishop, S. F., Lauzon, N. M., Sun, N., & Laviolette, S. R. (2008) · Neuropharmacology · doi:10.1016/j.neuropharm.2008.12.008 · Cited by 46 · see citing works
Caillé, S., Guillem, K., Cador, M., Manzoni, O., & Georges, F. (2009) · The Journal of Neuroscience · doi:10.1523/jneurosci.2950-09.2009 · Cited by 43 · see citing works
Perez, X. A., O’Leary, K. T., Parameswaran, N., McIntosh, J. M., & Quik, M. (2009) · Molecular Pharmacology · doi:10.1124/mol.108.053801 · Cited by 38 · see citing works
Dong, Y., Zhang, T., Li, W., Doyon, W., & Dani, J. A. (2010) · Journal of Molecular Neuroscience · doi:10.1007/s12031-009-9231-6 · Cited by 23 · see citing works
Jin, Y., Yang, K., Wang, H., & Wu, J. (2010) · Synapse · doi:10.1002/syn.20850 · Cited by 22 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
Sofouglu, M., Herman, A. I., Robinson, C. D., & Waters, A. J. (2014) · Lincoln (University of Nebraska) · Cited by 417 · see citing works
Nicotinic acetylcholine receptors and nicotine addiction: A brief introduction
Wittenberg, R. E., Wolfman, S. L., Biasi, M. D., & Dani, J. A. (2020) · Neuropharmacology · doi:10.1016/j.neuropharm.2020.108256 · Cited by 200 · see citing works
“These effects increase dopamine neuron firing rates and phasic burst activity, elevating dopamine levels in the NAc (Placzek et al., 2009; Tsai et al., 2009; Zhang et al., 2009).”
BackgroundInfluentialSelf-citationMcLaughlin, I., Dani, J. A., & De Biasi, M. (2015) · Current Topics in Behavioral Neurosciences · doi:10.1007/978-3-319-13482-6_4 · Cited by 173 · see citing works
“A reduction in basal DA levels was observed to linger for at least 5 days in mice following 12 weeks of chronic nicotine treatment (Zhang et al. 2012).”
BackgroundSelf-citationVTA CRF neurons mediate the aversive effects of nicotine withdrawal and promote intake escalation
Grieder, T. E., Herman, M. A., Contet, C., Tan, L. A., Vargas-Pérez, H., Cohen, A., Chwalek, M., Maal‐Bared, G., Freiling, J., Schlosburg, J. E., et al. (2014) · Nature Neuroscience · doi:10.1038/nn.3872 · Cited by 132 · see citing works
Pistillo, F., Clementi, F., Zoli, M., & Gotti, C. (2014) · Progress in Neurobiology · doi:10.1016/j.pneurobio.2014.10.002 · Cited by 113 · see citing works
Irritability as a Transdiagnostic Vulnerability Trait:Current Issues and Future Directions
Beauchaine, T. P., & Tackett, J. L. (2019) · Behavior Therapy · doi:10.1016/j.beth.2019.10.009 · Cited by 101 · see citing works
Doyon, W. M., Dong, Y., Ostroumov, A., Thomas, A. M., Zhang, T. A., & Dani, J. A. (2013) · Neuron · doi:10.1016/j.neuron.2013.06.006 · Cited by 104 · see citing works
“susceptibility to drug and alcohol abuse (Martinez et al., 2005; Volkow et al., 1996; Zhang et al., 2012).”
Self-citationNew mechanisms and perspectives in nicotine withdrawal
Jackson, K. J., Muldoon, P. P., Biasi, M. D., & Damaj, M. I. (2014) · Neuropharmacology · doi:10.1016/j.neuropharm.2014.11.009 · Cited by 103 · see citing works
“Using microdialysis and fast-scan cyclic voltammetry, Zhang et al. (2012) recently showed that upon withdrawal from chronic nicotine exposure in drinking water, the basal dopamine concentration and tonic and phasic dopamine release in the NAc decreased.”
Kollins, S. H., & Adcock, R. A. (2014) · Progress in Neuro-Psychopharmacology and Biological Psychiatry · doi:10.1016/j.pnpbp.2014.02.002 · Cited by 95 · see citing works
“Dotted lines and citations refer to work that has been conducted to lin enhanced sensitivity of DA release to phasic stimulation, such as with acute nicotine administration (Zhang et al., 2012).”
BackgroundE‐cigarettes, nicotine, the lung and the brain: multi‐level cascading pathophysiology
Herman, M. A., & Tarran, R. (2020) · The Journal of Physiology · doi:10.1113/jp278388 · Cited by 85 · see citing works
“VTA dopamine cell firing (Liu & Jin, 2004), tonic and phasic dopamine release and extracellular dopamine levels in striatal regions of rodents and non-human primates (Takahashi et al. 1998; Rahman et al. 2004; Domino & Tsukada; Zhang et al. 2012), and dopamine metabolite levels in cerebrospinal fluid from human smoker…”
BackgroundInfluentialLi, X., Semenova, S., D’Souza, M. S., Stoker, A. K., & Markou, A. (2013) · Neuropharmacology · doi:10.1016/j.neuropharm.2013.05.042 · Cited by 83 · see citing works
“, 2000), and NAc (Zhang et al., 2012) and decreased 5-hydroxytryptamine (5-HT) transmission in the striatum (Slotkin and Seidler, 2007; Varani et al.”
Jamal, M., van der Does, W. A. J., Elzinga, B. M., Molendijk, M. L., & Penninx, B. W. J. H. (2014) · Nicotine & Tobacco Research · doi:10.1093/ntr/ntu151 · Cited by 83 · see citing works
Dopamine Receptor Activation Increases HIV Entry into Primary Human Macrophages
Gaskill, P. J., Yano, H., Kalpana, G. V., Javitch, J. A., & Berman, J. W. (2014) · PLoS ONE · doi:10.1371/journal.pone.0108232 · Cited by 80 · see citing works
“are large differences in dopamine response between chronic drug abusers and intermittent or naive users [107–109].”
BackgroundDoyon, W. M., Thomas, A. M., Ostroumov, A., Dong, Y., & Dani, J. A. (2013) · Biochemical Pharmacology · doi:10.1016/j.bcp.2013.07.007 · Cited by 77 · see citing works
“A stronger inhibition of the tonic DA response after nicotine withdrawal increases the ratio between tonic and phasic DA signaling [134].”
Self-citationFerris, M. J., Calipari, E. S., Yorgason, J. T., & Jones, S. R. (2013) · ACS Chemical Neuroscience · doi:10.1021/cn400026v · Cited by 68 · see citing works
Associations Among Smoking, Anhedonia, and Reward Learning in Depression
Liverant, G. I., Sloan, D. M., Pizzagalli, D. A., Harte, C. B., Kamholz, B. W., Rosebrock, L. E., Cohen, A. L., D, M. F. M., & Kaplan, G. B. (2014) · Behavior Therapy · doi:10.1016/j.beth.2014.02.004 · Cited by 77 · see citing works
L-DOPA reduces model-free control of behavior by attenuating the transfer of value to action
Kroemer, N. B., Lee, Y., Pooseh, S., Eppinger, B., Goschke, T., & Smolka, M. N. (2018) · NeuroImage · doi:10.1016/j.neuroimage.2018.10.075 · Cited by 64 · see citing works
“56, range [30-42]) who completed both drug and placebo sessions without severe side effects (N = 10 had only one visit; N = 5 reported severe side effects in the second session) and passed extensive quality control (N = 4 were excluded because of low fMRI data quality, N = 2 because of >20% missing trials in one sessi…”
The nucleus accumbens in reward and aversion processing: insights and implications
Xu, Y., Lin, Y., Yu, M., & Zhou, K. (2024) · Frontiers in Behavioral Neuroscience · doi:10.3389/fnbeh.2024.1420028 · Cited by 77 · see citing works
The Role of the Habenula in Nicotine Addiction
Baldwin, P. R., Alanis, R., & Salas, R. (2012) · Journal of Addiction Research & Therapy · doi:10.4172/2155-6105.s1-002 · Cited by 67 · see citing works
“In addition, during withdrawal the dopamine concentration in the striatum is decreased [43].”
BackgroundCholinergic modulation of dopamine pathways through nicotinic acetylcholine receptors
de Kloet, S. F., Mansvelder, H. D., & De Vries, T. J. (2015) · Biochemical Pharmacology · doi:10.1016/j.bcp.2015.07.014 · Cited by 69 · see citing works
Collo, G., Cavalleri, L., & Spano, P. (2014) · Frontiers in Pharmacology · doi:10.3389/fphar.2014.00259 · Cited by 66 · see citing works
Divito, C. B., Steece‐Collier, K., Case, D. T., Williams, S. G., Stancati, J. A., Zhi, L., Rubio, M. E., Sortwell, C. E., Collier, T. J., Sulzer, D. L., et al. (2015) · Journal of Neuroscience · doi:10.1523/jneurosci.2124-15.2015 · Cited by 61 · see citing works
“Repeated cocaine administration increases the formation of unstable dendritic spines in ventral MSNs, which contain only NMDA and not AMPA receptors and are thus referred to as silent synapses (Huang et al., 2009; Brown et al., 2011; Lee and Dong, 2011; Zhang et al., 2012; Lee et al., 2013).”
BackgroundAddiction‐related neuroadaptations following chronic nicotine exposure
Wills, L., & Kenny, P. J. (2021) · Journal of Neurochemistry · doi:10.1111/jnc.15356 · Cited by 61 · see citing works
Karoly, H. C., Bryan, A. D., Weiland, B. J., Mayer, A. R., Dodd, A. B., & Ewing, S. W. F. (2015) · Developmental Cognitive Neuroscience · doi:10.1016/j.dcn.2015.05.005 · Cited by 58 · see citing works
Jenson, D., Yang, K., Acevedo-Rodriguez, A., Levine, A., Broussard, J. I., Tang, J., & Dani, J. A. (2015) · Neuropharmacology · doi:10.1016/j.neuropharm.2014.10.029 · Cited by 52 · see citing works
Self-citationTargeting GLP-1 receptors to reduce nicotine use disorder: Preclinical and clinical evidence
Herman, R. J., & Schmidt, H. D. (2024) · Physiology & Behavior · doi:10.1016/j.physbeh.2024.114565 · Cited by 53 · see citing works
Reward Sensitization: Effects of Repeated Nicotine Exposure and Withdrawal in Mice
Hilário, M. R. F., Turner, J. R., & Blendy, J. A. (2012) · Neuropsychopharmacology · doi:10.1038/npp.2012.130 · Cited by 48 · see citing works
“This phasic/tonic dopamine signaling ratio increase, as observed during withdrawal in previous studies (Grieder et al, 2012; Zhang et al, 2012), is implicated in habit learning (Aggarwal and Wickens, 2011), enhanced reward association and acquisition of incentive salience (Grieder et al, 2012).”
BackgroundE-cigarettes may serve as a gateway to conventional cigarettes and other addictive drugs
Chen, G. L., Rahman, S., & Lutfy, K. (2023) · Advances in Drug and Alcohol Research · doi:10.3389/adar.2023.11345 · Cited by 47 · see citing works
“This reduced dopamine signal has been associated to increased likelihood for alcohol and drug abuse as well as increased impulsivity; in other words, disruption of the GABAergic system has been positively associated with increased alcohol consumption [49, 50].”
BackgroundLong-Term Nicotine Exposure Depresses Dopamine Release in Nonhuman Primate Nucleus Accumbens
Perez, X. A., Ly, J., McIntosh, J. M., & Quik, M. (2012) · Journal of Pharmacology and Experimental Therapeutics · doi:10.1124/jpet.112.194084 · Cited by 43 · see citing works
“These showed that there was a decline in both low- and high-frequencystimulated dopamine release 1 day after nicotine removal, as well as a decrease in nAChR-modulated release (Zhang et al., 2012).”
BackgroundDiacylglycerol lipase disinhibits VTA dopamine neurons during chronic nicotine exposure
Buczynski, M. W., Herman, M. A., Hsu, K., Natividad, L. A., Irimia, C., Polis, I. Y., Pugh, H. M., Chang, J. W., Niphakis, M. J., Cravatt, B. F., et al. (2016) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1522672113 · Cited by 42 · see citing works
“The present study investigated the possible contribution of this effect to aberrant VTA DA cell excitation present following CNE (15).”
BackgroundHerman, R. J., Hayes, M. R., Audrain-McGovern, J. E., Ashare, R. L., & Schmidt, H. D. (2023) · Psychopharmacology · doi:10.1007/s00213-023-06376-w · Cited by 44 · see citing works
“Furthermore, nicotine withdrawal has been shown to alter dopamine signaling dynamics (Epping-Jordan et al. 1998; Jo et al. 2002; Zhang et al. 2012).”
BackgroundOpioid withdrawal: role in addiction and neural mechanisms
Monroe, S. C., & Radke, A. K. (2023) · Psychopharmacology · doi:10.1007/s00213-023-06370-2 · Cited by 45 · see citing works
“In other words, withdrawal may be critical to the development of addiction because it enhances the “signal-to-noise” ratio of the DA response (Wanat et al. 2009; Zhang et al. 2012).”
BackgroundPerez, E. E., Cardé, N. A. Q., & Biasi, M. D. (2015) · Neuropsychopharmacology · doi:10.1038/npp.2015.80 · Cited by 41 · see citing works
“In the drinking water of treatment and control groups, 2% saccharine was added (to mask the bitter flavor of nicotine) (Salas et al, 2009; Sparks and Pauly, 1999; Zhang et al, 2012).”
Sweet taste potentiates the reinforcing effects of e-cigarettes
Kroemer, N. B., Veldhuizen, M. G., Delvy, R., Patel, B. P., O’Malley, S. S., & Small, D. M. (2018) · European Neuropsychopharmacology · doi:10.1016/j.euroneuro.2018.07.102 · Cited by 277 · see citing works
Nicotinic Receptor Subtype-Selective Circuit Patterns in the Subthalamic Nucleus
Xiao, C., Miwa, J. M., Henderson, B. J., Wang, Y., Deshpande, P., McKinney, S. L., & Lester, H. A. (2015) · Journal of Neuroscience · doi:10.1523/jneurosci.3528-14.2015 · Cited by 39 · see citing works
“That chronic nicotine suppresses firing in SNc DA neurons is consistent with decreased dopamine release in the striatum of chronic nicotine-treated animals, observed in previous in vivo microdialysis and in vivo cyclic voltammetry studies (Rahman et al., 2004; Zhang et al., 2012; Koranda et al., 2014).”
BackgroundResultExley, R. A., Clements, M. A., Hartung, H., McIntosh, J. M., Franklin, M., Bermúdez, I., & Cragg, S. J. (2013) · European Journal of Neuroscience · doi:10.1111/ejn.12298 · Cited by 40 · see citing works
“A similar change has been shown during nicotine withdrawal in NAc shell in mice (Zhang et al., 2012), reported as an increase in the ratio of DA release evoked by ‘phasic vs. tonic’ activity, but this change might reflect long-lasting effects of chronic nicotine that persist into withdrawal…”
BackgroundInhibition of monoacylglycerol lipase reduces nicotine withdrawal
Muldoon, P. P., Chen, J., Harenza, J., Abdullah, R. A., Sim‐Selley, L. J., Cravatt, B. F., Miles, M. F., Chen, X., Lichtman, A. H., & Damaj, M. I. (2014) · British Journal of Pharmacology · doi:10.1111/bph.12948 · Cited by 40 · see citing works
“Indeed, dopaminergic neuronal activity in the VTA (Liu and Jin, 2004) and decreased dopamine output in the NAc are believed to contribute to nicotine withdrawal (Hildebrand et al., 1998; Rada et al., 2001; Zhang et al., 2012).”
BackgroundNicotinic alteration of decision-making
Naudé, J., Dongelmans, M., & Faure, P. (2015) · Neuropharmacology · doi:10.1016/j.neuropharm.2014.11.021 · Cited by 39 · see citing works
“Moreover, both chronic nicotine exposure and withdrawal durably affect dopamine release in the striatum (Rahman et al., 2004; Zhang et al., 2013), probably affecting a wide range of decision processes.”
Addicted to palatable foods: comparing the neurobiology of Bulimia Nervosa to that of drug addiction
Hadad, N. A., & Knackstedt, L. A. (2014) · Psychopharmacology · doi:10.1007/s00213-014-3461-1 · Cited by 39 · see citing works
“…et al. 2002; Pothos et al. 1991; Tanda et al. 1997), whereas withdrawal from these substances decreases NAc DA (Acquas and Di Chiara 1992; Barak et al. 2011; Gaddnas et al. 2002; Mateo et al. 2005; Natividad et al. 2010; Pothos et al. 1991; Rada et al. 2001; Weiss et al. 1992; Zhang et al. 2012).”
BackgroundPadovano, H. T., Piasecki, T. M., McCarthy, D. E., & Baker, T. B. (2014) · Journal of Caffeine Research · doi:10.1089/jcr.2014.0007 · Cited by 38 · see citing works
“Likewise, mild tobacco deprivation may modulate the impact of dopaminergic agonists so that caffeine consumption becomes increasingly influential as interoceptive withdrawal signals increase, manifesting as increased impact of caffeine since time of last smoking.(33,36,37,38) Such effects might also Table 3.”
BackgroundTobacco smoking and dopaminergic function in humans: a meta-analysis of molecular imaging studies
Ashok, A. H., Mizuno, Y., & Howes, O. D. (2019) · Psychopharmacology · doi:10.1007/s00213-019-05196-1 · Cited by 36 · see citing works
Kollins, S. H., English, J. S., Roley‐Roberts, M. E., O’Brien, B., Blair, J., Lane, S. D., & McClernon, F. J. (2012) · Psychopharmacology · doi:10.1007/s00213-012-2937-0 · Cited by 37 · see citing works
“In contrast, chronic nicotine exposure and subsequent acute withdrawal both result in substantial reductions in tonic dopamine activity and associated reward-related brain function (Epping-Jordan et al. 1998; Perez et al. 2012; Zhang et al. 2012).”
BackgroundMarks, M. J., Grady, S. R., Salminen, O., Paley, M. A., Wageman, C. R., McIntosh, J. M., & Whiteaker, P. (2014) · Journal of Neurochemistry · doi:10.1111/jnc.12721 · Cited by 37 · see citing works
“…food, with or without cycles of withdrawal in mice, rats, or monkeys have shown changes in reward behavior as well as changes in modulation of dopamine (DA) release by cyclic voltammetry methods (Hilario et al. 2012; Perez et al. 2012; Zhang et al. 2012; Baker et al. 2013; Bordia et al. 2013).”
BackgroundDickson, P. E., Miller, M. M., Rogers, T. D., Blaha, C. D., & Mittleman, G. (2012) · Addiction Biology · doi:10.1111/j.1369-1600.2012.00496.x · Cited by 35 · see citing works
“Additionally, it has recently been shown in B6 mice that dopamine dynamics in the nucleus accumbens are temporarily disrupted during nicotine withdrawal (Zhang et al. 2012).”
BackgroundPistillo, F., Fasoli, F., Moretti, M., McClure‐Begley, T. D., Zoli, M., Marks, M. J., & Gotti, C. (2015) · Pharmacological Research · doi:10.1016/j.phrs.2015.11.016 · Cited by 34 · see citing works
The Role of Mesoaccumbens Dopamine in Nicotine Dependence
Balfour, D. J. K. (2015) · Current topics in behavioral neurosciences · doi:10.1007/978-3-319-13482-6_3 · Cited by 34 · see citing works
“Nicotine injections also temporarily reverse the reduction in extracellular DA observed in the accumbens of mice following the withdrawal of chronic nicotine (Zhang et al. 2012).”
BackgroundResultInfluentialMesolimbic Dopamine and Habenulo-Interpeduncular Pathways in Nicotine Withdrawal
Dani, J. A., & De Biasi, M. (2013) · Cold Spring Harbor Perspectives in Medicine · doi:10.1101/cshperspect.a012138 · Cited by 34 · see citing works
“Likewise, withdrawal from chronic nicotine use also induces a hypodopaminergic state (Epping-Jordan et al. 1998; Zhang et al. 2012).”
BackgroundSelf-citationNymberg, C., Banaschewski, T., Bokde, A. L. W., Büchel, C., Conrod, P., Flor, H., Frouin, V., Garavan, H., Gowland, P. A., Heinz, A., et al. (2014) · Neuropsychopharmacology · doi:10.1038/npp.2014.83 · Cited by 34 · see citing works
Neurobiological and Neurophysiological Mechanisms Underlying Nicotine Seeking and Smoking Relapse
Schmidt, H. D., Rupprecht, L. E., & Addy, N. (2018) · Complex Psychiatry · doi:10.1159/000494799 · Cited by 32 · see citing works
Brain Responses to Smoking Cues Differ Based on Nicotine Metabolism Rate
Falcone, M., Cao, W., Bernardo, L., Tyndale, R. F., Loughead, J., & Lerman, C. E. (2015) · Biological Psychiatry · doi:10.1016/j.biopsych.2015.11.015 · Cited by 33 · see citing works
Prasopthum, A., Pouyfung, P., Sarapusit, S., Srisook, E., & Rongnoparut, P. (2015) · Drug Metabolism and Pharmacokinetics · doi:10.1016/j.dmpk.2014.12.005 · Cited by 32 · see citing works
“Moreover medications that could help stabilizing dopamine level through inhibition of MAO during tobacco withdrawal have been proposed as a treatment for tobacco dependence [8].”
BackgroundEffects of smoking and smoking abstinence on spatial vision in chronic heavy smokers
Fernandes, T. P., de Almeida, N. L. P., & dos Santos, N. A. (2017) · Scientific Reports · doi:10.1038/s41598-017-01877-z · Cited by 28 · see citing works
Perez, X. A., Khroyan, T. V., McIntosh, J. M., & Quik, M. (2014) · Pharmacology Research & Perspectives · doi:10.1002/prp2.105 · Cited by 29 · see citing works
“Nicotine treatment was given for 2–3 months, as other studies have shown that the changes that arise during such a time period may model those in long-term smokers (Zhang et al. 2011; Perez et al. 2013).”
BackgroundResultInfluentialThe role of withdrawal in mesocorticolimbic drug cue reactivity in opioid use disorder
Shi, Z., Jagannathan, K., Padley, J. H., Wang, A., Fairchild, V. P., O’Brien, C. P., Childress, A. R., & Langleben, D. D. (2020) · Addiction Biology · doi:10.1111/adb.12977 · Cited by 28 · see citing works
Tobacco Use Decreases Visual Sensitivity in Schizophrenia
Fernandes, T. M. P., de Andrade, M. J. O., Santana, J. B., Nogueira, R. M. T. B. L., & dos Santos, N. A. (2018) · Frontiers in Psychology · doi:10.3389/fpsyg.2018.00288 · Cited by 26 · see citing works
“Under light-adapted conditions, dopamine receptors are able to either decrease or increase the size of the receptive field (Zhang et al., 2011, 2012).”
BackgroundThe striatal cholinergic system in l-dopa-induced dyskinesias
Perez, X. A., Bordia, T., & Quik, M. (2018) · Journal of Neural Transmission · doi:10.1007/s00702-018-1845-9 · Cited by 24 · see citing works
The acute effects of nicotine on corticostriatal responses to distinct phases of reward processing
Wang, K. S., Zegel, M., Molokotos, E. K., Moran, L. V., Olson, D. P., Pizzagalli, D. A., & Janes, A. C. (2020) · Neuropsychopharmacology · doi:10.1038/s41386-020-0611-5 · Cited by 29 · see citing works
Perez, X. A., McIntosh, J. M., & Quik, M. (2013) · Journal of Neurochemistry · doi:10.1111/jnc.12442 · Cited by 27 · see citing works
“Nicotine treatment was given for 2–3 months, as other studies have shown that the changes that arise during such a time period may model those in long-term smokers (Zhang et al. 2011).”
BackgroundOrganic Cation Transporter Variation and Response to Smoking Cessation Therapies
Bergen, A. W., Javitz, H. S., Krasnow, R. E., Michel, M., Nishita, D., Conti, D. V., Edlund, C. K., Kwok, P., McClure, J. B., Kim, R. B., et al. (2014) · Nicotine & Tobacco Research · doi:10.1093/ntr/ntu161 · Cited by 27 · see citing works
Sex differences in VTA GABA transmission and plasticity during opioid withdrawal
Kalamarides, D. J., Singh, A., Wolfman, S. L., & Dani, J. A. (2023) · Scientific Reports · doi:10.1038/s41598-023-35673-9 · Cited by 24 · see citing works
Self-citationMorud, J., Adermark, L., Pérez-Alcázar, M., Ericson, M., & Söderpalm, B. (2015) · Addiction Biology · doi:10.1111/adb.12219 · Cited by 25 · see citing works
“These changes generate alterations in the DA system that first appear after repeated exposure and not during acute drug exposure in nicotine-naïve animals (Robinson & Berridge 1993; Zhang et al. 2012).”
BackgroundPatten, T., Dreier, A., Herman, R. J., Kimball, B. A., & Biasi, M. D. (2021) · Neuropharmacology · doi:10.1016/j.neuropharm.2021.108672 · Cited by 25 · see citing works
Herman, A. I., Jatlow, P. I., Gelernter, J. E., Listman, J. B., & Sofuoglu, M. (2013) · The Pharmacogenomics Journal · doi:10.1038/tpj.2013.1 · Cited by 22 · see citing works
“This reduced tonic DA release in smokers with the Val allele, may be further accentuated by smoking abstinence, which also reduces DA transmission in subcortical regions (56).”
BackgroundSmoking Decisions: Altered Reinforcement Learning Signals Induced by Nicotine State
Baker, T. E., Zeighami, Y., Dagher, A., & Holroyd, C. B. (2018) · Nicotine & Tobacco Research · doi:10.1093/ntr/nty136 · Cited by 21 · see citing works
Fennell, A. M., Pitts, E. G., Sexton, L. L., & Ferris, M. J. (2020) · Scientific Reports · doi:10.1038/s41598-019-56884-z · Cited by 21 · see citing works
Wilkinson, D. S., & Gould, T. J. (2013) · Behavioural Brain Research · doi:10.1016/j.bbr.2013.04.053 · Cited by 20 · see citing works
“These results are similar to previous research that found nicotine challenge produced a greater relative change in dopamine response in the nucleus accumbens in nicotine- versus saline-withdrawn mice [21].”
ResultCiudad‐Roberts, A., Camarasa, J., Pubill, D., & Escubedo, E. (2013) · Progress in Neuro-Psychopharmacology and Biological Psychiatry · doi:10.1016/j.pnpbp.2013.02.013 · Cited by 19 · see citing works
“(Zhang et al., 2012) and are supplemented with deficits in contextual learning (Gould et”
Molecular, Neuronal, and Behavioral Effects of Ethanol and Nicotine Interactions
Klenowski, P. M., & Tapper, A. R. (2018) · Handbook of experimental pharmacology · doi:10.1007/164_2017_89 · Cited by 15 · see citing works
Both nicotine reward and withdrawal are enhanced in a rodent model of diabetes
Pipkin, J. A., Cruz, B., Flores, R. J., Hinojosa, C. A., Carcoba, L. M., Ibarra, M., Francis, W. S., Nazarian, A., & O’Dell, L. E. (2017) · Psychopharmacology · doi:10.1007/s00213-017-4592-y · Cited by 20 · see citing works
Sweitzer, M. M., Kollins, S. H., Kozink, R. V., Hallyburton, M., English, J. S., Addicott, M. A., Oliver, J. A., & McClernon, F. J. (2017) · Neuropsychopharmacology · doi:10.1038/npp.2017.248 · Cited by 17 · see citing works
“Nicotine withdrawal is also associated with perturbation of dopaminergic neurotransmission (Zhang et al, 2012) and changes in task-related brain activation in executive control regions, including the rIFG, dorsolateral prefrontal cortex (DLPFC), and ACC (Ashare et al, 2014; McClernon et al, 2015).”
BackgroundCano, M., Reynaga, D. D., Belluzzi, J. D., Loughlin, S. E., & Leslie, F. (2020) · Neuropharmacology · doi:10.1016/j.neuropharm.2020.108308 · Cited by 17 · see citing works
“Several other areas modulate the negative aversive state of nicotine dependence, including the amygdala, LH, and MB-IPN circuit (Kenny & Markou, 2001; Natividad et al., 2010; Zhang et al., 2012; Antolin-Fontes et al., 2015).”
BackgroundAltered Accumbal Dopamine Terminal Dynamics Following Chronic Heroin Self-Administration
George, B. E., Dawes, M. H., Peck, E. G., & Jones, S. R. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms23158106 · Cited by 17 · see citing works
“This idea is further supported by evidence showing that chronic nicotine exposure leads to reduced single-pulse dopamine release, increased paired-pulse ratios, and increased phasic/tonic ratios in the NAc [98,99].”
BackgroundTetrahydroprotoberberines: A Novel Source of Pharmacotherapies for Substance Use Disorders?
Nesbit, M. O., & Phillips, A. G. (2020) · Trends in Pharmacological Sciences · doi:10.1016/j.tips.2019.12.007 · Cited by 20 · see citing works
Pierucci, M., Delicata, F., Colangeli, R., Marino, A., Pitruzzella, A., Casarrubea, M., Deurwaerdère, P. D., & Giovanni, G. D. (2021) · Neuropharmacology · doi:10.1016/j.neuropharm.2021.108859 · Cited by 17 · see citing works
“…and other stimuli (Johnson, Blomqvist, Engel, & Söderpalm, 1995; Vihavainen et al., 2008), resulting in sensitized DA release in the nucleus accumbens (Vincenzo Di Matteo, Massimo Pierucci, & Ennio Esposito, 2004; Zhang, Dong, Doyon, & Dani, 2012) and increased motivation for nicotine intake.”
Bidwell, L. C., Karoly, H. C., Hutchison, K. E., & Bryan, A. D. (2017) · Drug and Alcohol Dependence · doi:10.1016/j.drugalcdep.2017.06.020 · Cited by 18 · see citing works
“These molecular actions may also explain varenicline’s efficacy in reducing withdrawal, given that nicotine withdrawal is associated with reductions in basal dopamine levels in the striatum (Zhang et al., 2012).”
BackgroundSimmons, S. J., & Gould, T. J. (2014) · Journal of Clinical Pharmacy and Therapeutics · doi:10.1111/jcpt.12171 · Cited by 16 · see citing works
Ashare, R. L., Wileyto, E. P., Ruparel, K., Goelz, P. M., Hopson, R. D., Valdez, J. N., Gur, R. C., Loughead, J., & Lerman, C. E. (2013) · Drug and Alcohol Dependence · doi:10.1016/j.drugalcdep.2013.09.003 · Cited by 16 · see citing works
“Nicotine withdrawal also alters prefrontal dopamine levels (Grieder et al., 2012; Zhang et al., 2012), which may partially account for inconsistencies between studies.”
ResultGenetic and Epigenetic Regulation of Organic Cation Transporters.
Kölz, C., Schaeffeler, E., Schwab, M., & Nies, A. (2021) · Handbook of Experimental Pharmacology · doi:10.1007/164_2021_450 · Cited by 14 · see citing works
D2/3Agonist during Learning Potentiates Cued Risky Choice
Mortazavi, L., Hynes, T. J., Chernoff, C. S., Ramaiah, S., Brodie, H. G., Russell, B., Hathaway, B. A., Kaur, S., & Winstanley, C. A. (2023) · Journal of Neuroscience · doi:10.1523/jneurosci.1459-22.2022 · Cited by 16 · see citing works
Dong, Y., Dani, J. A., & Blakely, R. (2013) · Biochemical Pharmacology · doi:10.1016/j.bcp.2013.07.019 · Cited by 14 · see citing works
“Microdialysis guide cannulas (CMA/7) (CMA/Microdialysis, Solna, Sweden) were positioned in the medial nucleus accumbens (NAc) directed toward the shell and were secured with acrylic cement and three screws in the skull [33,34].”
MethodSelf-citationBrain substrates of early (4 h) cigarette abstinence: Identification of treatment targets
Franklin, T. R., Jagannathan, K., Hager, N., Fang, Z., Xu, S., Wong, J., Childress, A. R., Detre, J. A., Rao, H., & Wetherill, R. R. (2017) · Drug and Alcohol Dependence · doi:10.1016/j.drugalcdep.2017.10.010 · Cited by 13 · see citing works
“…mesolimbic dopaminergic function and impairments in reward function during nicotine withdrawal and provide translational evidence of similar mechanisms underlying nicotine addiction across species (Corrigall et al., 1992; Epping-Jordan et al., 1998; Rada et al., 2001; Zhang et al., 2012).”
BackgroundResultErdö, F. (2015) · Clinical and Experimental Pharmacology · doi:10.4172/2161-1459.1000180 · Cited by 13 · see citing works
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 · see citing works
Self-citationMagnesium and Zinc Involvement in Tobacco Addiction
Nechifor, M. (2012) · Journal of Addiction Research & Therapy · doi:10.4172/2155-6105.s2-005 · Cited by 10 · see citing works
“Zinc-containing fibers connect these regions to brain areas involved in addiction (limbic system, striatum and others) [1].”
BackgroundNew medications development for smoking cessation
Lengel, D., & Kenny, P. J. (2023) · Addiction Neuroscience · doi:10.1016/j.addicn.2023.100103 · Cited by 12 · see citing works
Comparison 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 · see citing works
A Critical Review of Repurposing Apomorphine for Smoking Cessation
Morales‐Rosado, J. A., Cousin, M. A., Ebbert, J. O., & Klee, E. W. (2015) · Assay and Drug Development Technologies · doi:10.1089/adt.2015.680 · Cited by 11 · see citing works
“1).(47) Such observations may explain why the majority of people who attempt to quit smoking unaided by pharmacologic agents relapse within the first 2 weeks.”
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 · see citing works
Nicotine Withdrawal Induces Neural Deficits in Reward Processing
Oliver, J. A., Evans, D. E., Addicott, M. A., Potts, G. F., Brandon, T. H., & Drobes, D. J. (2017) · Nicotine & Tobacco Research · doi:10.1093/ntr/ntx067 · Cited by 11 · see citing works
L-DOPA Reduces Model-Free Control of Behavior by Attenuating the Transfer of Value to ActionPreprint
Kroemer, N. B., Lee, Y., Pooseh, S., et al. (2016) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/086116 · Cited by 10 · see citing works
Han, 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 7 · see citing works
“Our results showed that, first, at the same dosage, compared with nicotine-freebase, nicotine salts resulted in greater drug delivery, while nicotine-freebase caused stronger withdrawal-induced anxiety symptoms and a greater extracellular dopamine increase in the NAc.”
InfluentialSmokers 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 · see citing works
Sofuoglu, M., Herman, A. I., Robinson, C. D., & Waters, A. J. (2014) · Elsevier eBooks · doi:10.1016/b978-0-12-418679-8.00012-5 · Cited by 8 · see citing works
Costa, G. P. A., Nunes, J. C., Suh, R., Sofuoglu, M., & Aquino, J. P. D. (2025) · Drug and Alcohol Dependence · doi:10.1016/j.drugalcdep.2025.112552 · Cited by 9 · see citing works
Cardé, N. A. Q., Perez, E. E., Feinn, R., Kranzler, H. R., & Biasi, M. D. (2021) · Neuropharmacology · doi:10.1016/j.neuropharm.2021.108783 · Cited by 8 · see citing works
Golden, A. K., & Davis, J. M. (2025) · Journal of Multidisciplinary Healthcare · doi:10.2147/jmdh.s509971 · Cited by 10 · see citing works
Winzer‐Serhan, U. H. (2015) · Open Access Journal of Toxicology · doi:10.19080/oajt.2015.01.555552 · Cited by 7 · see citing works
“Nicotine, the major psychoactive ingredient in tobacco smoke [3], facilitates dopamine release and activates the reward pathway [4,5], and as such is considered an addictive drug, and strongly implicated in tobacco dependence [6,7].”
BackgroundCiccocioppo, R., de Guglielmo, G., Li, H., Melis, M., Caffino, L., Shen, Q., Domi, A., Fumagalli, F., Demopulos, G. A., & Gaitanaris, G. (2021) · Journal of Neuroscience · doi:10.1523/jneurosci.3180-20.2021 · Cited by 7 · see citing works
“…D1 receptors that will increase DA-mediated neurotransmission at the postsynaptic level, counteracting the hypo-DAergic state that occurs during abstinence from nicotine (Rahman et al., 2004; Domino et al., 2009; Sotty et al., 2009; Natividad et al., 2010; Zhang et al., 2012; Carcoba et al., 2017).”
BackgroundInfluentialAddicott, M. (2020) · Cognition and Addiction · doi:10.1016/b978-0-12-815298-0.00009-5 · Cited by 3 · see citing works
Monical, A., & McGehee, D. S. (2025) · Journal of Neuroscience · doi:10.1523/jneurosci.2405-24.2025 · Cited by 7 · see citing works
“Dopamine in the NAc is suppressed during nicotine withdrawal Nicotine withdrawal leads to attenuated extracellular DA levels in the NAc as measured by microdialysis in rat and mouse (Hildebrand et al., 1998; Carboni et al., 2000; Rada et al., 2001; Zhang et al., 2012).”
- Authors
- Zhang, L., Dong, Y., Doyon, W. M., & Dani, J. A.
- Affiliations
- Baylor College of Medicine (US)
- Corresponding author
- Dani, John A.
- Venue
- Biological Psychiatry
- Publisher
- Elsevier BV
- Published
- 2012-02
- Volume
- 71
- Issue
- 3
- Pages
- 184-191
- ISSN
- 0006-3223 (ISSN-L)
- PMC
- PMC3227792
- OpenAlex
- W2048204840
- Semantic Scholar
- e6dc3f1c865f68e0eb62cbc1880eee4b26ae5ba3
- Cited by
- 135
- References
- 50
- Citations by year
- 2026: 7 · 2025: 7 · 2024: 4 · 2023: 11 · 2022: 7 · 2021: 6 · 2020: 8 · 2019: 5 · 2018: 7 · 2017: 9 · 2016: 6 · 2015: 15 · 2014: 22 · 2013: 14 · 2012: 7
- FWCI
- 9.38
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Biological Psychiatry (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Diana Helis Henry Medical Research Foundation
- National Institutes of Health (NS21229)
- National Institute on Drug Abuse (DA09411, R01DA009411)
- National Institute of Neurological Disorders and Stroke (NS 21229, R37NS021229, R01NS021229)
- Topics
- Health Sciences › Medicine › Physiology › Smoking Behavior and Cessation
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Nicotinic Acetylcholine Receptors Study
- Keywords
- nicotine withdrawal, dopamine signaling, nucleus accumbens, chronic nicotine exposure, phasic dopamine release, tonic dopamine release, signal-to-noise ratio, relapse, smoking cessation, nicotine dependence
- MeSH terms
- Animals, Dihydro-beta-Erythroidine, Dopamine, Drug Administration Schedule, Mice, Inbred C57BL, Nicotine, Nucleus Accumbens, Self Administration, Substance Withdrawal Syndrome, Time Factors, Nicotinic Agonists, Nicotinic Antagonists, Mice
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
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.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
