Nicotine Withdrawal

“The emergence of depression-like symptoms during withdrawal can be assessed with the forced swim test (FST), which assesses learned helplessness by monitoring passive coping strategies such as immobility (Cryan et al. 2002; Thanos et al. 2013).”

“The EPM consists of two enclosed arms with walls running along their periphery, and two open arms with no walls that present an environment resembling elevated cliffs (Crawley et al. 1997).”

“The five-choice serial reaction time task (5-CSRTT), also called operant signal detection, is a behavioral test used to characterize the effects of treatments on sustained and divided attention (Robbins 2002).”

“While the DAergic VTA has been widely implicated in the rewarding aspects of addictive drugs, it has also been shown to participate in the signaling of aversion and lack of expected reward (Schultz et al. 1998; Ungless et al. 2004; Tobler et al. 2007; De Biasi and Dani 2011).”

“…accumbens, ventral pallidum/globus pallidus, laterodorsal tegmentum, pedunculopontine nuclei, diagonal band of Broca, bed nucleus of the stria terminalis, and the caudal tip of the VTA, termed the rostromedial tegmental nucleus (RMTg) (Geisler and Zahm 2005; Jhou et al. 2009; Kaufling et al. 2009).”

“Subjects must learn contextual information and form an association between the context and an aversive electric shock (Fanselow and Poulos 2005; Sigurdsson et al. 2007).”

“…Mechanisms Involved in the Nicotine Withdrawal Syndrome 4.1 nAChR Upregulation Long-term exposure to nicotine leads to an increase, or upregulation, of nicotinebinding sites in the brain of smokers (Benwell et al. 1988) and rodents subjected to repeated nicotine administrations (Marks et al. 1983).”

“While the DAergic VTA has been widely implicated in the rewarding aspects of addictive drugs, it has also been shown to participate in the signaling of aversion and lack of expected reward (Schultz et al. 1998; Ungless et al. 2004; Tobler et al. 2007; De Biasi and Dani 2011).”

“1988) and rodents subjected to repeated nicotine administrations (Marks et al. 1983).”

“This longlasting level of nicotine ensures that high-affinity nAChRs recurrently bind and unbind nicotine throughout the day (Picciotto et al. 2008).”

“Because desensitized nAChR conformations have a higher affinity for agonist, nAChRs will increasingly adopt desensitized conformations in response to chronic nicotine exposure (Quick and Lester 2002; Picciotto et al. 2008).”

“Additionally, the genetic differences that distinguish each inbred strain of mice have important consequences for behavior, as each strain is characterized by a unique repertoire of consistent behavioral traits (Crawley 1996, 2008; Krackow et al. 2010; Matsuo et al. 2010).”

“Activity in the RMTg increases upon exposure to aversive stimuli and decreases upon exposure to reward stimuli, representing inversely correlated signaling patterns (Hong et al. 2011).”

“It has been suggested that receptor desensitization may be a major contributor to the upregulation observed in chronic users of nicotine-containing products (Benowitz 2008).”

“…accumbens, ventral pallidum/globus pallidus, laterodorsal tegmentum, pedunculopontine nuclei, diagonal band of Broca, bed nucleus of the stria terminalis, and the caudal tip of the VTA, termed the rostromedial tegmental nucleus (RMTg) (Geisler and Zahm 2005; Jhou et al. 2009; Kaufling et al. 2009).”

“…accumbens, ventral pallidum/globus pallidus, laterodorsal tegmentum, pedunculopontine nuclei, diagonal band of Broca, bed nucleus of the stria terminalis, and the caudal tip of the VTA, termed the rostromedial tegmental nucleus (RMTg) (Geisler and Zahm 2005; Jhou et al. 2009; Kaufling et al. 2009).”

“Using transgenic mouse lines or viral delivery, designer receptors [DREADDs (Rogan and Roth 2011)] and light-driven ion channels [opsins (Yizhar et al. 2011)] can be expressed in particular anatomical structures or in particular neuronal types.”

“A variety of cellular processes influence receptor upregulation (Govind et al. 2009; Rezvani et al. 2009, 2010; Henderson et al. 2014).”

“Subjects must learn contextual information and form an association between the context and an aversive electric shock (Fanselow and Poulos 2005; Sigurdsson et al. 2007).”

“While the DAergic VTA has been widely implicated in the rewarding aspects of addictive drugs, it has also been shown to participate in the signaling of aversion and lack of expected reward (Schultz et al. 1998; Ungless et al. 2004; Tobler et al. 2007; De Biasi and Dani 2011).”

“A uthor M anuscript A uthor M anuscript A uthor M anuscript A uthor M anuscript avoiding environments paired with withdrawal serves as an indicator of the severity of aversion (Kenny and Markou 2001).”

“…that the physical manifestations of nicotine abstinence are contextdependent, as α2 KO mice exhibit more somatic symptoms of withdrawal in novel environments (Lotfipour et al. 2013), but display no somatic signs of withdrawal in habituated environments (i.e., the home cage) (Salas et al. 2009).”

“However, increased inhibitory input to the VTA is a potential mechanism, as GABA input is sufficient to suppress burst firing even with excitatory inputs intact (Lobb et al. 2010; Jalabert et al. 2011).”

“The α5 null mutation does not appear to influence affective symptoms such as withdrawal-induced CPA (Jackson et al. 2008).”

“However, increased inhibitory input to the VTA is a potential mechanism, as GABA input is sufficient to suppress burst firing even with excitatory inputs intact (Lobb et al. 2010; Jalabert et al. 2011).”

“Nicotine withdrawal leads to an increase in CRF in the CeA, and blockade of CRF1 receptors diminishes nicotine withdrawalinduced anxiety-like behavior (George et al. 2007).”

“DA release in the NAcc following nicotine administration is regulated in part by α6containing (α6*) nAChRs on DAergic terminals in the dorsal and ventral striatum (Exley et al. 2008) and DAergic somata in the VTA (Grady et al.”

“Using a radioligand with specificity for β2containing nAChRs, which enabled the use of single-photon emission computed tomography (SPECT) (Staley et al. 2006), it was found that chronic smokers have more cortical, striatal, and cerebellar β2* nAChRs than non-smokers (Staley et al.”

“In rodents, α2 mRNA levels are highest in the interpeduncular nucleus (IPN), with more restricted expression in scattered neurons within the amygdala, hippocampus, cortex, retina, spinal cord, and cerebellum (Lotfipour et al. 2013).”

“They are each densely expressed in the MHb and/or IPN (Salas et al. 2003b, 2004) and are potential targets for treatments of the nicotine withdrawal syndrome (Grady et al. 2009).”

“Gene variants within the cluster have been repeatedly shown to affect nicotine dependence and smoking quantity (Saccone et al. 2009).”

“The α5 null mutation does not appear to influence affective symptoms such as withdrawal-induced CPA (Jackson et al. 2008).”

“Dopaminergic deficits in the mesolimbic pathway, particularly in the nucleus accumbens, are among the neurochemical mechanisms underlying the symptoms of nicotine withdrawal (Hildebrand et al. 1998; Carboni et al. 2000; Rada et al. 2001).”

“…define dependence, and the population considered, heritability contributes 50–75 % of the risk for dependence (Dokal et al. 1989; Hall et al. 2002; Lessov et al. 2004; Furberg et al. 2010; Nugent et al. 2014; also see chapters entitled Genetics of Smoking Behaviour and Pharmacogenetics of…”

“Additionally, the genetic differences that distinguish each inbred strain of mice have important consequences for behavior, as each strain is characterized by a unique repertoire of consistent behavioral traits (Crawley 1996, 2008; Krackow et al. 2010; Matsuo et al. 2010).”

“After at least a week of chronic nicotine administration in mice, cessation of nicotine exposure or administration of a nAChR antagonist induces affective, somatic, and cognitive signs of withdrawal (Malin et al. 1994; De Biasi and Salas 2008).”

“Several other pharmacogenetic studies, including a couple of genome-wide association study (GWAS) analyses, have examined genetic influences on smoking cessation and response to therapy (Leeb and Tamse 1985; Uhl et al. 2007; Furberg et al. 2010; Gold and Lerman 2012; King et al. 2012; Bloom et al. 2013; Chen et al. 20…”

“A uthor M anuscript A uthor M anuscript A uthor M anuscript A uthor M anuscript NJ, Sanders AR, Schwartz AG, Shete S, Shi J, Spitz M, Stefansson K, Swan GE, Thorgeirsson T, Volzke H, Wei Q, Wichmann HE, Amos CI, Breslau N, Cannon DS, Ehringer M, Grucza R, Hatsukami D, Heath A, Johnson EO, Kaprio J, Madden P, Martin NG…”

“For example, inclusion of the α5 subunit into α4β2* nAChRs decreases the extent of desensitization (Bailey et al. 2010).”

“Contextual FC is dependent upon hippocampal signaling (Davis et al. 2005), and during spontaneous withdrawal from nicotine, mice exhibit deficient contextual FC relative to saline-treated controls (Davis et al.”

“Additionally, the genetic differences that distinguish each inbred strain of mice have important consequences for behavior, as each strain is characterized by a unique repertoire of consistent behavioral traits (Crawley 1996, 2008; Krackow et al. 2010; Matsuo et al. 2010).”

“In addition, there are cognitive deficits that manifest during nicotine withdrawal, including difficulty concentrating, increased reaction times in tasks requiring sustained attention, and impaired episodic and working memory (Myers et al. 2008; Wesnes et al. 2013).”

“The habenula has been demonstrated to participate in the signaling underlying fear, anxiety, depression, and stress (Viswanath et al. 2013).”

“Dopaminergic deficits in the mesolimbic pathway, particularly in the nucleus accumbens, are among the neurochemical mechanisms underlying the symptoms of nicotine withdrawal (Hildebrand et al. 1998; Carboni et al. 2000; Rada et al. 2001).”

“Genetic factors may also account for 29–53 % of the variance in withdrawal symptoms and approximately 50 % of the variance in quitting success (Xian et al. 2003, 2005; Pergadia et al. 2006).”

“SNPs in CHRNB2 and the CHRNA5-CHRNA3-CHRNB4 cluster seem to influence smoking cessation, although the reported effects are not always reproducible (Conti et al. 2008; Baker et al. 2009; Perkins et al. 2009; Gold and Lerman 2012; Hartz et al. 2012).”

“As these differences can translate to increased or decreased detectability of behavioral changes induced by withdrawal, it is prudent to establish which strain is most sensitive to the hypothesized behavioral changes in question (Bailey et al. 2006; Crawley 2008; Lalonde and Strazielle 2008; Wahlsten 2010).”

“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).”

“Similar to what was found for phenotypes related to nicotine dependence, there are also associations of CYP2A6 enzyme activity and nicotine metabolic rates with smoking cessation and smoking cessation strategies (Lee et al. 2007; Chen et al. 2014).”

“However, increased inhibitory input to the VTA is a potential mechanism, as GABA input is sufficient to suppress burst firing even with excitatory inputs intact (Lobb et al. 2010; Jalabert et al. 2011).”

“Through this projection, the MHb releases acetylcholine (ACh), substance P (SP), and glutamate onto the IPN (Zhao-Shea et al. 2013).”

“In rodents, α2 mRNA levels are highest in the interpeduncular nucleus (IPN), with more restricted expression in scattered neurons within the amygdala, hippocampus, cortex, retina, spinal cord, and cerebellum (Lotfipour et al. 2013).”

“Individuals carrying the null activity allele, CYP2A6*2, are twice as likely to quit smoking as subjects without that allele (Gu et al. 2000).”

“The impact of the mutation that defines the risk allele has been validated repeatedly in vitro and in animal models (Kuryatov et al. 2011; Morel et al. 2014).”

“The influence of CHRNA5-CHRNA3CHRNB4 haplotypes on tolerance, craving, and loss of control seems greatest in individuals who began smoking early in life, suggesting that the risk associated with those genes is greatest with early tobacco exposure (Baker et al. 2009).”

“Fortunately, analytical tools, such as the Encyclopedia of DNA Elements (ENCODE), can help the design of experiments that explore disease-related variants located within noncoding regions (Siggens and Ekwall 2014).”

“…parameters used to define dependence, and the population considered, heritability contributes 50–75 % of the risk for dependence (Dokal et al. 1989; Hall et al. 2002; Lessov et al. 2004; Furberg et al. 2010; Nugent et al. 2014; also see chapters entitled Genetics of Smoking Behaviour and…”

“A lowered threshold resulting from a treatment is suggested to represent increased reward signaling along the pathway, while a heightened threshold is interpreted as indicating a state of greater anhedonia (O’Dell and Khroyan 2009).”

“As these differences can translate to increased or decreased detectability of behavioral changes induced by withdrawal, it is prudent to establish which strain is most sensitive to the hypothesized behavioral changes in question (Bailey et al. 2006; Crawley 2008; Lalonde and Strazielle 2008; Wahlsten 2010).”

“Indeed, a non-nicotine pharmaceutical currently FDA approved for the treatment of smoking cessation, varenicline, acts as a partial agonist at α6β2* nAChRs (Grady et al. 2010; Bordia et al. 2012).”

“The hyperalgesia symptoms that emerge during mecamylamine-precipitated withdrawal are reduced in α7 KO mice (Grabus et al. 2005).”

“Dopaminergic deficits in the mesolimbic pathway, particularly in the nucleus accumbens, are among the neurochemical mechanisms underlying the symptoms of nicotine withdrawal (Hildebrand et al. 1998; Carboni et al. 2000; Rada et al. 2001).”

“After at least a week of chronic nicotine administration in mice, cessation of nicotine exposure or administration of a nAChR antagonist induces affective, somatic, and cognitive signs of withdrawal (Malin et al. 1994; De Biasi and Salas 2008).”

“The rs8192475 variant in CHRNA3 was shown to predict withdrawal symptoms and craving after quitting (Sarginson et al. 2011).”

“Several other pharmacogenetic studies, including a couple of genome-wide association study (GWAS) analyses, have examined genetic influences on smoking cessation and response to therapy (Leeb and Tamse 1985; Uhl et al. 2007; Furberg et al. 2010; Gold and Lerman 2012; King et al. 2012; Bloom et al. 2013; Chen et al. 20…”

“Conversely, smokers with high-activity alleles (CYP2A6*1/*1B) experience more severe withdrawal symptoms when trying to quit (Kubota et al. 2006).”

“Genetic factors may also account for 29–53 % of the variance in withdrawal symptoms and approximately 50 % of the variance in quitting success (Xian et al. 2003, 2005; Pergadia et al. 2006).”

“Overall, linkage analyses have highlighted 13 regions on 11 chromosomes that include genes with potential influences on nicotine dependence (Leeb and Tamse 1985; Li 2008).”

“…nicotine administration has been observed to generate cognitive enhancements, rats withdrawing from nicotine have been observed to exhibit attention deficits in the 5-CSRTT paradigm (Shoaib and Bizarro 2005), reflecting some of the symptoms that human smokers report while undergoing withdrawal.”

“If β4 replaces β2 subunits in either α3* or α4* nAChRs, receptor upregulation is significantly reduced (Wang et al. 1998; Sallette et al. 2004).”

“It has also been shown that α5containing nAChRs do not regulate the reward-inhibiting effects induced by nicotine withdrawal in the ICSS paradigm (Fowler et al. 2013), suggesting that the receptors do not influence anhedonia.”

“Similarly, in rodents, nAChR upregulation in the dorsal hippocampus was associated with withdrawal-related deficits in hippocampal learning (Gould et al. 2012; Portugal et al. 2012).”

“The increased pool of nAChRs arising from chronic nicotine exposure may drive symptoms associated with the nicotine withdrawal syndrome (Turner et al. 2011; Gould et al. 2012) and might impact the ability to maintain abstinence in the clinical population (Staley et al. 2006).”

“As replacement of β2 by β4 is sufficient to increase nAChR levels at the plasma membrane in the absence of nicotine, the proposed “chaperoning” function of nicotine might not be as effective (Srinivasan et al. 2011; Henderson et al. 2014).”

“straightforward, as Chrna5 deletion reduces anxiety in the EPM in basal conditions independent of nicotine treatment (Gangitano et al. 2009).”

“As for the physical signs of abstinence, α7 null mice exhibit significantly reduced withdrawal symptoms immediately after precipitation of withdrawal by mecamylamine injection (Salas et al. 2007).”

“Conversely, co-expression of β3 increases α6β2 and α6β4 receptor levels and enhances nicotine-induced upregulation of α6β2β3 receptors compared to α6β2 receptors (Tumkosit et al. 2006).”

“Indeed, a non-nicotine pharmaceutical currently FDA approved for the treatment of smoking cessation, varenicline, acts as a partial agonist at α6β2* nAChRs (Grady et al. 2010; Bordia et al. 2012).”

“In rodents, α2 mRNA levels are highest in the interpeduncular nucleus (IPN), with more restricted expression in scattered neurons within the amygdala, hippocampus, cortex, retina, spinal cord, and cerebellum (Lotfipour et al. 2013).”

“Genetic factors may also account for 29–53 % of the variance in withdrawal symptoms and approximately 50 % of the variance in quitting success (Xian et al. 2003, 2005; Pergadia et al. 2006).”

“Additionally, studies have demonstrated that upregulation of nAChR expression can persist for several days following termination of chronic nicotine (Pietila et al. 1998; Staley et al. 2006).”

“Similar deficits of contextual fear learning were observed when a nAChR antagonist (dihydro-β-erythroidine) was infused into the hippocampus of WT mice chronically treated with nicotine (Davis and Gould 2009).”

“Rare missense variants at conserved residues in CHRNB4 (T375I and T91I) are associated with reduced numbers of cigarettes per day and fewer signs of withdrawal (Haller et al. 2012).”

“The CRF/CRF1 receptor signaling in the CeA also mediates nicotine withdrawalinduced increases in nociceptive sensitivity in rats that are dependent on nicotine (Baiamonte et al. 2014).”

“The MHb also hosts the expression of norepinephrine (NE), serotonin, ATP, and several neuropeptides (Dao et al. 2014).”

“Furthermore, chronic nicotine treatment upregulated a variety of nAChRs in the hippocampus, and the duration of β2 subunit upregulation relative to other nAChR subunits most closely corresponded to the total duration of memory-associated withdrawal symptoms (Gould et al. 2012).”

“Acute nicotine administration enhances contextual FC, while nicotine withdrawal impairs it (Davis and Gould 2008).”

“2009), β3 KO mice have altered hypothalamic pituitary adrenal axis responses (Booker et al. 2007).”

“A variety of cellular processes influence receptor upregulation (Govind et al. 2009; Rezvani et al. 2009, 2010; Henderson et al. 2014).”

“A variety of cellular processes influence receptor upregulation (Govind et al. 2009; Rezvani et al. 2009, 2010; Henderson et al. 2014).”

“SNPs in CHRNB2 and the CHRNA5-CHRNA3-CHRNB4 cluster seem to influence smoking cessation, although the reported effects are not always reproducible (Conti et al. 2008; Baker et al. 2009; Perkins et al. 2009; Gold and Lerman 2012; Hartz et al. 2012).”

“It should be noted that in a study of European Americans and African-Americans, CHRNA2 showed a strong association with the Fagerström Test for Nicotine Dependence (FTND) after correction for multiple testing (Wang et al. 2014).”

“Several other pharmacogenetic studies, including a couple of genome-wide association study (GWAS) analyses, have examined genetic influences on smoking cessation and response to therapy (Leeb and Tamse 1985; Uhl et al. 2007; Furberg et al. 2010; Gold and Lerman 2012; King et al. 2012; Bloom et al. 2013; Chen et al. 20…”

“In contrast to wild-type mice, α7 null mice failed to exhibit elevated ICSS thresholds during nicotine withdrawal between 3 and 6 h after their last nicotine exposure (Stoker et al. 2012).”

“An earlier study reported that DRD2 TaqI-B polymorphisms influence abstinence and withdrawal symptoms (Robinson et al. 2007).”

“In addition, there are cognitive deficits that manifest during nicotine withdrawal, including difficulty concentrating, increased reaction times in tasks requiring sustained attention, and impaired episodic and working memory (Myers et al. 2008; Wesnes et al. 2013).”

“Several other pharmacogenetic studies, including a couple of genome-wide association study (GWAS) analyses, have examined genetic influences on smoking cessation and response to therapy (Leeb and Tamse 1985; Uhl et al. 2007; Furberg et al. 2010; Gold and Lerman 2012; King et al. 2012; Bloom et al. 2013; Chen et al. 20…”

“The study revealed a linkage signal that meets genome-wide significance on chromosome 11p15 in the Finnish families (Pergadia et al. 2009).”

“In oocytes, the T22I mutation changes the sensitivity to nicotine of α2β4-containing nAChRs (Dash et al. 2014).”

“…heritability contributes 50–75 % of the risk for dependence (Dokal et al. 1989; Hall et al. 2002; Lessov et al. 2004; Furberg et al. 2010; Nugent et al. 2014; also see chapters entitled Genetics of Smoking Behaviour and Pharmacogenetics of Nicotine and Associated Smoking Behaviors;…”

“The emergence of depression-like symptoms during withdrawal can be assessed with the forced swim test (FST), which assesses learned helplessness by monitoring passive coping strategies such as immobility (Cryan et al. 2002; Thanos et al. 2013).”

“Depending on the parameters used to define dependence, and the population considered, heritability contributes 50–75 % of the risk for dependence (Dokal et al. 1989; Hall et al. 2002; Lessov et al. 2004; Furberg et al. 2010; Nugent et al. 2014; also see chapters entitled Genetics of Smoking…”

“…to change behavior, such as to help people overcome addiction, many of the rewards for changing behavior are delayed (e.g., better health after quitting smoking) and opposed by immediate punishers (e.g., anxiety, difficulty concentrating, insomnia, irritability; see McLaughlin et al., 2015).”

“Nicotine withdrawal effects such as irritability, anxiety, poor concentration, memory impairment, and insomnia can occur after cessation of chronic nicotine use [3].”