Divergent Functional Effects of Sazetidine-A and Varenicline During Nicotine Withdrawal
Open accessAbstract
Smoking is the largest preventable cause of death in the United States. Furthermore, a recent study found that <10% of quit attempts resulted in continuous abstinence for 1 year. With the introduction of pharmacotherapies like Chantix (varenicline), a selective α4β2 nicotinic partial agonist, successful quit attempts have significantly increased. Therefore, novel subtype-specific nicotinic drugs, such as sazetidine-A, present a rich area for investigation of therapeutic potential in smoking cessation. The present studies examine the anxiety-related behavioral and functional effects of the nicotinic partial agonists varenicline and sazetidine-A during withdrawal from chronic nicotine in mice. Our studies indicate that ventral hippocampal-specific infusions of sazetidine-A, but not varenicline, are efficacious in reducing nicotine withdrawal-related anxiety-like phenotypes in the novelty-induced hypophagia (NIH) paradigm. To further investigate functional differences between these partial agonists, we utilized voltage-sensitive dye imaging (VSDi) in ventral hippocampal slices to determine the effects of sazetidine-A and varenicline in animals chronically treated with saline, nicotine, or undergoing 24 h withdrawal. These studies demonstrate a functional dissociation of varenicline and sazetidine-A on hippocampal network activity, which is directly related to previous drug exposure. Furthermore, the effects of the nicotinic partial agonists in VSDi assays are significantly correlated with their behavioral effects in the NIH test. These findings highlight the importance of drug history in understanding the mechanisms through which nicotinic compounds may be aiding smoking cessation in individuals experiencing withdrawal-associated anxiety.
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Written from the paper’s full text.
TL;DR
In mice withdrawn from chronic nicotine, the α4β2-selective compound sazetidine-A reduced anxiety-like behavior in the novelty-induced hypophagia (NIH) test, whereas varenicline did not. The two partial agonists also produced divergent, drug-history-dependent effects on ventral hippocampal CA1 network activity, which correlated with NIH behavior.
Key findings
- Chronic nicotine was anxiolytic and 24 h withdrawal was anxiogenic in the NIH test: chronic nicotine reduced latency to feed in a novel environment, while 24 h withdrawal increased it relative to saline and chronic nicotine (*P*<0.001; n=6).
- Systemic sazetidine-A (0.01 or 0.1 mg/kg) reversed 24 h withdrawal-induced anxiogenesis in the NIH test, but varenicline (0.01, 0.1, or 1.0 mg/kg) did not. In the marble-burying test, sazetidine-A (0.1 mg/kg) and varenicline (1.0 mg/kg) both reduced marbles buried during 24 h withdrawal (###*P*<0.001; ##*P*<0.01; n=6–8).
- Ventral hippocampal infusions of sazetidine-A (10 or 1000 pM) reduced latency to feed during 24 h withdrawal (*P*<0.05; P*<0.01), whereas varenicline (10 or 1000 pM) had no effect (n=6–7).
- Chronic nicotine increased [3H]epibatidine (1.5 nM) and [3H]2-FA-85380 (1.8 nM) binding in hippocampus and cortex, persisting after 24 h withdrawal (P*<0.01; *P*<0.001; n=3–7). Voltage-sensitive dye imaging showed chronic nicotine increased CA1 peak excitation amplitude and activated area versus saline and 24 h withdrawal (*P*<0.05; P*<0.01), with no tau differences; CA1 excitability significantly correlated with NIH latency (*P*<0.05).
Methods
- Male 129SvEv;C57Bl/6J F1 hybrid mice (7–12 weeks, 25–35 g) received chronic nicotine (18 mg/kg/day) or saline via 14-day subcutaneous osmotic minipumps; withdrawal was induced by pump removal 24 h before testing.
- Behavioral assays included the NIH test, marble-burying test, and locomotor activity; drugs were given intraperitoneally or infused bilaterally into the ventral hippocampus.
- Receptor binding used hippocampal and cortical homogenates with [3H]epibatidine or [3H]2-FA-85380; ventral hippocampal slices were assessed with voltage-sensitive dye imaging during Schaffer collateral stimulation. Analyses used one- or two-way ANOVA with Bonferroni tests and Pearson correlation.
Limitations
- Stated in the paper: the precise neural substrates underlying the marble-burying task are unknown; the consequences of nAChR upregulation are not fully understood; and studies of smoking cessation drugs are often conducted in naïve animals, so it is unknown whether the upregulated nAChR pool is critical for therapeutic efficacy.
- Evident from the text: all experiments used male mice only; withdrawal was assessed at a single 24 h time point; the VSDi–behavior relationship is correlational using group data; and the 1.0 mg/kg sazetidine-A dose was excluded from behavioral analyses due to profound hypolocomotion.
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Claims the paper makes
0 of 78 cited sources checked · 0 supported · 0 flagged
- Findingown data§ RESULTS
Ventral hippocampal infusion of sazetidine-A at 10 pM or 1000 pM significantly reduced the latency to feed during 24 h withdrawal in the NIH test.
“As shown in Figure 4a, infusion of sazetidine-A at either the low (10 pM) or high (1000 pM) concentration resulted in significant reduction in the latency to feed during 24 h WD in the NIH test.”
Quote in the paperSubstantial claim - Findingown data§ RESULTS
Acute administration of varenicline (0.01, 0.1, or 1.0 mg/kg) did not ameliorate nicotine withdrawal behaviors in the NIH test.
“In contrast, acute administration of varenicline at a range of doses (0.01, 0.1, or 1.0 mg/kg) did not ameliorate nicotine withdrawal behaviors in the NIH test (Figure 3b).”
Quote in the paperSubstantial claim - Findingown data§ RESULTS
Treatment with sazetidine-A (0.1 mg/kg) or varenicline (1.0 mg/kg) during 24 h withdrawal significantly reduces the number of marbles buried in the marble-burying test compared with animals undergoing 24 h withdrawal.
“In this task, we observe that treatment with sazetidine-A (0.1 mg/kg) as well as varenicline (1.0 mg/kg) significantly reduces the number of marbles buried in this task compared with animals undergoing 24 h WD (Figure 3c).”
Quote in the paperSubstantial claim - Findingown data§ RESULTS
There were no differences in locomotor activity between treatment groups.
“However, as shown in Figure 3d, no differences in locomotor activity were observed.”
Quote in the paperNot a substantial claim - Findingown data§ RESULTS
Animals undergoing 24 h withdrawal from chronic nicotine show an increased latency to feed in a novel environment relative to saline controls.
“In contrast, those animals undergoing 24 h WD show an increased latency to feed relative to saline controls, indicative of an anxiogenic response.”
Quote in the paperSubstantial claim
- Findingown data§ RESULTS
Acute i.p. administration of sazetidine-A (0.01 or 0.1 mg/kg) during 24 h nicotine withdrawal reversed the anxiogenic effects of withdrawal in the NIH test.
“However, an acute i.p. administration of sazetidine-A (0.01 or 0.1 mg/kg) given to a mouse undergoing nicotine withdrawal 10 min before testing reversed the anxiogenic effects of 24 h WD (Figure 3a).”
Quote in the paperSubstantial claim - Findingown data§ RESULTS
Heightened CA1 evoked responses in the hippocampus significantly correlate with reduced anxiety in the NIH test.
“We found that heightened CA1 evoked responses in the hippocampus significantly correlate with reduced anxiety in the NIH test (Figure 6c).”
Quote in the paperSubstantial claim - Findingown data§ RESULTS
Ventral hippocampal infusion of varenicline at 10 or 1000 pM had no significant effect on the latency to feed in the novel environment.
“In contrast, ventral hippocampal infusions of varenicline at either dose (10 or 1000 pM) had no significant effect on the latency to feed in the novel environment.”
Quote in the paperSubstantial claim - Findingcitation§ RESULTS
Chronic treatment with nicotine reduced the latency to feed in a novel environment relative to saline controls.
“Animals chronically treated with nicotine show a reduced latency to feed in a novel environment relative to saline controls, indicating an anxiolytic response (Figure 1) (Turner et al, 2010).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Turner et al, 2010 source
Not checked in the free run.
- Findingown data§ RESULTS
nAChR upregulation persisted in both hippocampus and cortex despite 24 h cessation of nicotine treatment.
“In both the hippocampus and cortex, nAChR upregulation persisted despite 24 h cessation of nicotine treatment (Figure 2b), indicating that these increased numbers of receptors are present during withdrawal.”
Quote in the paperSubstantial claim - Findingown data§ DISCUSSION
The α4β2 selective nicotinic compounds sazetidine-A and varenicline exhibit very different effects during nicotine withdrawal.
“we also show that the a4b2 selective nicotinic compounds sazeti- dine-A and varenicline exhibit very different effects during nicotine withdrawal.”
Quote in the paperSubstantial claim - Findingown data§ DISCUSSION
In vitro application of varenicline did not potentiate evoked responses in the hippocampus.
“application of varenicline did not.”
Quote in the paperSubstantial claim - Findingown data§ DISCUSSION
Neither i.p. injections nor hippocampal infusions of varenicline had any effect on nicotine-withdrawal deficits in the NIH test.
“neither i.p. injections nor hippocampal infusions of varenicline had any effect on nicotine- withdrawal deficits in the NIH test (Figures 3b and 4).”
Quote in the paperSubstantial claim - Findingown data§ DISCUSSION
The study demonstrates an increase in network-level neuronal activity following chronic in vivo nicotine administration.
“specifically demonstrating an increase in network-level neuronal activity following chronic in vivo nicotine admin- istration (Figure 5).”
Quote in the paperSubstantial claim - Findingown data§ DISCUSSION
In the marble-burying test, acute treatment with either sazetidine-A (0.1 mg/kg) or varenicline (1.0 mg/kg) during 24 h WD is anxiolytic.
“in the marble-burying test, we observe that acute treatment with either sazetidine-A (0.1 mg/kg) or varenicline (1.0 mg/kg) during 24 h WD is anxiolytic”
Quote in the paperSubstantial claim - Findingown data§ DISCUSSION
Hippocampal-specific treatment with sazetidine-A at either 10 or 1000 pM reduced the latency to consume food in the novel environment compared with nicotine withdrawal.
“Hippocampal-specific treatment with sazetidine-A at either 10 or 1000 pM reduced the latency to consume food in the novel environment (*Po0.05; **Po0.01), compared with nicotine withdrawal.”
Quote in the paperSubstantial claim - Findingown data§ DISCUSSION
No significant treatment effects were observed in the home environment.
“No significant treatment effects were observed in the home environment.”
Quote in the paperNot a substantial claim - Findingown data§ Abstract
The effects of the nicotinic partial agonists in VSDi assays are significantly correlated with their behavioral effects in the NIH test.
“Furthermore, the effects of the nicotinic partial agonists in VSDi assays are significantly correlated with their behavioral effects in the NIH test.”
Quote in the paperSubstantial claim - Findingown data§ DISCUSSION
Alterations in anxiety-related behaviors are paralleled by a nicotine-induced change in ventral hippocampal activation.
“these alterations in anxiety-related behaviors are paralleled by a nicotine-induced change in ventral hippocampal activation”
Quote in the paperSubstantial claim - Findingown data§ DISCUSSION
During nicotine withdrawal, acute administration of sazetidine-A, whether administered i.p. or specifically infused into the ventral hippocampus, successfully rescued nicotine-withdrawal deficits in the NIH test.
“During nicotine withdrawal, we find that acute administration of sazetidine-A, whether administered i.p. or specifically infused into the ventral hippocampus, successfully rescued nicotine-withdrawal deficits in the NIH test (Figures 3a and 4).”
Quote in the paperSubstantial claim - Findingown data§ DISCUSSION
None of the effects were due to differences in locomotion.
“None of these effects were due to differences in locomotion (Figure 3d).”
Quote in the paperSubstantial claim - Findingown data§ DISCUSSION
In vitro application of sazetidine-A potentiated evoked responses in the hippocampus.
“application of sazetidine-A potentiated evoked responses in the hippo- campus”
Quote in the paperSubstantial claim - Findingown data§ DISCUSSION
The NIH test is sensitive to the effects of chronic nicotine and 24 h nicotine withdrawal.
“Our results show that the NIH test is sensitive to the effects of chronic nicotine and 24 h nicotine withdrawal.”
Quote in the paperSubstantial claim - Findingown data§ DISCUSSION
The amplitude of peak SR excitation significantly correlated with the latency to feed in the NIH paradigm on Novel Test Day.
“The amplitude of peak SR excitation significantly correlated with the latency to feed in the NIH paradigm on Novel Test Day (Po0.05).”
Quote in the paperNot a substantial claim - Findingown data§ DISCUSSION
The effects of both sazetidine-A and varenicline are critically dependent upon previous nicotine administration.
“demonstrate that the effects of both sazetidine-A and varenicline are critically dependent upon previous nicotine administration.”
Quote in the paperSubstantial claim - Findingown data§ DISCUSSION
No differences in tau were observed in the SR between treatment groups.
“No differences in tau (f) were observed in the SR between treatment groups.”
Quote in the paperNot a substantial claim - Findingown data§ DISCUSSION
In vitro sazetidine-A (1 μM) treatment has no effect in chronic nicotine-treated animals.
“has no effect in chronic nicotine- treated animals”
Quote in the paperSubstantial claim - Interpretationown data§ RESULTS
Increased numbers of nAChRs are present during nicotine withdrawal.
“In both the hippocampus and cortex, nAChR upregulation persisted despite 24 h cessation of nicotine treatment (Figure 2b), indicating that these increased numbers of receptors are present during withdrawal.”
Quote in the paperSubstantial claim - Premisecitation§ RESULTS
[3H]2-FA-85380 binds selectively to β2-containing nAChRs.
“In contrast, [3H]2-FA-85380 binds selectively to b2-containing nAChRs (Brody et al, 2006; Deuther-Conrad et al, 2006; Vaupel et al, 2005).”
Quote in the paperSubstantial claim0 of 3 sources checked - Premisecitation§ INTRODUCTION
Studies in rodents have shown that lesions to the hippocampus impact anxiety behaviors, including hyponeophagia.
“Furthermore, studies in rodents have shown that lesions to the hippocampus impact anxiety behaviors, including hyponeophagia (Bannerman et al, 2003, 2004; McHugh et al, 2004, 2011; Kalisch et al, 2006).”
Quote in the paperSubstantial claim0 of 3 sources checked- cites Bannerman et al, 2003, 2004
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- cites McHugh et al, 2004, 2011
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- cites Kalisch et al, 2006 source
Not checked in the free run.
- Premisecitation§ INTRODUCTION
Varenicline is a potent partial agonist at α4β2 nAChRs.
“Varenicline, the most effective medication for smoking cessation currently available (Chantix; Pfizer), is a potent partial agonist for a4b2 nAChRs, as well as a weak partial agonist at a3b4 nAChRs and a full agonist at a7 nAChRs (Coe et al, 2005; Rollema et al, 2007).”
Quote in the paperSubstantial claim0 of 2 sources checked - Interpretationcitation§ RESULTS
Chronic nicotine has an anxiolytic effect in the NIH test.
“Animals chronically treated with nicotine show a reduced latency to feed in a novel environment relative to saline controls, indicating an anxiolytic response (Figure 1) (Turner et al, 2010).”
Quote in the paperSubstantial claim - Premisecitation§ INTRODUCTION
Sazetidine-A quickly and thoroughly desensitizes the receptor after brief partial agonism.
“Sazetidine-A is a recently developed nicotinic compound with high affinity and selectivity for a4b2 nAChRs, but not a3b4 or a7 nAChRs (Xiao et al, 2006), that quickly and thoroughly desensitizes the receptor after brief partial agonism (Xiao et al, 2006; Zwart et al, 2008).”
Quote in the paperSubstantial claim0 of 2 sources checked - Interpretationown data§ RESULTS
The modulatory effects of sazetidine-A and varenicline in the hippocampus differ depending on the in vivo drug history (saline, nicotine, or 24 h withdrawal).
“Thus, the modulatory effects of sazetidine-A and varenicline in the hippocampus differ depending on the in vivo drug history (eg, saline, nicotine, or 24 h WD) (Figure 6b).”
Quote in the paperSubstantial claim - Premisecitation§ INTRODUCTION
Varenicline is a weak partial agonist at α3β4 nAChRs.
“Varenicline, the most effective medication for smoking cessation currently available (Chantix; Pfizer), is a potent partial agonist for a4b2 nAChRs, as well as a weak partial agonist at a3b4 nAChRs and a full agonist at a7 nAChRs (Coe et al, 2005; Rollema et al, 2007).”
Quote in the paperSubstantial claim0 of 2 sources checked - Premisecitation§ INTRODUCTION
Varenicline is a full agonist at α7 nAChRs.
“Varenicline, the most effective medication for smoking cessation currently available (Chantix; Pfizer), is a potent partial agonist for a4b2 nAChRs, as well as a weak partial agonist at a3b4 nAChRs and a full agonist at a7 nAChRs (Coe et al, 2005; Rollema et al, 2007).”
Quote in the paperSubstantial claim0 of 2 sources checked - Interpretationown data§ RESULTS
24 h withdrawal from chronic nicotine has an anxiogenic effect in the NIH test.
“In contrast, those animals undergoing 24 h WD show an increased latency to feed relative to saline controls, indicative of an anxiogenic response.”
Quote in the paperSubstantial claim - Premisecitation§ RESULTS
Microdialysis studies in naive animals have found low micromolar levels of endogenous acetylcholine in the hippocampus.
“Microdialysis studies in naı̈ve animals have found low micromolar levels of endogenous acetylcholine in the hippocampus (Marrosu et al, 1995).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Marrosu et al, 1995 source
Not checked in the free run.
- Premisecitation§ DISCUSSION
Prolonged varenicline treatment significantly decreases relapse rates during the period of administration.
“prolonged varenicline treatment has been shown to significantly decrease relapse rates during the period of administration (Lee et al, 2008)”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Lee et al, 2008 source
Not checked in the free run.
- Premisecitation§ DISCUSSION
More than 50% of test subjects relapsed at 1 year post quit irrespective of the treatment group.
“450% of the test subjects relapsed at 1 year post quit irrespective of the treatment group (Tonstad et al, 2006).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Tonstad et al, 2006 source
Not checked in the free run.
- Premisecitation§ DISCUSSION
There was no effect on novel object recognition during nicotine withdrawal.
“there was no effect on novel object recognition (Kenney et al, 2011)”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Kenney et al, 2011 source
Not checked in the free run.
- Interpretationown data§ DISCUSSION
The dissociable effects of varenicline and sazetidine-A are paradigm specific.
“We also find that the dissociable effects of varenicline and sazetidine-A are also paradigm specific.”
Quote in the paperSubstantial claim - Premisecitation§ RESULTS
Varenicline levels in brain following acute administration remain in the low micromolar range for up to 6 h.
“In addition, deposition studies show that varenicline levels in brain following an acute administration remain in the low micromolar range for up to 6 h (Rollema et al, 2010).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Rollema et al, 2010 source
Not checked in the free run.
- Interpretationown data§ Abstract
Ventral hippocampal-specific infusions of sazetidine-A, but not varenicline, are efficacious in reducing nicotine withdrawal-related anxiety-like phenotypes in the NIH paradigm.
“Our studies indicate that ventral hippocampal-specific infusions of sazetidine-A, but not varenicline, are efficacious in reducing nicotine withdrawal-related anxiety-like phenotypes in the novelty-induced hypophagia (NIH) paradigm.”
Quote in the paperSubstantial claim - Premisecitation§ DISCUSSION
A network level balance between activation and desensitization is important in eliciting the behavioral effects of nicotinic compounds.
“Current studies indicate a network level balance between activation and desensitization is important in eliciting the behavioral effects of nicotinic compounds (for review, see Picciotto et al, 2008).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Picciotto et al, 2008 source
Not checked in the free run.
- Premisecitation§ DISCUSSION
There is a selective deficit in spatial object recognition during nicotine withdrawal.
“there is a selective deficit in spatial object recognition during nicotine withdrawal”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Kenney et al, 2011 source
Not checked in the free run.
- Interpretationcitation§ DISCUSSION
The phenomenon of increased relapse rate following cessation of varenicline treatment may be related to varenicline's ability to induce nAChR upregulation.
“This phenomenon of increased relapse rate following cessation of varenicline treatment may be related to varenicline's ability to induce nAChR upregulation (Turner et al, 2011).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Turner et al, 2011 source
Not checked in the free run.
- Interpretationcitation§ DISCUSSION
This hyperexcitability may underlie many of the nicotine withdrawal symptoms.
“This hyperexcitability may underlie many of the nicotine withdrawal symptoms (Kenney et al, 2008).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Kenney et al, 2008 source
Not checked in the free run.
- Interpretationreasoning§ DISCUSSION
Continuous modulation of these inputs, as in chronic nicotine exposure, may lead to long-lasting CA1 hyperexcitability following chronic nicotine treatment and withdrawal.
“Continuous modulation of these inputs, as in the case with chronic nicotine exposure, may lead to the long-lasting CA1 hyperexcitability, which we observe following chronic nicotine treatment and withdrawal.”
Quote in the paperSubstantial claim - Premisecitation§ DISCUSSION
The therapeutic window for varenicline corresponds to the point at which there is enough unbound agonist to elicit combined desensitization and receptor activation.
“recent evidence suggests that the therapeutic window for varenicline corresponds to the point at which there is enough unbound agonist to elicit combined desensitization and receptor activation (Rollema et al, 2010).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Rollema et al, 2010 source
Not checked in the free run.
- Interpretationreasoning§ DISCUSSION
These results may be due to differential effects of varenicline and sazetidine-A on nAChR activation and desensitization.
“Therefore, these results may be due to differential effects of varenicline and sazetidine-A on nAChR activation and desensitization (Caldarone et al, 2011; Rollema et al, 2010; Xiao et al, 2006; Zwart et al, 2008).”
Quote in the paperSubstantial claim0 of 3 sources checked - Interpretationreasoning§ Abstract
These findings highlight the importance of drug history in understanding the mechanisms through which nicotinic compounds may be aiding smoking cessation in individuals experiencing withdrawal-associated anxiety.
“These findings highlight the importance of drug history in understanding the mechanisms through which nicotinic compounds may be aiding smoking cessation in individuals experiencing withdrawal-associated anxiety.”
Quote in the paperSubstantial claim - Premisecitation§ DISCUSSION
Cholinergic signaling is important in the integration of excitatory inputs, specifically via α4β2 nAChRs.
“Recent voltage-sensitive dye imaging (VSDi) studies have demonstrated the importance of cholinergic signaling in the integration of excitatory inputs, specifically via a4b2 nAChRs (Bell et al, 2011; McQuiston, 2010).”
Quote in the paperSubstantial claim0 of 2 sources checked - Premisecitation§ DISCUSSION
Low concentrations of sazetidine-A profoundly desensitize α4β2 nAChRs for prolonged periods.
“In vitro studies show that low concentrations of sazetidine-A profoundly desensitize a4b2 nAChRs for prolonged periods (Xiao et al, 2006; Zwart et al, 2008).”
Quote in the paperSubstantial claim0 of 2 sources checked - Interpretationcitation§ DISCUSSION
Cognitive impairments following nicotine withdrawal are not novelty related.
“suggesting that the cognitive impairments following nicotine withdrawal are not novelty related.”
Quote in the paperSubstantial claim - Interpretationown data§ Abstract
These studies demonstrate a functional dissociation of varenicline and sazetidine-A on hippocampal network activity, which is directly related to previous drug exposure.
“These studies demonstrate a functional dissociation of varenicline and sazetidine-A on hippocampal network activity, which is directly related to previous drug exposure.”
Quote in the paperSubstantial claim - Premisecitation§ DISCUSSION
Previous studies examined the effects of sazetidine-A and varenicline in naïve animals, not nicotine-dependent animals.
“these previous studies examined the effects of sazetidine-A and varenicline in naı̈ve animals, in not nicotine-dependent animals.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Turner et al, 2010 source
Not checked in the free run.
- Interpretationcitation§ DISCUSSION
It is unlikely that potential impairment of cognitive processing related to novelty impacts the interpretation of the NIH test.
“While nicotine withdrawal may potentially impair cognitive processing related to novelty, it is unlikely that this impacts our interpretation of the NIH test.”
Quote in the paperSubstantial claim - Interpretationreasoning§ DISCUSSION
The study provides a novel behaviorally validated outcome measure for future drug and therapy development targeting smoking cessation.
“we provide a novel behaviorally validated outcome measure for future drug and therapy development that target the still recalcitrant problem of successful smoking cessation.”
Quote in the paperSubstantial claim - Premisecitation§ DISCUSSION
Sazetidine-A does not upregulate nAChRs.
“sazetidine-A does not upregulate nAChRs (Hussmann et al, 2012).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Hussmann et al, 2012 source
Not checked in the free run.
- May combine two claims. 17
- The quote only partly states this claim. 5
- Classified as probably not a substantial claim. 24
May combine two claims.
Findingown data§ RESULTSThere are no differences in latency to feed or amount consumed in the home environment on Home Day 1 or Home Day 2.
“These effects were not attributable to changes in appetitive behavior as there are no differences in the latency to feed (P40.05) or in the amount consumed (P40.05) in the home environment on Home Day 1 or Home Day 2.”
Quote in the paperSubstantial claimThe quote only partly states this claim.
Findingown data§ DISCUSSIONIn vitro varenicline (1 μM) treatment significantly attenuates CA1 excitatory responses in chronic nicotine-treated animals.
“significantly attenuating CA1 excitatory responses in both chronic nicotine and 24 h nicotine withdrawal conditions.”
Quote in the paperSubstantial claimThe quote only partly states this claim.
Findingown data§ DISCUSSIONIn vitro sazetidine-A (1 μM) treatment attenuates CA1 excitatory responses in saline animals.
“In vitro sazetidine-A (1mM) treatment attenuates CA1 excitatory responses in saline animals”
Quote in the paperSubstantial claimThe quote only partly states this claim.
Findingown data§ DISCUSSIONIn vitro sazetidine-A (1 μM) treatment enhances peak excitatory responses during 24 h withdrawal from chronic nicotine.
“enhances peak excitatory responses during 24 h withdrawal from chronic nicotine.”
Quote in the paperSubstantial claimThe quote only partly states this claim.
Findingown data§ DISCUSSIONIn vitro varenicline (1 μM) treatment significantly attenuates CA1 excitatory responses in 24 h nicotine withdrawal conditions.
“significantly attenuating CA1 excitatory responses in both chronic nicotine and 24 h nicotine withdrawal conditions.”
Quote in the paperSubstantial claimThe quote only partly states this claim.
Findingown data§ DISCUSSIONIn vitro varenicline (1 μM) treatment slightly enhances CA1 excitatory responses in saline animals.
“in vitro treatment with varenicline (1mM) slightly enhances CA1 excitatory responses in saline animals”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Premisecitation§ DISCUSSIONfMRI connectivity studies in human subjects have shown that the hippocampus controls emotional responses in the amygdala and other brain regions.
“Recently, this has been demonstrated experimentally in human subjects in fMRI connectivity studies showing that the hippocampus controls emotional responses in the amygdala and other brain regions (Hahn et al, 2010).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Hahn et al, 2010 source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
Premisecitation§ INTRODUCTIONA follow-up study observed that hippocampal volume could be correlated with successful quit attempts.
“In addition, a follow-up study observed that hippocampal volume could be correlated with successful quit attempts (Froeliger et al, 2010).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Froeliger et al, 2010 source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductown data§ MATERIALS AND METHODSData with the 1.0 mg/kg dose of sazetidine-A were excluded due to profound reduction in locomotor activity.
“Data with the 1.0 mg/kg dose of sazetidine-A were excluded due to profound reduction in locomotor activity.”
- Also stated in: § MATERIALS AND METHODS · plain
“Again, data with the 1.0 mg/kg dose of sazetidine-A were excluded due to profound hypolocomotion.”
Quote in the paperNot a substantial claim- Also stated in: § MATERIALS AND METHODS · plain
Probably not a substantial claim: may not pass S3 (load-bearing).
Premisecitation§ RESULTSRecent studies in humans have suggested a functional role of these receptors in relapse vulnerability.
“A hallmark of chronic nicotine administration is the upregulation of nicotinic receptors in the brain (Marks et al, 1983; Schwartz and Kellar, 1983) and recent studies in humans have suggested a functional role of these receptors in relapse vulnerability (Cosgrove et al, 2009).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Cosgrove et al, 2009 source
Not checked in the free run.
May combine two claims.
Interpretationown data§ RESULTSChronic administration of nicotine impacts predominantly the excitatory components governing network activity of the CA1, which return to control levels following 24 h of withdrawal.
“This suggests that chronic administration of nicotine impacts predominantly the excitatory components governing network activity of the CA1, which return to control levels following 24 h of WD.”
Quote in the paperSubstantial claimMay combine two claims.
Premisecitation§ INTRODUCTIONSazetidine-A has high affinity and selectivity for α4β2 nAChRs, but not α3β4 or α7 nAChRs.
“Sazetidine-A is a recently developed nicotinic compound with high affinity and selectivity for a4b2 nAChRs, but not a3b4 or a7 nAChRs (Xiao et al, 2006), that quickly and thoroughly desensitizes the receptor after brief partial agonism (Xiao et al, 2006; Zwart et al, 2008).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Xiao et al, 2006 source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
Premisecitation§ DISCUSSIONRodent literature demonstrates that lesions of the ventral hippocampus specifically, but not the dorsal hippocampus or amygdala, impact anxiety behaviors in conflict and hyponeophagia paradigms like the NIH test.
“Furthermore, there is a large body of rodent literature demonstrating that lesions of the ventral hippocampus specifically, but not the dorsal hippocampus or amygdala, impact anxiety behaviors in conflict and hyponeophagia paradigms like the NIH test (Bannerman et al, 2002, 2003, 2004; McHugh et al, 2004, 2011).”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites Bannerman et al, 2002, 2003, 2004
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- cites McHugh et al, 2004, 2011
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
Study design and conductcitation§ MATERIALS AND METHODSDirect infusions into the ventral hippocampus have very good anatomical precision, with spread of infusion using this procedure about 1 mm3 after 24-48 h.
“Direct infusions, as opposed to i.c.v. or systemic infusions, have very good anatomical precision, as the spread of infusion using this procedure is B1 mm3 after 24–48 h (Davis et al, 2007; Lewis and Gould, 2007).”
Quote in the paperNot a substantial claim0 of 2 sources checkedClassified as probably not a substantial claim. May combine two claims.
Study design and conductcitation§ MATERIALS AND METHODSThe marble-burying test is a rodent model of anxiety that has high predictive value to detect anxiolytic-like activity of acutely administered drugs.
“The marble-burying test is a rodent model of anxiety that has high predictive value to detect anxiolytic-like activity of acutely administered drugs (Nicolas et al, 2006).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Nicolas et al, 2006 source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
Premisecitation§ INTRODUCTIONHippocampal volume can also be correlated with anxiety levels in patients with anxiety disorders.
“Hippocampal volume can also be correlated with anxiety levels in patients with anxiety disorders (Bremner et al, 1995; Stein et al, 1997).”
Quote in the paperNot a substantial claim0 of 2 sources checkedClassified as probably not a substantial claim.
Premisecitation§ RESULTSA hallmark of chronic nicotine administration is the upregulation of nicotinic receptors in the brain.
“A hallmark of chronic nicotine administration is the upregulation of nicotinic receptors in the brain (Marks et al, 1983; Schwartz and Kellar, 1983) and recent studies in humans have suggested a functional role of these receptors in relapse vulnerability (Cosgrove et al, 2009).”
Quote in the paperSubstantial claim0 of 2 sources checked- cites Marks et al, 1983
Not checked in the free run.
- cites Schwartz and Kellar, 1983 source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
Premisecitation§ INTRODUCTIONCraving and cognitive impairments are reliable markers of nicotine withdrawal.
“Although craving and cognitive impairments are reliable markers of nicotine withdrawal (Kenney and Gould, 2008; Levin et al, 2006; McClernon et al, 2004; Rezvani and Levin, 2001), anxiety has been shown to impact relapse rate as well (Dani and Harris, 2005; DiMatteo et al, 2000).”
Quote in the paperNot a substantial claim0 of 3 sources checkedMay combine two claims.
Interpretationreasoning§ RESULTSReduced hippocampal excitability accompanies anxiogenic effects observed in 24 h withdrawal animals and following treatment with varenicline during 24 h withdrawal.
“Conversely, reduced hippocampal excitability accompanies anxiogenic effects observed in 24 h WD animals (Figures 1a and 2) and following treatment with varenicline during 24 h WD (Figure 2).”
Quote in the paperSubstantial claimClassified as probably not a substantial claim.
Premisecitation§ INTRODUCTIONAnxiety has been shown to impact relapse rate.
“Although craving and cognitive impairments are reliable markers of nicotine withdrawal (Kenney and Gould, 2008; Levin et al, 2006; McClernon et al, 2004; Rezvani and Levin, 2001), anxiety has been shown to impact relapse rate as well (Dani and Harris, 2005; DiMatteo et al, 2000).”
Quote in the paperSubstantial claim0 of 2 sources checkedMay combine two claims.
Interpretationown data§ RESULTSIncreased hippocampal excitability accompanies both anxiolytic effects of chronic nicotine and anxiolytic effects of sazetidine-A in 24 h withdrawal animals.
“These data conclude that increased hippocampal excitability accompanies both anxiolytic effects of chronic nicotine (Figures 1a and 2) and anxiolytic effects of sazetidine-A in 24 h WD animals (Figure 2).”
Quote in the paperSubstantial claimMay combine two claims.
Study design and conductcitation§ MATERIALS AND METHODSBehavioral testing 10-15 min after infusion is the best time and earliest time point to observe a behavioral effect without drug delivery impacting the anxiety measure.
“Behavioral testing was carried out 10–15 min after the infusion procedure because previous data with various behavioral assays as well as locomotor studies indicated that this was the best time and the earliest time point to observe a behavioral effect without drug delivery impacting the anxiety measure (Turner et al, 2010).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Turner et al, 2010 source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
Premisecitation§ DISCUSSIONThe hippocampus has been proposed as the neurobiological correlate of trait anxiety in the brain, and systems responsible for anxious behaviors during conflict are theorized to be mediated by the hippocampus.
“Gray and McNaughton (1996, 2000) have proposed the hippocampus as the neurobiological correlate of trait anxiety in the brain and theorized that those systems responsible for anxious behaviors during conflict are mediated by the hippocampus.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Gray and McNaughton (1996, 2000)
Not checked in the free run.
Classified as probably not a substantial claim. May combine two claims.
Premisecitation§ RESULTSEpibatidine is a broad-spectrum nAChR ligand that binds with very high affinity (25-300 pM) to all known heteromeric nAChRs.
“Epibatidine is a broad-spectrum nAChR ligand that binds with very high affinity (25–300 pM) to all known heteromeric nAChRs (Avalos et al, 2002; Houghtling et al, 1995; Xiao and Kellar, 2004).”
Quote in the paperSubstantial claim0 of 3 sources checkedProbably not a substantial claim: may not pass S3 (load-bearing).
Premisecitation§ DISCUSSIONHippocampal volume has been shown to predict smoking cessation treatment outcomes.
“hippocampal volume has been shown to predict smoking cessation treatment outcomes (Froeliger et al, 2010).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Froeliger et al, 2010 source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
Premisecitation§ DISCUSSIONBoth sazetidine-A and varenicline reduce nicotine self-administration.
“reduce nicotine self-administration (Levin et al, 2010; O'Connor et al, 2010; Rezvani et al, 2010).”
Quote in the paperNot a substantial claim0 of 3 sources checkedMay combine two claims.
Premisecitation§ DISCUSSIONPrevious work has shown that while nicotine withdrawal at the same dose significantly impairs hippocampal-dependent contextual learning in C57/Bl6 mice, the 129SvEv;C57Bl/6J F1 hybrid mice utilized in these studies do not exhibit learning impairments.
“our previous work has shown that while nicotine withdrawal at the same dose significantly impairs hippocampal-dependent contextual learning in C57/Bl6 mice, the 129SvEv;C57Bl/6J F1 hybrid mice utilized in these studies do not exhibit learning impairments (Wilkinson et al, 2013).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Wilkinson et al, 2013 source
Not checked in the free run.
Classified as probably not a substantial claim.
Premisecitation§ DISCUSSIONBoth sazetidine-A and varenicline ameliorate cognitive withdrawal symptoms.
“both sazetidine-A and varenicline ameliorate cognitive with- drawal symptoms (Raybuck et al, 2008; Rezvani et al, 2011)”
Quote in the paperSubstantial claim0 of 2 sources checkedProbably not a substantial claim: may not pass S3 (load-bearing).
Premisecitation§ RESULTSThe CA1 region is selectively affected in individuals with anxiety disorders.
“Electrical stimulation of the Schaffer collateral pathway (Figure 5a and b) results in robust activation of the CA1, a region of the hippocampus sensitive to stress-induced synaptic remodeling (Dalla et al, 2009; Joels et al, 2004, 2008; McEwen, 2001; McEwen and Magarinos, 2001; Shors et al, 1997, 2001) and shown to be selectively affected in individuals with anxiety disorders (Cole et al, 2010).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Cole et al, 2010 source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
Premisecitation§ DISCUSSIONBoth varenicline and sazetidine-A have shown antidepressant efficacy in the forced swim test.
“both varenicline and sazetidine-A have shown antidepres- sant efficacy in the forced swim test (Caldarone et al, 2011; Kozikowski et al, 2009; Mineur et al, 2011; Rollema et al, 2009; Turner et al, 2010).”
Quote in the paperNot a substantial claim0 of 3 sources checkedProbably not a substantial claim: may not pass S3 (load-bearing).
Premisecitation§ RESULTSThe CA1 region of the hippocampus is sensitive to stress-induced synaptic remodeling.
“Electrical stimulation of the Schaffer collateral pathway (Figure 5a and b) results in robust activation of the CA1, a region of the hippocampus sensitive to stress-induced synaptic remodeling (Dalla et al, 2009; Joels et al, 2004, 2008; McEwen, 2001; McEwen and Magarinos, 2001; Shors et al, 1997, 2001) and shown to be selectively affected in individuals with anxiety disorders (Cole et al, 2010).”
Quote in the paperNot a substantial claim0 of 3 sources checked- cites Dalla et al, 2009 source
Not checked in the free run.
- cites Joels et al, 2004, 2008
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- cites McEwen, 2001
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
Classified as probably not a substantial claim.
Premisecitation§ DISCUSSIONIncreased excitability in CA1 pyramidal neurons persists even after prolonged withdrawal (24 h-9 months).
“increased excitability in CA1 pyramidal neurons persists even after prolonged withdrawal (24 h–9 months) (Penton et al, 2011).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Penton et al, 2011 source
Not checked in the free run.
Classified as probably not a substantial claim.
Premisecitation§ DISCUSSIONHippocampal activation due to smoking cue presentation is associated with anxiety symptoms in abstinent smokers.
“hippocampal activation due to smoking cue presentation is associated with anxiety symptoms in abstinent smokers (McClernon et al, 2008).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites McClernon et al, 2008 source
Not checked in the free run.
Classified as probably not a substantial claim. May combine two claims.
Interpretationnone given§ DISCUSSIONThe present studies are the first concerted effort to determine the anxiolytic efficacy of these drugs in nicotine-dependent animals and to evaluate the effect of these drugs on hippocampal network function following chronic treatment with nicotine and withdrawal.
“the present studies are the first concerted effort to (1) determine the anxiolytic efficacy of these drugs in nicotine-dependent animals and (2) evaluate the effect of these drugs on hippocampal network function following chronic treatment with nicotine and withdrawal.”
Quote in the paperSubstantial claimMay combine two claims.
Premisecitation§ DISCUSSIONThe ventral hippocampus, in contrast to the dorsal hippocampus, is thought to contribute to anxiety-related phenotypes and not spatial memory, per se.
“these studies specifically target alterations in the ventral hippocampus, which in contrast to the dorsal hippocampus, is thought to contribute to anxiety-related phenotypes and not spatial memory, per se.”
Quote in the paperSubstantial claim0 of 3 sources checkedMay combine two claims.
Premisecitation§ DISCUSSIONIn conflict anxiety paradigms like the NIH test, chronic sazetidine-A has anxiolytic effects, while varenicline does not.
“in conflict anxiety paradigms like the NIH test, we have previously shown that chronic sazetidine-A has anxiolytic effects, while varenicline does not (Turner et al, 2010).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Turner et al, 2010 source
Not checked in the free run.
Probably not a substantial claim: may not pass S2 (checkable).
Interpretationreasoning§ DISCUSSIONThese combined studies provide a paradigm for using currently available drugs to broadly probe nAChR plasticity.
“Thus, these combined studies provide a paradigm for using currently available drugs to broadly probe nAChR plasticity.”
Quote in the paperNot a substantial claimClassified as probably not a substantial claim.
Premisecitation§ DISCUSSIONNicotinic receptor availability is directly related to increased relapse rate.
“a recent SPECT study has suggested that nicotinic receptor availability is directly related to increased relapse rate (Cosgrove et al, 2009).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Cosgrove et al, 2009 source
Not checked in the free run.
The paper relies on this without support.
The neural substrates associated with nicotine withdrawal are not as well characterized as the rewarding properties of nicotine.
“While the rewarding properties of nicotine have been extensively studied (Corrigall et al, 1992, 1994; Grieder et al, 2012; Laviolette et al, 2008; Laviolette and van der Kooy, 2003), the neural substrates associated with withdrawal are not as well characterized.”
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.
Figure 3 assigns two P-value thresholds to the same significance marker
MinorThe Figure 3 caption uses *** for both P<0.05 and P<0.001, making the stated significance threshold for the sazetidine-A comparison inconsistent.
“relative to both saline treatment (***Po0.05) and 24 h WD”
“Nicotine withdrawal significantly increased the latency to approach and consume food in the novel environment compared with saline (***Po0.001; **Po0.01).”
Withdrawal-related CA1 hyperexcitability contradicts the reported return to baseline
MinorThe Discussion says CA1 hyperexcitability was observed following withdrawal, but the Results state that hippocampal responses returned to control levels after 24 hours of withdrawal. This changes the interpretation of a central functional result.
“the long-lasting CA1 hyperexcitability, which we observe following chronic nicotine treatment and withdrawal.”
“chronic administration of nicotine impacts predominantly the excitatory components governing network activity of the CA1, which return to control levels following 24 h of WD.”
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Self-citationAnxiety and Hippocampus Volume in the Rat
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Subregional hippocampal deformations in major depressive disorder
Cole, J., Toga, A. W., Hojatkashani, C., Thompson, P., Costafreda, S. G., Cleare, A. J., Williams, S. C. R., Bullmore, E. T., Scott, J. L., & Mitterschiffthaler, M. T. (2010) · Journal of Affective Disorders · doi:10.1016/j.jad.2010.03.004 · Cited by 94 · see citing works
Tolerance to nicotine's effects in the elevated plus-maze and increased anxiety during withdrawal
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Varenicline ameliorates nicotine withdrawal-induced learning deficits in C57BL/6 mice.
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Self-citationHippocampal nAChRs mediate nicotine withdrawal-related learning deficits
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Self-citationSeptal gabaergic and hippocampal cholinergic systems interact in the modulation of anxiety
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Anxiolytic effect of serotonin depletion in the novelty-induced hypophagia test
Bechtholt, A. J., Hill, T. E., & Lucki, I. (2007) · Psychopharmacology · doi:10.1007/s00213-006-0615-9 · Cited by 48 · see citing works
Caldarone, B. J., Wang, D., Paterson, N. E., Manzano, M., Fedolak, A., Cavino, K., Kwan, M., Hanania, T., Chellappan, S. K., Kozikowski, A. P., et al. (2011) · Psychopharmacology · doi:10.1007/s00213-011-2271-y · Cited by 47 · see citing works
Lewis, M. C., & Gould, T. J. (2007) · Hippocampus · doi:10.1002/hipo.20284 · Cited by 42 · see citing works
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Bechtholt, A. J., Valentino, R. J., & Lucki, I. (2008) · Neuropsychopharmacology · doi:10.1038/sj.npp.1301616 · Cited by 40 · see citing works
Gamble‐George, J., Conger, J. R., Hartley, N. D., Gupta, P., Sumislawski, J. J., & Patel, S. (2013) · Psychopharmacology · doi:10.1007/s00213-013-3042-8 · Cited by 39 · see citing works
Avalos, M., Parker, M. J., Maddox, F. N., Carroll, F. I., & Luetje, C. W. (2002) · The Journal of Pharmacology and Experimental Therapeutics · doi:10.1124/jpet.102.035899 · Cited by 36 · see citing works
Kozikowski, A. P., Eaton, J. B., Bajjuri, K. M., Chellappan, S. K., Chen, Y., Karadi, S., He, R., Caldarone, B., Manzano, M., Yuen, P., et al. (2009) · ChemMedChem · doi:10.1002/cmdc.200900079 · Cited by 36 · see citing works
Mild anxiogenic effects of nicotine withdrawal in mice
Jonkman, S., Henry, B., Semenova, S., & Markou, A. (2005) · European Journal of Pharmacology · doi:10.1016/j.ejphar.2005.04.032 · Cited by 35 · see citing works
A Longer Course of Varenicline Therapy Improves Smoking Cessation Rates
Lee, J. H., Jones, P. G., Bybee, K., & O’Keefe, J. H. (2008) · Preventive Cardiology · doi:10.1111/j.1751-7141.2008.00003.x · Cited by 34 · see citing works
Hussmann, G. P., Turner, J. R., Lomazzo, E., Venkatesh, R., Cousins, V., Xiao, Y., Yasuda, R. P., Wolfe, B. B., Perry, D. C., Rezvani, A. H., et al. (2012) · The Journal of Pharmacology and Experimental Therapeutics · doi:10.1124/jpet.112.198085 · Cited by 34 · see citing works
Self-citationWilkinson, D. S., Turner, J. R., Blendy, J. A., & Gould, T. J. (2013) · Psychopharmacology · doi:10.1007/s00213-012-2808-8 · Cited by 32 · see citing works
Self-citationGoeldner, C., Spooren, W. P. J. M., Wichmann, J., & Prinssen, E. P. M. (2012) · Psychopharmacology · doi:10.1007/s00213-012-2636-x · Cited by 30 · see citing works
Running‐induced anxiety is dependent on increases in hippocampal neurogenesis
Onksen, J. L., Briand, L. A., Galante, R. J., Pack, A. I., & Blendy, J. A. (2012) · Genes, Brain and Behavior · doi:10.1111/j.1601-183x.2012.00788.x · Cited by 29 · see citing works
Self-citationVaupel, D. B., Tella, S. R., Huso, D. L., Wagner, V. O., Mukhin, A. G., Chefer, S. I., Horti, A. G., London, E. D., Koren, A. O., & Kimes, A. S. (2005) · The Journal of Pharmacology and Experimental Therapeutics · doi:10.1124/jpet.104.073999 · Cited by 28 · see citing works
Short- and Long-Lasting Consequences of<i>In Vivo</i>Nicotine Treatment on Hippocampal Excitability
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Brain monoamines and antidepressant-like responses in MRL/MpJ versus C57BL/6J mice
Balu, D. T., Turner, J. R., Brookshire, B. R., Hill‐Smith, T. E., Blendy, J. A., & Lucki, I. (2012) · Neuropharmacology · doi:10.1016/j.neuropharm.2012.11.027 · Cited by 10 · see citing works
Self-citation
Flagged first, then by citations
1 of the 110 references couldn’t be matched to a known paper.
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Recent Developments in Novel Antidepressants Targeting α4β2-Nicotinic Acetylcholine Receptors
Yu, L.-F., Zhang, H.-K., Caldarone, B. J., Eaton, J. B., Lukas, R. J., & Kozikowski, A. P. (2014) · Journal of Medicinal Chemistry · doi:10.1021/jm401937a · Cited by 56 · see citing works
Evidence from mouse and man for a role of neuregulin 3 in nicotine dependence
Turner, J. R., Ray, R., Lee, B., Everett, L. J., Xiang, J. J., Jepson, C., Kaestner, K. H., Lerman, C. E., & Blendy, J. A. (2013) · Molecular Psychiatry · doi:10.1038/mp.2013.104 · Cited by 46 · see citing works
Self-citationMolecular Mechanisms Associated with Nicotine Pharmacology and Dependence
Fowler, C. D., Turner, J. R., & Damaj, M. I. (2019) · Handbook of experimental pharmacology · doi:10.1007/164_2019_252 · Cited by 45 · see citing works
Self-citationFisher, M. L., LeMalefant, R., Zhou, L., Huang, G., & Turner, J. R. (2016) · Neuropsychopharmacology · doi:10.1038/npp.2016.257 · Cited by 31 · see citing works
“Reciprocal studies from Turner et al (2013) showed that microinjecting nicotinic compounds specifically into the ventral hippocampus could ameliorate anxiety-like nicotine WD symptoms in mice (Turner et al, 2013).”
BackgroundMethodInfluentialSelf-citationNicotine and opioid co-dependence: Findings from bench research to clinical trials
Custodio-Patsey, L., Malone, S. G., Bardo, M. T., & Turner, J. R. (2021) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2021.12.030 · Cited by 33 · see citing works
Self-citationYohn, N. L., Turner, J. R., & Blendy, J. A. (2014) · The Journal of Pharmacology and Experimental Therapeutics · doi:10.1124/jpet.113.211706 · Cited by 28 · see citing works
“Furthermore, although α7 nAChRs have not been implicated directly in anxiety (Paylor et al., 1998; Vicens et al., 2011) they are necessary in the ventral tegmental area (VTA) for the expression of withdrawal from nicotine suggesting that targeting of the α7 subtype may also relieve nicotine withdrawal symptoms (Nomiko…”
BackgroundSelf-citationThyroid hormone signaling: Contribution to neural function, cognition, and relationship to nicotine
Leach, P. T., & Gould, T. J. (2015) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2015.09.001 · Cited by 24 · see citing works
Self-citationOrthosteric and Allosteric Ligands of Nicotinic Acetylcholine Receptors for Smoking Cessation
Mohamed, T. S., Jayakar, S. S., & Hamouda, A. K. (2015) · Frontiers in Molecular Neuroscience · doi:10.3389/fnmol.2015.00071 · Cited by 27 · see citing works
“Sazetidine A binds with higher affinity at α4β2 than other nAChR subtypes and shows reduced withdrawal symptoms and nicotine self-administration (Levin et al., 2010), albeit with different functional and behavioral profiles than varenicline (Turner et al., 2013).”
BackgroundCole, R. D., Poole, R. L., Guzman, D. M., Gould, T. J., & Parikh, V. (2014) · Psychopharmacology · doi:10.1007/s00213-014-3754-4 · Cited by 24 · see citing works
“Nicotine was administered at a dose of 18 mg kg −1 day -1 (reported as free base) previously reported to desensitize nAChRs (Turner et al. 2010, 2013; Wilkinson et al. 2013) and produce reversal learning deficits in mice (Ortega et al. 2013).”
Self-citationDissociation of tolerance and nicotine withdrawal-associated deficits in contextual fear
Gould, T. J., Wilkinson, D. S., Yildirim, E., Blendy, J. A., & Adoff, M. D. (2014) · Brain Research · doi:10.1016/j.brainres.2014.02.038 · Cited by 25 · see citing works
“In support, it reduced nicotine self-administration in rats (Levin et al., 2010) and ventral hippocampal infusion of sazetidine-A reduced nicotine withdrawal-associated changes in anxiety (Turner et al., 2013).”
BackgroundSelf-citationLaikowski, M. M., Reisdorfer, F., & Moura, S. (2018) · Current Medicinal Chemistry · doi:10.2174/0929867325666180410105135 · Cited by 17 · see citing works
Subchronic effects of plant alkaloids on anxiety-like behavior in zebrafish
Hawkey, A. B., Hoeng, J., Peitsch, M. C., Levin, E. D., & Koshibu, K. (2021) · Pharmacology Biochemistry and Behavior · doi:10.1016/j.pbb.2021.173223 · Cited by 15 · see citing works
“Several α4β2 nAChR agonists, such as TC-2216 and sazetidine-A, have been shown to induce antidepressant- and anxiolytic-like effects in rodents, for example (Romanelli et al., 2007; Turner et al., 2013; Yu et al., 2014).”
BackgroundSimmons, S. J., & Gould, T. J. (2014) · Journal of Clinical Pharmacy and Therapeutics · doi:10.1111/jcpt.12171 · Cited by 16 · see citing works
“However, one animal study showed that varenicline might not be effective in reducing anxiety during short-term nicotine withdrawal.(151) Varenicline treatment reduced negative affect and improved performance in neurocognitive tests of sustained attention and working memory in smokers undergoing short-term withdrawal.”
BackgroundSelf-citationTranslational Research on Nicotine Dependence
Falcone, M., Lee, B., Lerman, C. E., & Blendy, J. A. (2015) · Current topics in behavioral neurosciences · doi:10.1007/7854_2015_5005 · Cited by 15 · see citing works
“However, only infusions of sazetidine-A (but not varenicline) into the ventral hippocampus are efficacious in reducing nicotine withdrawal-related anxiety-like phenotypes (Turner et al. 2013).”
BackgroundSelf-citationGlial cells as therapeutic targets for smoking cessation
Kumar, M., Adeluyi, A., Anderson, E. L., & Turner, J. R. (2020) · Neuropharmacology · doi:10.1016/j.neuropharm.2020.108157 · Cited by 12 · see citing works
“Similar behavioral phenotypes are also observed in rodents that have undergone chronic nicotine exposure and withdrawal (Adeluyi et al., 2019; Hussmann et al., 2014; Turner et al., 2013b; Yohn et al., 2014).”
BackgroundSelf-citationAlzualde, A., Jaka, O., Latino, D. A. R. S., Alijevic, O., Iturria, I., de Mendoza, J. H., Pospíšil, P., Frentzel, S., Peitsch, M. C., Hoeng, J., et al. (2021) · Journal of Natural Medicines · doi:10.1007/s11418-021-01544-8 · Cited by 11 · see citing works
Forcelli, P. A., Turner, J. R., Lee, B. G., Olson, T. T., Xie, T., Xiao, Y., Blendy, J. A., & Kellar, K. J. (2015) · Neuropharmacology · doi:10.1016/j.neuropharm.2015.09.012 · Cited by 11 · see citing works
“This mouse strain was selected as it has previously been used for examining anxiety and depression-like behaviors in mice (e.g., Turner et al., 2010, 2011, 2013; Hussmann et al., 2014).”
MethodSelf-citationLeach, P. T., Holliday, E. D., Kutlu, M. G., & Gould, T. J. (2014) · Nicotine & Tobacco Research · doi:10.1093/ntr/ntu229 · Cited by 12 · see citing works
Self-citationKeady, J. V., Hessing, M. C., Songrady, J. C., McLaurin, K. A., & Turner, J. R. (2024) · Biology of Sex Differences · doi:10.1186/s13293-024-00656-6 · Cited by 9 · see citing works
“This dose is based on previous work [58, 62–64] and corresponds to plasma levels of ∼ 0.3 µM [65], a concentration similar to that observed in human smokers consuming an average of 17 cigarettes a day (plasma levels between 0.06 and 0.31 µM) [65].”
MethodInfluentialSelf-citationEnhancement of alcohol aversion by the nicotinic acetylcholine receptor drug sazetidine‐A
Touchette, J. C., Moen, J. K., Robinson, J. M., & Lee, A. M. (2020) · Addiction Biology · doi:10.1111/adb.12908 · Cited by 6 · see citing works
“29 Furthermore, acute varenicline injection, but not acute sazetidine-A injection, produces anxiolytic effects in the marble-burying test and in novelty-induced hypophagia in mice.”
BackgroundKutlu, M. G., Tumolo, J. M., Cann, C., & Gould, T. J. (2018) · Psychopharmacology · doi:10.1007/s00213-018-4837-4 · Cited by 5 · see citing works
“All doses, routes of administration, and injection times are based on previous studies from our laboratory (Davis and Gould 2006; Turner et al. 2013).”
InfluentialSelf-citationTranslational Research in Nicotine AddictionPreprint
Fisher, M. L., Pauly, J. R., Froeliger, B., & Turner, J. R. (2020) · Cold Spring Harbor Perspectives in Medicine · doi:10.1101/cshperspect.a039776 · Cited by 6 · see citing works
Self-citationDynamic Effects of Ventral Hippocampal NRG3/ERBB4 Signaling on Nicotine Withdrawal-Induced Responses
Fisher, M. L., Prantzalos, E. R., O’Donovan, B., Anderson, T. L., Sahoo, P. K., Twiss, J. L., Ortinski, P. I., & Turner, J. R. (2023) · Neuropharmacology · doi:10.1016/j.neuropharm.2024.109846 · Cited by 6 · see citing works
Self-citationAge‐specific impacts of nicotine and withdrawal on hippocampal neuregulin signalling
Keady, J. V., Fisher, M. L., Anderson, E., LeMalefant, R., & Turner, J. R. (2022) · European Journal of Neuroscience · doi:10.1111/ejn.15780 · Cited by 6 · see citing works
“This dose, reported as freebase weight and based off of previous work (Turner et al., 2010, 2011, 2013, 2014), corresponds to plasma levels of 0.3 μM (Matta et al., 2007), a concentration similar to that observed in human smokers consuming an average of 17 cigarettes a day (plasma levels between…”
ResultInfluentialSelf-citationNeurobiology and Mechanisms of Nicotine Addiction
Gogineni, H. P., Sachs, D. P. L., & Brunzell, D. H. (2023) · Respiratory medicine · doi:10.1007/978-3-031-24914-3_3 · Cited by 2 · see citing works
Enhancement of alcohol aversion by the nicotinic acetylcholine receptor drug sazetidine-APreprint
Touchette, J. C., Moen, J. K., Robinson, J. M., & Lee, A. M. (2019) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/723916 · Cited by 1 · see citing works
Dynamic Effects of Ventral Hippocampal NRG3/ERBB4 Signaling on Nicotine Withdrawal-Induced ResponsesPreprint
Fisher, M. L., Prantzalos, E. R., O’Donovan, B., et al. (2023) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2023.01.17.524432 · Cited by 1 · see citing works
Self-citationNgolab, J. (2015) · The Journal of the American Medical Association (JAMA) Network (American Medical Association) · doi:10.13028/m2730b
“Furthermore, current smoking cessation therapeutics are minimally successful in mitigating nicotine withdrawal symptoms (Cinciripini et al., 2013; Foulds et al., 2013; Turner et al., 2013).”
BackgroundNicotine use disorder and Neuregulin 3: Opportunities for precision medicine
Elder, T. R., & Turner, J. R. (2024) · Advances in pharmacology · doi:10.1016/bs.apha.2023.10.001
Self-citationMolecular mechanisms of nicotinic acetylcholine receptors in mood dysregulation
Murthy, M. K., & Samal, D. (2026) · Progress in Neuro-Psychopharmacology and Biological Psychiatry · doi:10.1016/j.pnpbp.2026.111880
- Authors
- Turner, J. R., Wilkinson, D. S., Poole, R. L., Gould, T. J., Carlson, G. C., & Blendy, J. A.
- Affiliations
- University of Pennsylvania (US)
- Temple University (US)
- Corresponding author
- Blendy, Julie A
- Venue
- Neuropsychopharmacology
- Published
- 2013-04-29
- Volume
- 38
- Issue
- 10
- Pages
- 2035-2047
- ISSN
- 0893-133X (ISSN-L)
- 1740-634X
- PMC
- PMC3746688
- OpenAlex
- W2028195938
- Semantic Scholar
- 9dd5747b2b423e643d3a6e6270103b636b2ca5e7
- Cited by
- 29
- References
- 110
- Citations by year
- 2026: 1 · 2024: 2 · 2023: 2 · 2022: 1 · 2021: 3 · 2020: 3 · 2019: 2 · 2018: 2 · 2016: 1 · 2015: 5 · 2014: 6 · 2013: 1
- FWCI
- 3.24
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Neuropsychopharmacology (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Pfizer
- AstraZeneca
- National Institutes of Health (1-F32-)
- National Institute on Drug Abuse (F32DA026236, 1-F32-DA026236, R00DA032681, K99DA032681, 1-K99-DA032681, DA024787-01A1S1, R01DA024787)
- National Cancer Institute (CA-143187, P50CA143187)
- Topics
- Health Sciences › Medicine › Physiology › Smoking Behavior and Cessation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Nicotinic Acetylcholine Receptors Study
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Keywords
- varenicline, nicotine withdrawal, smoking cessation, novelty-induced hypophagia, ventral hippocampus, hippocampal network activity, drug history, α4β2 nicotinic acetylcholine receptor
- MeSH terms
- Varenicline, Animals, Anxiety, Azetidines, Benzazepines, Cerebral Cortex, Dose-Response Relationship, Drug, Evoked Potentials, Hippocampus, Male, Microinjections, Motor Activity, Nicotine, Pyridines, Quinoxalines, Receptors, Nicotinic, Substance Withdrawal Syndrome, Up-Regulation, Smoking Cessation, Nicotinic Agonists, Mice, Drug Partial Agonism
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Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
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