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Link to original content: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4444410
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Published in final edited form as: Neuropharmacology. 2014 Nov 26;96(0 0):223–234. doi: 10.1016/j.neuropharm.2014.11.009

New mechanisms and perspectives in nicotine withdrawal

KJ Jackson a, PP Muldoon c, M De Biasi b, MI Damaj c
PMCID: PMC4444410  NIHMSID: NIHMS645482  PMID: 25433149

Abstract

Diseases associated with tobacco use constitute a major health problem worldwide. Upon cessation of tobacco use, an unpleasant withdrawal syndrome occurs in dependent individuals. Avoidance of the negative state produced by nicotine withdrawal represents a motivational component that promotes continued tobacco use and relapse after smoking cessation. With the modest success rate of currently available smoking cessation therapies, understanding mechanisms involved in the nicotine withdrawal syndrome are crucial for developing successful treatments. Animal models provide a useful tool for examining neuroadaptative mechanisms and factors influencing nicotine withdrawal, including sex, age, and genetic factors. Such research has also identified an important role for nicotinic receptor subtypes in different aspects of the nicotine withdrawal syndrome (e.g., physical vs. affective signs). In addition to nicotinic receptors, the opioid and endocannabinoid systems, various signal transduction pathways, neurotransmitters, and neuropeptides have been implicated in the nicotine withdrawal syndrome. Animal studies have informed human studies of genetic variants and potential targets for smoking cessation therapies. Overall, the available literature indicates that the nicotine withdrawal syndrome is complex, and involves a range of neurobiological mechanisms. As research in nicotine withdrawal progresses, new pharmacological options for smokers attempting to quit can be identified, and treatments with fewer side effects that are better tailored to the unique characteristics of patients may become available.

Keywords: nicotine, nicotine withdrawal, nicotinic receptors, nicotine dependence, tobacco dependence

1. Introduction

Tobacco dependence is the leading cause of preventable mortality in the United States. Maintenance of smoking behavior is largely due to nicotine, the main addictive component of tobacco (Stolerman and Jarvis 1995). Globally, smoking-related illnesses cause over four million deaths annually. Addiction to tobacco smoking depends not only on the positive reinforcing and hedonic actions of nicotine, but also on escape from the aversive consequences of nicotine withdrawal. Many studies suggest that avoidance of the negative emotional state produced by nicotine withdrawal represents a motivational component that promotes continued tobacco use and relapse after smoking cessation. The nicotine withdrawal syndrome is considered to be one of the major causes of high relapse rate in individuals undergoing smoking cessation (Le Foll and Goldberg 2009). Indeed, withdrawal duration and severity can accurately predict relapse in abstinent human smokers (Allen et al. 2008; Zhou et al. 2009). Among adult smokers, 80% report the desire to quit completely; however, those who attempt to quit on their own relapse within the first month and only 3% remain abstinent after 6 months (Hughes et al., 1992). While there are smoking cessation therapies available, which include nicotine replacement therapies, the anti-depressant bupropion (Zyban ®), and the partial nicotinic agonist varenicline (Chantix ®) (Cummings and Mahoney 2006; Jorenby et al. 2006), the success rate of these therapies after one year remains only about 20–25% (Gonzales et al. 2006). Indeed, severity of the withdrawal syndrome is a better predictor of unsuccessful smoking attempts than smoke intake or dependence (West et al. 1989).

Smoking cessation after chronic tobacco use produces a well characterized and defined withdrawal syndrome. The nicotine withdrawal syndrome in abstinent smokers is comprised of ‘physical’ or somatic components, cognitive, and ‘affective’ components. The somatic signs include bradycardia, gastrointestinal discomfort, and increased appetite. Affective symptoms primarily include depressed mood including anhedonia, dysphoria, anxiety, irritability, difficulty concentrating, and craving (Hughes 2007). Although the somatic manifestations of withdrawal from drugs of abuse are certainly unpleasant, escape from affective components of withdrawal play a more important role in the maintenance of dependence to drugs of abuse, including nicotine (Koob and Le Moal 2005; Koob and Volkow 2010). The negative affective symptoms can start as soon as 4 hours after the last cigarette, peak in about three days, and are still measurable a month after cessation of tobacco use (Swan et al. 1996; Ward et al. 2001; Hughes 2007).

Withdrawal effects are largely mediated through nicotinic acetylcholine receptors (nAChRs), which are the primary binding sites for nicotine, and the endogenous neurotransmitter acetylcholine. Neuronal nAChRs are cation-permeable, ligand gated homomeric or heteromeric complexes composed of α and β subunits. To date, twelve neuronal nAChR subunits have been identified, including α2-α10 and β2-β4, making it possible to have a large variety in subtype composition and a great range of pharmacological and physiological effects in response to nicotine. The main nAChR subtypes in the brain are the α7 and α4β2* subtypes (Changeux et al. 1998), where * denotes possible assembly with other nAChR subunits. Once activated, neuronal nAChRs can elevate intracellular calcium directly, via influx through the nAChR channel, indirectly, via Na+ influx, subsequent membrane depolarization, and activation of voltage-gated calcium channels, and through calcium-induced calcium release from intracellular stores (De Biasi and Dani, 2011). Presynaptic nAChRs facilitate calcium-dependent release of many neurotransmitters and activation of various downstream signaling cascades involved in gene transcription (Wonnacott 1997). The neuroadaptations that occur as a result of chronic nicotine exposure reflect nicotine’s influence on neurotransmitter systems such as dopamine, glutamate, γ-aminobutyric acid (GABA) and serotonin (De Biasi and Salas 2008). Further, it has been proposed that the desensitization and upregulation of nAChRs following chronic nicotine exposure is influential in producing withdrawal symptoms upon cessation of smoking (Benwell et al. 1988; Dani and Heinemann 1996; Balfour and Fagerstrom 1996), and that maintained nAChR desensitization may be important for relieving nicotine withdrawal in humans (Brody et al. 2006).

2. Animal models of nicotine dependence

Animal models of nicotine withdrawal have been developed and are useful tools for elucidating mechanisms associated with nicotine withdrawal behaviors. These rodent models measure multiple signs of withdrawal; somatic signs, affective signs, and cognitive changes. The emergence of negative affective and cognitive symptoms and, to a lesser extent, the somatic manifestations of withdrawal, underlies nicotine-seeking behavior (Koob et al. 1993; Markou et al. 1998; De Biasi and Dani 2011). Mice and rats are rendered dependent on nicotine using various routes of exposure, including chronic infusion through osmotic mini pumps (Damaj et al. 2003; Malin et al. 2006), chronic injections (Liu et al. 2005; Miura et al. 2006), oral route via drinking water (Liu et al. 2005; Grabus et al. 2005a), or intravenous administration (Wilkinson and Bevins 2008). Withdrawal may be precipitated in nicotine-exposed animals with nicotinic antagonists, such as the non-selective nAChR antagonist mecamylamine, or evaluated spontaneously by the cessation of chronic nicotine treatment. Physical signs in rodents are typically measured as somatic signs (Malin et al. 1992; Hildebrand et al. 1997; Damaj et al. 2003), hyperalgesia (Salas et al. 2004; Grabus et al. 2005b), and changes in locomotor activity (Hildebrand et al. 1999; Nomikos et al. 1999), while affective signs are typically measured as anxiety-related behaviors (Damaj et al. 2003; Stoker et al. 2008), elevated reward thresholds through the intracranial self-stimulation procedure (ICSS) (Cryan et al. 2003; Bruijnzeel and Markou 2004; Johnson et al. 2008), and conditioned place aversion (CPA) (Suzuki et al. 1996; Malin et al. 2006; Jackson et al. 2009a). Smoking cessation is associated with disrupted cognition (Lerman et al. 2007), and in mouse models, hippocampus-dependent learning is particularly sensitive to the effects of nicotine withdrawal (Kenney and Gould 2008), including contextual fear conditioning (Davis et al. 2005). In addition, a nicotine withdrawal-potentiated acoustic startle procedure was developed to measure negative affective withdrawal behaviors after repeated nicotine exposure and withdrawal episodes (Engelmann et al. 2009). It was observed that intermittent exposure to nicotine results in escalating levels of withdrawal-potentiated startle response in rats (Engelmann et al. 2009). The relevance of the model is evident in that elevated startle response has been used to accurately assess opiate (Stine et al. 2001) and ethanol withdrawal (Krystal et al. 1997; Saladin et al. 2002) in humans. Further, this model allows for the assessment of altered anxiety levels to be detected at the earliest stages of addiction, and thus may be a valid model to measure nicotine dependence in adolescent rodent models (Engelmann et al. 2009). These various aspects of nicotine withdrawal are likely to be mediated by different brain substrates that express multiple nAChRs subtypes. For example, studies have shown that somatic signs of nicotine withdrawal are mediated by both central and peripheral nAChRs, while affective signs are mediated solely through central nAChR populations such as nucleus accumbens (NAc), habenulo-interpeduncular system, amygdala, and hippocampus (Watkins et al. 2000; De Biasi and Dani 2011).

2.1. Withdrawal models using tobacco smoke

While the currently available animal models of nicotine exposure have provided a wealth of information on mechanisms of nicotine withdrawal, evidence suggests that tobacco constituents aside from nicotine may contribute to tobacco addiction (Fowler et al. 2003; Talhout et al. 2007), thus animal models that more closely mimic human tobacco use and smoke exposure are warranted. Recently, animal models allowing for assessment of the full spectrum of tobacco smoke constituents have been developed to examine nicotine dependence and withdrawal. Exposure to tobacco smoke for 4 h per day for 28 consecutive days induced a significant increase in brain reward threshold and significant nicotine withdrawal somatic signs in rats (Small et al. 2010), indicating that exposure to tobacco smoke constituents through inhalation is sufficient to produce both somatic and affective nicotine withdrawal. Additionally, a non-invasive chronic nicotine vapor exposure technique was developed in rats to produce consistent levels of nicotine in the blood relevant to both heavy smokers and second-hand smoke, and to mimic the intermittent nicotine exposure and most common route of nicotine administration in humans (George et al. 2010). Rats chronically and intermittently exposed to nicotine vapor expressed significant somatic withdrawal signs after mecamylamine treatment (George et al. 2010; Gilpin et al. 2012) implicating the reliability of such a model to measure nicotine withdrawal signs and provide new insight into neuroadaptive changes occurring from second-hand smoke exposure.

2.2. Influence of modalities of exposure, sex, age, and genetic factors

Rodent models provide a vital tool for examining mechanisms related to sex, age, and genetic differences in response to nicotine withdrawal. In a study by Hamilton et al. (2009), which assessed sex differences in nicotine withdrawal, somatic signs were measured in male and female rats in two distinct environments, a brightly lit and a dimly lit environment. While females exhibited similar levels of somatic signs in both environments, in male rats, somatic withdrawal signs were more severe in the brightly lit environment than the dimly lit environment, suggesting that environmental factors more strongly affect behavioral symptoms of withdrawal in males than females. Because rodents are nocturnal, and exposure to bright light can be considered a stressor for rats, this study may reflect differences in coping mechanisms related to nicotine withdrawal in males and females. Similarly, the stress hormones, adrenocorticotropin hormone and corticosterone, were significantly reduced in male and female rats that received environmental enrichments in the home cage (Skwara et al. 2012). The stress hormones were reduced to a greater extent in females than males, suggesting that females were more sensitive to the anxiolytic effects of the environmental enrichment compared to males (Skwara et al. 2012). These studies emphasize the importance of environmental factors and their differences in the impact on anxiety levels in males and females with regards to nicotine withdrawal severity. Sex differences in nicotine withdrawal are also evident in adolescent rats, where, compared to male adolescents, female adolescents did not exhibit significant somatic nicotine withdrawal signs after cessation of nicotine treatment (Hamilton et al. 2010). Such information is valuable when considering the best behavioral measures to treat tobacco cessation in adult and adolescent males and females.

In addition to sex differences, studies evaluating age differences in nicotine withdrawal largely indicate diminished physical, affective, or cognitive nicotine withdrawal signs in adolescent rodents compared to adults (O'Dell et al. 2006; Wilmouth and Spear 2006; O'Dell et al. 2007; Kota et al. 2007; Shram et al. 2008; Jackson et al. 2009a; Portugal et al. 2012b); however, studies have also reported enhanced nicotine withdrawal-induced cognitive impairment in adolescent rodents compared to adults (Wilmouth and Spear 2006), or no difference in affective withdrawal measures (e.g., elevated plus maze, CPA) between adults and adolescents (Kota et al. 2008). The differences in findings (i.e., diminished effects, enhanced effect, or no effect) between adult and adolescent nicotine withdrawal studies reflect the importance of additional factors that can impact withdrawal behaviors, including sex (Kota et al. 2008), the withdrawal measure being assessed (Wilmouth and Spear 2006; Kota et al. 2008), and whether the model uses spontaneous or precipitated withdrawal (Shram et al. 2008). In addition, the modality of nicotine administration preceding withdrawal was found to impact the type of withdrawal signs after cessation of the drug. For example, earlier studies showed while somatic signs were observed in rats with short access to nicotine i.v. self-administration, anxiety-like behaviors and hyperalgesia were not (Irvine et al., 2001; O'Dell et al., 2007; Cohen et al., 2013). However, when rats were given long access (>21 hours/day) to nicotine self-administration, increase in anxiety-like behavior, nociceptive thresholds, somatic signs of withdrawal were observed after 3 days of abstinence (Cohen et al., 2013).

Previous studies also reported enhanced nicotine withdrawal-induced cognitive impairment in adolescent rodents compared to adults (Wilmouth and Spear 2006), or no difference between adults and adolescents (Kota et al. 2008; Shram et al. 2008). Studies exploring the neurochemical mechanisms that contribute to age differences in withdrawal response suggest increased nAChR functionality in adolescents compared to adults (Kota et al. 2007), alterations in kappa opioid receptor (KOR) regulation of mesolimbic dopamine transmission (Tejeda et al. 2012) and adolescent resistance to withdrawal-related neurochemical processes that inhibit mesolimbic dopamine function in adults experiencing nicotine withdrawal (Natividad et al. 2010; Natividad et al. 2012) as possible contributing factors. Understanding differences underlying nicotine withdrawal mechanisms between adults and adolescents will increase effectiveness of tobacco cessation therapies across different age groups.

Genetic factors also play a significant role in nicotine addiction and withdrawal response Portugal and Gould 2008; Portugal et al. 2012a), as will be discussed in detail later in this review. Using spontaneous and antagonist-precipitated mouse models of nicotine withdrawal, strain differences in the magnitude of withdrawal signs (Damaj et al. 2003; Hamilton et al. 2010) and in the manifestation of physical vs. affective withdrawal signs (Jackson et al. 2009c) have been identified in adult and adolescent rodents. Recently, it was observed that various mouse strains exhibited differential responses to nicotine withdrawal induced deficits in contextual conditioning, indicating the importance of genetic variability in response to nicotine withdrawal induced cognitive impairment (Portugal et al. 2012a; Wilkinson et al. 2013). The duration of chronic nicotine induced upregulation of high-affinity nAChRs in the hippocampus mediates, in part, the cognitive impairment observed during nicotine withdrawal (Gould et al. 2012), and genetic background was found to play a significant role in chronic nicotine induced nAChR upregulation, particularly in the dorsal hippocampus (Wilkinson et al. 2013). Additionally, recent studies using the BXD strain, a recombinant inbred strain of the C57BL/6 and DBA/2 strains, revealed that manifestation of nicotine withdrawal somatic signs is driven by multiple genes of modest effect size (Jackson et al. 2011).

3. Recent advances in mechanisms of nicotine withdrawal: Findings from animal studies

3.1. Role of nicotinic transmission

While early studies with non-selective nicotinic antagonists suggested that multiple nAChRs regulate expression of nicotine dependence, recent findings in nAChR knockout (−/−) mice have provided insight into the specific nAChR subtypes that regulate affective and somatic aspects of nicotine withdrawal. Neuronal nAChRs play a differential role in physical and affective nicotine withdrawal signs. Previously, β2 (Jackson et al. 2008; Jackson et al. 2009a) and α6 (Jackson et al. 2009b) nAChRs have been implicated in affective nicotine withdrawal measures, while α7, α3(Jackson et al. 2013), α5 (Jackson et al. 2008; Salas et al. 2009), β4 (Salas et al. 2004; Stoker et al. 2012b; Jackson et al. 2013), and α2 (Salas et al. 2009; Lotfipour et al. 2013) nAChRs are involved in physical nicotine withdrawal signs. Although the α3, α5, and β4 nAChR subunits, which can co-assemble to form functional receptors, have all been implicated in physical nicotine withdrawal, recent studies suggest that the α3β4* nAChR subtype can mediate withdrawal-induced somatic signs independently of the α5 subunit (Jackson et al. 2013).

Studies implicating specific nAChR subtypes and brain regions involved in nicotine withdrawal behaviors have also begun to develop. Emerging evidence demonstrates a major role for the habenulo-interpeduncular system, composed of the medial habenula (MHb) and the interpeduncular nucleus (IPN), and the nAChRs expressed therein, in the manifestation of somatic nicotine withdrawal symptoms (Salas et al. 2009; Baldwin et al. 2011). Specifically, microinjection of mecamylamine into the habenula and IPN, but not the cortex, VTA, or hippocampus, precipitated somatic nicotine withdrawal signs in mice (Salas et al. 2009).

More recently, studies show that the pacemaking activity of hyperpolarization-activated cyclic nucleotide-gated (HCN) channels in the MHb is altered during nicotine withdrawal (Gorlich et al. 2013). Specifically, spontaneous action potential frequency was potentiated upon reexposure to nicotine in MHb neurons from nicotine withdrawn mice compared to saccharin withdrawn mice. This increase in pacemaking activity was blocked my mecamylamine, indicating an effect mediated via nAChRs. Of interest, inhibition of HCN channels in the MHb precipitated somatic withdrawal signs and anxiety-like behavior in nicotine naïve mice, which suggests a role for behavioral mechanisms mediated independently of nicotine (Gorlich et al. 2013). Alternatively, a recent study by Shih et al. (2014) examined functional properties of the lateral and central parts of the MHb and found that the lateral MHb (MHbVL) neurons were more excitable to nicotine than central MHb neurons. In contrast to Gorlich et al. (2013), activity of MHbVL neurons from nicotine withdrawn mice was reduced upon reexposure to nicotine compared to MHbVL neurons from saline withdrawn mice. Despite this discrepancy between studies, which is likely attributed to examining the entire MHb versus specific MHb regions, an important role for nAChRs in the MHb is evident.

The hippocampus has also been identified as a brain region involved in nicotine withdrawal mechanisms related to cognitive effects. Galantamine, an acetylcholinesterase inhibitor and positive allosteric modulator of nAChRs, reversed the nicotine withdrawal deficits in contextual fear conditioning in mice, possibly through enhanced levels of acetylcholine via acetylcholinesterase inhibition and/or actions at hippocampal α4β2* nAChRs (Wilkinson and Gould 2011), supporting a role for hippocampal α4β2* nAChR-mediated responses in nicotine withdrawal induced cognitive deficits.

Systemic (Markou and Paterson 2001; Harrison et al. 2002) or intra-VTA (Bruijnzeel and Markou 2004) administration of the β2* selective nAChR antagonist DHβE precipitated withdrawal-associated elevations of ICSS thresholds in nicotine-dependent rats. Therefore, these data provide pharmacological support of a role of α4* and β2* nAChR subtypes, particularly those located in the VTA, in regulating the development of nicotine dependence and the expression of nicotine withdrawal induced anhedonia. Interestingly, a recent study that assessed the role of β4 and α7 nAChRs in the anhedonic aspects of nicotine withdrawal in mice found that the onset of the anhedonic aspects of the ICSS procedure was delayed in β4 and α7 nAChR −/− mice, suggesting that blockade of either nAChR subunit may alleviate anhedonic aspects of the early nicotine withdrawal syndrome (Bauzo and Bruijnzeel 2012; Stoker et al. 2012b). This is the first study to implicate α7 and β4 nAChRs in affective nicotine withdrawal behaviors. Overall, these studies reinforce the notion that different aspects of the nicotine withdrawalsyndrome are mediated by different nAChR subtypes in different brain regions.

3.1.1. Bupropion and its metabolites

Bupropion, a dopamine reuptake inhibitor (Cooper et al. 1994) and non-competitive nAChR antagonist (Fryer and Lukas 1999; Slemmer et al. 2000; Damaj et al. 2004), is an approved pharmacotherapy (Zyban®) for nicotine dependence in humans. In contrast to rats, humans and mice metabolize bupropion through the CYP2B6 enzyme to hydroxybupropion, a compound with longer half-life than the parent drug, and substantial activity on neuronal transporters and nAChRs (Cooper et al. 1984; Damaj et al. 2004). Recently, studies in mice showed that, similar to bupropion, enantiomers of hydroxybupropion, (2R,3R) and (2S,3S)-hydroxybupropion, reverse affective and somatic nicotine withdrawal signs, with (2S,3S)-hydroxybupropion having higher potency (Damaj et al. 2010) . Thus, actions of bupropion, its metabolites, or a combination of both, likely contribute to the pharmacotherapeutic effect of bupropion in smoking cessation. Interestingly, hydroxybupropion seems to contribute to the pharmacologic effects of bupropion for smoking cessation, and the variability in response to bupropion treatment is related to variability in CYP2B6-mediated hydroxybupropion formation in humans (Zhu et al. 2012).

3.2. Calcium-dependent mechanisms

Recent studies have begun to shed light on the importance of calcium-dependent mechanisms in nicotine dependence and withdrawal. In mice, L-type calcium channel blockers attenuated physical (somatic signs, hyperalgesia), but not affective (CPA, anxiety-like response) nicotine withdrawal signs, implicating L-type calcium channels in physical nicotine dependence (Jackson and Damaj 2009). More recently, other investigators showed that L-type calcium channels attenuated expression of CPA in rats, suggesting involvement of L-type calcium channels in this affective nicotine withdrawal measure (Budzynska et al. 2012) in a species-specific fashion.

Additionally, biochemical studies revealed that CaMKII total and phosphorylated protein levels, as well as total and phosphorylated protein levels of the vesicle associated protein essential for neurotransmitter release, synapsin I, were increased in the NAc after chronic nicotine treatment, but decreased after precipitated and spontaneous nicotine withdrawal (Jackson and Damaj 2013). Behaviorally, CaMKII antagonists attenuated somatic withdrawal signs, but enhanced affective nicotine withdrawal signs, suggesting opposing roles for CaMKII in affective vs. somatic nicotine withdrawal behaviors (Jackson and Damaj 2009). Similarly, studies with the less abundant kinase, CaMKIV, reveal that affective, but not physical measures are attenuated in CaMKIV −/− mice (Jackson et al. 2012).

It is possible that CaMKII heterozygote mice, which possess 50% of the enzyme activity, do not have sufficient loss of enzyme activity to induce expression of the altered nicotine withdrawal responses observed with the antagonist. Further, because CaMKII antagonists have been shown to block both CaMKII and CaMKIV activity (Hook and Means 2001), it is possible that the effects produced by the antagonist reflect blockade of both kinases. Although the exact role of calcium signaling mechanisms appears complicated, the current evidence supports the relevance of these mechanisms in behavioral and biochemical nicotine withdrawal responses.

3.3. Classical neurotransmitters: GABA, Glutamate, Dopamine, and Serotonin

Activation of nAChRs promotes the release of various neurotransmitters in the brain, including GABA, glutamate, and dopamine.

3.3.1. Role of the GABAergic system in nicotine withdrawal

Recently, GABA, the primary inhibitory neurotransmitter in the CNS, was found to mediate both affective and somatic nicotine withdrawal signs. Mecamylamine-precipitated somatic nicotine withdrawal signs were attenuated in GABAB −/− mice (Varani et al. 2012). Additionally, the reduction in c-Fos positive nuclei in the bed nucleus of the stria terminalis, basolateral amygdaloid nucleus, and the hippocampal dentate gyrus observed in GABAB +/+ mice after precipitated nicotine withdrawal, was absent in GABAB −/− mice, an effect that may be related to the attenuated somatic signs (Varani et al. 2012). In a similar study, the GABAB receptor agonist, baclofen, blocked somatic nicotine withdrawal signs in mice and restored nicotine withdrawal induced reductions in dopamine and dihydroxyphenyl acetic acid concentration in the prefrontal cortex, and dopamine and serotonin in the striatum (Varani et al. 2011). Conversely, treatment with a GABAB receptor agonist, antagonist or positive allosteric modulator exacerbated the anhedonic aspect of nicotine withdrawal by elevating the ICSS threshold after nicotine withdrawal in rats (Vlachou et al. 2011). These findings may reflect differential involvement of GABAB receptors in physical and affective nicotine withdrawal behaviors. Further, effects of the compounds used in the Vlachou et al. (2011) study are not selective for specific GABAB receptor isoforms (i.e., GABAS vs. GABAB2) and do not differentiate between pre- and postsynaptic GABAB receptors; thus, the observations in the latter study could be a manifestation of the effects from differential binding to GABAB receptors. Inconsistencies resulting from species differences are also a possibility. Zhao-Shea et al. (2013) showed that induction of physical nicotine withdrawal symptoms activates GABAergic neurons within the IPN.

3.3.2. Role of the glutamatergic system in nicotine withdrawal

The excitatory neurotransmitter glutamate plays an important role in modulating positive reinforcing responses to drugs of abuse (Harris and Aston-Jones 2003), and has been implicated in the negative reinforcing responses mediating nicotine withdrawal. Excessive activation of glutamatergic circuits from drug administration induces neuroadaptations aimed to prevent overactivation of the system, a phenomenon thought to underlie the negative affective state experienced when the drug is removed (Markou et al. 1998; Koob and Le Moal 2008). Indeed, the anhedonic component of nicotine withdrawal was reduced in nicotine dependent metabotropic glutamate receptor 5 (mGluR5) −/− mice and mecamylamine attenuated rather than precipitate somatic nicotine withdrawal signs in nicotine dependent mice (Stoker et al. 2012a). It was hypothesized that mGluR5 −/− mice do not develop neuroadaptations in the excitatory circuits, and thus develop a less severe negative state of nicotine withdrawal (Stoker et al. 2012a) .

3.3.3. Role of dopamine transmission in nicotine withdrawal

Similar to GABA and glutamate, dopamine, which plays a major role in rewarding responses to addictive drugs in the brain, also modulates affective and somatic nicotine withdrawal. Withdrawal from nicotine decreases basal dopamine levels in the rat NAc (Takahashi et al. 1998; Rahman et al. 2004) (Hildebrand et al. 1998; Rada et al. 2001) and monkey striatum (Domino and Tsukada 2009), and induces a hypofunctional dopamine state, which is reflected in decreased brain reward function (Epping-Jordan et al. 1998). 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. This decrease in dopamine transmission was accompanied by a decrease in β2 nAChRs, which was reversed by an acute nicotine treatment. The length of time that the low basal dopamine state lasted depended on the length of the chronic nicotine treatment. Coinciding with these findings, administration of the dopamine precursor, L-DOPA, attenuates somatic signs and reverses nicotine withdrawal depressive-like behaviors in the forced swim test, potentially by counteracting the decrease in DA levels associated with withdrawal (Ohmura et al. 2011a).

3.3.4. Role of the serotoninergic system in nicotine withdrawal

Serotonin (5-hydroxytryptamine; 5-HT) is associated with appetitive behavior and affective state, and previous studies support a role for 5-HT activation in aspects of the nicotine withdrawal syndrome, including CPA (Suzuki et al. 1997) and anxiety-like responses (West et al. 1991; Hilleman et al. 1992; Hilleman et al. 1994). More recently, 5-HT2C receptor agonists and a 5-HT2A antagonist were shown to block nicotine withdrawal-induced increases in immobility in rats subjected to the forced swim test, implicating the serotonergic system in the depressive-like effects of nicotine withdrawal (Zaniewska et al. 2010). 5-HT1A receptor expression was also significantly decreased in the mouse diencephalon for up to 30 days after nicotine withdrawal, and this reduction may be associated with nicotine withdrawal-induced depressive-like behaviors (Mannucci et al. 2011). Additionally, the serotonin precursor, 5-hydroxytryptophan, attenuated somatic signs of nicotine withdrawal in rats (Ohmura et al. 2011b) . Thus, as observed with GABA, glutamate, and dopamine, the serotonergic system mediates both affective and somatic nicotine withdrawal. Overall, these studies implicate the relevance of nicotine-induced activation of neurotransmitter systems in modulating multiple aspects of the nicotine withdrawal syndrome.

3.4. Role of peptidergic transmission

3.4.1. Galanin

The neuropeptide galanin is widely expressed in the CNS and is involved in modulation of food and alcohol intake, cognition, depression, and anxiety disorders (Holmes et al. 2003; Leibowitz 2005; Rustay et al. 2005). Studies implicate involvement of galanin and galanin receptors in mechanisms of nicotine withdrawal. Indeed, galanin receptors are expressed in brain areas implicated in drug dependence, including ventral midbrain (including the VTA), NAc, and locus coeruleus (LC) (Mennicken et al. 2002), and galanin modulates the mesolimbic dopamine system by inhibiting dopaminergic transmission (Tsuda et al. 1998; Ericson and Ahlenius 1999). The non-selective galanin receptor agonist, galnon, reverses mecamylamine-precipitated physical signs of nicotine withdrawal (Jackson et al. 2011). Further, expression of somatic nicotine withdrawal signs is correlated with galanin expression in the ventral midbrain and galanin receptor 1 expression in the NAc (Jackson et al. 2011). More recently, immunohistochemistry studies showed that galaninergic immunoreactivity is increased after nicotine withdrawal in the dorsal raphe nucleus subregions, and in the LC (Okere and Waterhouse 2013), further indicating the importance of galanin signaling in nicotine withdrawal.

3.4.2. Corticotropin Releasing Factor (CRF), src kinase, G protein-coupled receptor (GPCR) kinase 5

In recent years, a role for CRF, the principal neuropeptide involved in regulating stress response, in nicotine withdrawal has emerged. Antagonism of CRF prevented the nicotine withdrawal-induced elevations in reward threshold in rats using the ICSS procedure, supporting the hypothesis that hyperactivity of brain CRF contributes to the negative affective manifestations of nicotine withdrawal (Bruijnzeel et al. 2007). Specifically, these effects may be mediated by CRF1 receptors, as blockade of CRF1, but not CRF2 receptors, prevented nicotine withdrawal induced deficits in brain reward threshold in rats (Bruijnzeel et al. 2009). Additionally, blockade of CRF receptors in the NAc shell and central nucleus of the amygdala (CeA), but not the lateral bed nucleus of the stria terminalis, inhibited elevations in brain reward threshold in nicotine withdrawn rats, implicating that increased release of CRF in the NAc shell and CeA, specifically, partly mediates the negative emotional state associated with nicotine withdrawal (Marcinkiewcz et al. 2009). In support of this hypothesis, CRF levels were increased in the CeA in nicotine dependent rats following mecamylamine precipitated withdrawal (George et al. 2007). Similarly, CRF1 receptors in the CeA mediate the anhedonia associated with nicotine withdrawal, as intra-CeA administration of CRF1 receptor antagonists blocked elevations in reward threshold in rats (Bruijnzeel et al. 2012). In another assessment of nicotine withdrawal affective symptoms, increased CRF release and CRF1 receptor activity in the CeA were found to mediate anxiety-like behavior during precipitated withdrawal in nicotine dependent rats (George et al. 2007). Further, nicotine abstinence increased nicotine intake in rats in the self-administration test, an effect that was blocked by pretreatment with a CRF1 receptor antagonist (George et al. 2007). Overall, these studies indicate that increased CRF release and subsequent stimulation of CRF1 receptors in the NAc shell and CeA regulate, in part, the negative affective component of nicotine withdrawal.

Recently, a mechanistic link between the CRF system and activation of the cell signaling molecule, src kinase, was reported (Yuan et al. 2010). Administration of a selective src kinase inhibitor attenuated mecamylamine-precipitated nicotine withdrawal somatic signs and anxiety-like response in mice (Rehni et al. 2012), supporting a role for src kinase activation in physical and affective nicotine withdrawal behaviors. The potential link between src kinase and CRF activation, and their similar roles in nicotine withdrawal behaviors, suggests that src kinase activation may be linked to overactivation of the CRF system after nicotine withdrawal.

Furthermore, increased actvation of CRF receptors, which are GPCRs, leads to phosphorylation of the G protein Gαs subunit by GPCR kinases (GRKs). GRKs regulate CRF receptor signal transduction cascades (Teli et al. 2005; Hauger et al. 2009), thus promoting uncoupling of CRF from its receptor system, an effect that has been proposed to mediate the progression of aspects of the nicotine withdrawal syndrome (Dautzenberg et al. 2001; Teli et al. 2005; Hauger et al. 2009). Because of the role of CRF in nicotine withdrawal, and the ability of GRKs to mediate CRF signaling, a recent study examined the role of GRK 5 in nicotine withdrawal, as this particular kinase is highly expressed in brain regions shown to mediate the nicotine withdrawal syndrome, including the MHb and LC (Erdtmann-Vourliotis et al. 2001; Balfour 2004), and regulates GPCR-mediated regulation of nAChR signaling (Liu et al. 2000; Bibevski et al. 2000). As proposed, blockade of GRK 5 in mice attenuated physical nicotine withdrawal signs, measured as somatic signs and hyperalgesia response, and affective signs measured as anxiety-related response, implicating GRK 5 in both physical and affective nicotine withdrawal responses (Singh et al. 2013).

Taken together, these studies reveal a significant role and an interesting link between CRF, associated signaling molecules, and the physical and affective aspects of the nicotine withdrawal syndrome.

3.4.3. Orexin/hypocretin

Orexins, also known as hypocretins, are lateral hypothalamic neuropeptides that regulate feeding behavior, sleep, and wakefulness (Sakurai et al. 1998; Sakurai 2007). Recent evidence supports a role for hypocretin signaling in drug reward, addiction, and relapse (Aston-Jones et al. 2010; Plaza-Zabala et al. 2012b). While hypocretin signaling has been shown to regulate aspects of nicotine addiction, including nicotine reward and self-administration (Hollander et al. 2008; LeSage et al. 2010), acute nicotine anxiogenic-like response (Plaza-Zabala et al. 2010), and relapse to nicotine-seeking behavior (Plaza-Zabala et al. 2010; Plaza-Zabala et al. 2013), a recent study by Plaza-Zabala and colleagues (2012a) is among the first to examine the role of hypocretin signaling in somatic nicotine withdrawal. In preprohypocretin −/− mice, which do not produce hypocretin-1 or hypocretin-2 peptides, somatic nicotine withdrawal signs were significantly reduced following mecamylamine administration in nicotine-dependent mice. Similar results were observed in mice after treatment with a hypocretin-1 antagonist, but not a hypocretin-2 antagonist, indicating that the attenuation of withdrawal signs is specifically through a hypocretin-1 mechanism (Plaza-Zabala et al. 2012a). Additionally, mecamylamine led to the activation of neurons in the paraventricular nucleus of the hypothalamus (PVN), an effect that was absent in preprohypocretin −/− mice and blocked by hypocretin-1 antagonism, while intra-PVN injections of the hypocretin-1 antagonist decreased expression of somatic, mecamylamine-precipitated nicotine withdrawal signs in mice. Finally, increased hypocretin neuron activation in the perifornical area and dorsomedial hypothalamus (PFA/DMH), a brain region with a high proportion of hypocretin cells projecting to the PVN, was observed following precipitated nicotine withdrawal, and was blocked by hypocretin-1 receptor inhibition (Plaza-Zabala et al. 2012a). Overall, this study implicates a mechanism involving hypocretin and hypocretin-1 receptor activity in the PVN and PFA/DMH in the manifestation of somatic nicotine withdrawal signs. The role of this system in affective nicotine withdrawal behaviors has not been explored to date.

3.4.4. Neurokinins

Neurokinins (NK) are a group of peptides that includes substance P (SP), NKA, and NKB. Their effects are mediated by the GPCRs NK1, NK2, and NK3, respectively, and they act in the nervous system as neurotransmitters and neuromodulators (Pennefather et al. 2004). The peptides have been long known to participate in pain transduction, inflammation, smooth muscle contraction, vasodilation, gland secretion, and activation of the immune system (Kramer et al. 1998; Quartara and Maggi 1998; Severini et al. 2002), but more recently, they have been shown to influence affective and behavioral responses to stress and stress-related pathologies, including anxiety and depression (Ebner and Singewald 2006).

Substance P, NKB, and their respective receptors are expressed in the MHb, a brain area with major influence on the mechanisms underlying the somatic manifestations of nicotine abstinence (Lein et al. 2007; Salas et al. 2009). Using patch clamp electrophysiology in mouse brain slices, it was shown that nicotine increases intrinsic excitability in MHb neurons and that this phenomenon requires α5-containing nAChRs and depends on intact neurokinin signaling (Dao et al. 2014). In addition, microinjection of NK receptor antagonists into the MHb - but not the LHb-was sufficient to precipitate withdrawal behavior in chronic nicotine-treated mice. Therefore, this work implicates neurokinin peptides as one of the neuromodulatory signal systems through which nicotine acts to influence intrinsic excitability and produce neuroadaptations that lead to the emergence of nicotine withdrawal behavior.

3.4.5. Brain-derived neurotrophic factor (BDNF)

BDNF signaling in the adult brain is involved in regulation of neuronal survival and behavior-related plasticity, and its synthesis and release are initiated by activation of glutamate receptors (Lipsky and Marini 2007). Earlier studies show that BNDF expression is increased in the rat hippocampus in response to chronic nicotine (Kenny et al. 2000), and the gene has been implicated in tobacco smoking behaviors in human genetic association studies (Beuten et al. 2005; Lang et al. 2007; Li et al. 2008). In a recent study by (Kivinummi et al. 2011), alterations in BDNF levels were analyzed in the mouse NAc, VTA, and substantia nigra (SN) following chronic oral nicotine treatment and withdrawal. While chronic nicotine did not alter BDNF levels in any brain region, BDNF levels were significantly increased in all brain regions examined for up to 29 days following nicotine withdrawal (Kivinummi et al. 2011). These studies support a biochemical role for brain BDNF signaling after nicotine withdrawal, and indicate that nicotine’s effects on BNDF signaling may differ depending on the brain region. To date, the role of BDNF in nicotine withdrawal behaviors has not been examined, thus the behavioral relevance of these nicotine-induced alterations in neuronal BDNF level is unknown.

3.5. Opioid system

A growing number of studies suggest a role for the endogenous opioid system in mediating nicotine withdrawal in both humans and animals. The opioid receptor system consists of its endogenous peptides derived from three precursors; proopiomelanocortin (POMC), proenkephalin (PENK) and prodynorphin (PDYN) (Xue and Domino 2008). These precursors generate several peptides including β-endorphin, met- and leu-enkephalins, and dynorphins, which have varied affinities for the Gi/Go coupled opioid receptors. β–endorphin is the main peptide for mu-opioid receptors (MORs), enkephalins are the main peptide for delta-opioid receptors (DORs), and dynorphins are the main substrate for KORs (Roth-Deri et al. 2008). Early studies in humans and rodents suggest an alteration in the endogenous opiate system after smoking and nicotine withdrawal. Naloxone, a non-selective opioid antagonist, precipitated somatic and affective signs of withdrawal in a small group of smokers in a laboratory setting (Sutherland et al., 1995; Krishnan-Sarin et al., 1999), as well as in nicotine tolerant mice (Biala et al. 2005) and rats (Malin et al. 1993). In contrast, morphine was able to attenuate spontaneous and mecamylamine-induced nicotine withdrawal in rats (Malin et al. 1993; Ise et al. 2000). More recently, several studies using mice null for the various opiates receptors and their endogenous opiates investigated the role of individual opiate receptors in nicotine withdrawal. Nicotine physical dependence was reduced in both MOR and PENK (−/−) mice (Berrendero et al. 2002), suggesting an active involvement of MOR-dependent signaling in nicotine withdrawal. In contrast, the severity of nicotine physical withdrawal was not altered in β-endorphin and DOR (−/−) mice compared to the wild-type (+/+) counterparts (Galeote et al. 2009; Trigo et al. 2009; Berrendero et al. 2012). Interestingly, activation of DORs by the selective agonist TAN-67, was able to block nicotine withdrawal-induced CPA (Ise et al. 2000). Finally, several recent studies implicate a role for KORs in nicotine withdrawal. For example, dynorphin and PDYN peptide levels were shown to increase during nicotine withdrawal in various brain regions and at different time points (Mathieu et al. 1996; Mathieu-Kia and Besson 1998). Furthermore, recent reports show that JDTIC and norBNI, selective KOR antagonists, decreased the expression of both physical (somatic signs and hyperalgesia) and affective (anxiety-related behavior and CPA) nicotine withdrawal signs (Jackson et al. 2010).

3.6. Endocannabinoid system

Recent studies indicate that cannabinoids have a role in alleviating the somatic and affective signs of nicotine withdrawal. The endocannabinoid system (EC) consists of the endogenous cannabinoids N-arachidonoylethanolamine (anandamide; AEA)(Devane et al. 1992) and 2-arachidonylglycerol (2-AG) (Mechoulam et al. 1995; Sugiura et al. 1995), which are synthesized “on demand” and act as retrograde messengers which are tightly regulated by their degradative enzymes, fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL), respectively (Cravatt et al. 1996; Dinh et al. 2002). Both AEA and 2-AG primarily bind to Gprotein-coupled cannabinoid receptors (CB1 and CB2) (Matsuda et al. 1990; Munro et al. 1993). CB1 receptors are located in both the central and peripheral nervous systems whereas CB2 receptors are found in immune cells and microglia and brainstem neurons (Cabral and Marciano-Cabral 2005; Van Sickle et al. 2005). Recently, delta-9-tetrahydrocannabinol (THC), the primary active constituent of marijuana, was reported to decrease somatic signs and block CPA after withdrawal from chronic nicotine (Balerio et al. 2004). However, severity of physical nicotine withdrawal signs was not altered in CB1 −/− mice compared to wild-type animals or after pretreatment with rimonabant, a CB1 antagonist, in mice (Castane et al. 2002; Balerio et al. 2004; Merritt et al. 2008a). In addition, it was recently reported that genetic deletion of CB2 receptors does not alter the expression of anxiogenic-like withdrawal responses in the elevated plus maze, as CB2 −/− mice exhibited a similar magnitude of total somatic withdrawal signs to their control counterparts (Ignatowska-Jankowska et al. 2013). However,Navarrete et al. (2013) recently demonstrated a significant decrease in nicotine somatic withdrawal signs in CB2 −/− mice generated on CD-1 outbred genetic background. This discrepancy found in Navarrete et al. (2013) is likely due to differences in genetic background since previous results were obtained in CB2 −/− mice with a C57BL/6 genetic background (Ignatowska-Jankowska et al. 2013). Indeed, CB2 −/− generated on the same background did not display a different nicotine withdrawal phenotype compared to wild-type mice (Rafael Maldonado, personal communication). Such findings further emphasize the significant influence of genetics on nicotine withdrawal behaviors.

Recently, pharmacological and genetic approaches have been developed to prolong the availability of AEA and 2-AG by inhibiting their metabolic enzymes FAAH and MAGL, respectively. These inhibitors might have therapeutic utility without the undesirable side effects of direct CB1 agonists, such as THC (Cravatt et al. 1996; Solinas et al. 2007; Ahn et al. 2008; Long et al. 2009a; Long et al. 2009b). Two recent studies in rodents described the impact of FAAH inhibition on nicotine withdrawal. The first explored effects of URB597, a relatively selective FAAH inhibitor, on nicotine withdrawal in mice. While a high dose of URB597 (10mg/kg) significantly enhanced spontaneous nicotine somatic withdrawal signs, it failed to alter nicotine-induced CPA in nicotine-dependent mice (Merritt et al. 2008a). Furthermore, FAAH −/− mice exhibited significantly worse somatic nicotine withdrawal signs and nicotine withdrawal-induced CPA compared to FAAH +/+ mice (Merritt et al. 2008b). In the second, more recent study, the effect of URB597 on nicotine withdrawal was reported in rats implanted with transdermal nicotine patches. Rats rendered dependent on nicotine showed spontaneous nicotine somatic and anxiety-like induced withdrawal signs as measured at 16 and 36 hours, respectively (Cippitelli et al. 2011). URB597 at 0.1 and 0.3 mg/kg reduced withdrawal-induced anxiety as assessed by the elevated plus maze test and the shock-probe defensive burying paradigm, but did not prevent the occurrence of somatic signs. The discrepancy between these two studies could suggest possible species differences in the regulation of nicotine withdrawal mechanisms by FAAH inhibition between rats and mice (Muldoon et al. 2013). Furthermore, it is possible that increased AEA levels resulting from FAAH inhibition by URB597 modulated nicotine withdrawal-induced behaviors by acting on non-CB targets, such as TRPV1 and nAChRs. Indeed, AEA can directly inhibit the function of expressed (Oz et al. 2003; Spivak et al. 2007) and native (Butt et al. 2008) nAChRs in a CB1 receptor independent manner.

4. Recent advances in mechanisms of nicotine withdrawal: Human genetic and clinical studies

The 15q25 nAChR gene cluster contains the CHRNA5-CHRNA3-CHRNB4 genes, which encode for the α5, α3, and β4 nAChR subunits, respectively. While several studies identify associations with the gene cluster in multiple aspects of nicotine addiction (Thorgeirsson et al. 2008; Bierut et al. 2008; Baker et al. 2009; Chen et al. 2009; Caporaso et al. 2009) and smoking related disease (Thorgeirsson et al. 2008; Amos et al. 2008; Hung et al. 2008; Wang et al. 2009; Falvella et al. 2009), fewer studies have examined the influence of this gene cluster in smoking cessation, with contradictory findings. Sarginson et al. (2011) identified variants in the gene cluster associated with higher craving after quitting, increased withdrawal symptoms, and sustained abstinence from smoking after treatment. More recent studies support these findings, identifying variants and haplotypes in the 15q25 gene cluster associated with response to pharmacological smoking cessation therapies (Chen et al. 2012; King et al. 2012), as well as a weak association with short-term smoking cessation independent of treatment (Munafo et al. 2011). Conversely, studies also found no variants in the 15q25 gene cluster associated with smoking cessation or abstinence (De Ruyck et al. 2010; Bousman et al. 2012). Differences in these findings may be attributed to differences in how smoking cessation is defined between studies, sample size, differences in study population characteristics, and evaluation of different variants and regions of the 15q25 gene cluster. While studies support a role for 15q25 in smoking cessation, further studies are necessary to identify genetic mechanisms for tailored pharmacotherapies.

Studies have also examined variants in signaling and neurotransmitter genes that may influence smoking cessation. Reports indicate variation in the OPRM1 gene as a significant predictor of smoking abstinence and cessation in subjects receiving nicotine replacement therapy (Lerman et al. 2004; Ray et al. 2007; Munafo et al. 2007), though results conflicted regarding the specific alleles attributing to the effect (Lerman et al. 2004; Munafo et al. 2007). A more recent study, however, failed to replicate associations with OPRM1 and smoking cessation (Munafo et al. 2013), suggesting only a modest role for OPRM1. Variants in the DRD1 gene, coding for the dopamine receptor subtype 1, were associated with increased smoking abstinence in slow, but not rapid nicotine metabolizers (Lee et al. 2012), while variants in the DRD2 gene were not associated with smoking cessation (Breitling et al. 2011; Lee et al. 2012). Findings likely reflect differences in dopamine receptor subtype activity in response to nicotine. Recent findings also identified variants in the BDNF gene associated with smoking cessation (Breetvelt et al. 2012). Interestingly, changes in plasma BDNF levels were identified in abstinent smokers compared to nonsmokers, regardless of smoking cessation pharmacotherapy (Bhang et al. 2010). Though unclear, it is of future interest to determine whether these changes in BDNF plasma level after smoking cessation are correlated with BDNF variants. Animal studies of galanin have also prompted further study using human genetic association analyses. Variants in the galanin receptor gene are associated with severity of tobacco craving in smokers seeking smoking cessation treatment (Lori et al. 2011) and with reduced odds of quitting success and a faster rate of relapse in subjects taking bupropion, but not placebo or nicotine replacement therapy (Gold et al. 2012). With GALR1, as observed in other studies, associations with smoking cessation may differ by pharmacotherapy.

5. Conclusions

The neurophysiological mechanisms underlying nicotine dependence are complex, involving genetic predispositions and, among others, influences from age, gender, and the environment. Due to the broad expression of nAChRs in the brain, nicotine affects a large number of signaling pathways and circuits. Prolonged nicotine use produces a wide range of neuroplastic adaptations that render quitting very difficult. Through work with genetically modified mice and pharmacological agents, we have learned that particular nAChR subtypes appear to mediate specific symptoms of nicotine withdrawal, and that those symptoms reflect the engagement of a variety of neurotransmitter and receptor systems. Those systems represent potentially druggable targets that can be used together with established therapies for more effective pharmacological interventions. Obviously, effective treatments will need to address the mechanisms involved in dependence and relapse, but studies of approaches to treat physical, emotional, and cognitive withdrawal symptoms will be critical to the development of comprehensive therapies. As this research begins to yield new pharmacological options for smokers attempting to quit, clinicians will be able to offer treatments that have fewer side effects and are better tailored to the unique characteristics of patients.

Acknowledgements

Supported by grants # DA-12610 to MID and DA036572 and U19CA148127, Area 2, to MDB

Footnotes

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Disclosures: The authors have no conflicts of interest to disclose.

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