Functional Brain Imaging of Tobacco Exposure in Humans

ion Res ict ea d rc d h A & f o T Storage and Brody, J Addict Res Ther 2012, S2

l h

a Journal of Addiction DOI: 10.4172/2155-6105.S2-003 u p

o y

J ISSN: 2155-6105 Research & Therapy

Review Article Open Access Functional Brain Imaging of Tobacco Exposure in Humans Steven S Storage and Arthur L Brody* Department of Psychiatry & Biobehavioral Sciences, UCLA School of Medicine; Departments of Psychiatry and Research, VA Greater Los Angeles Healthcare System, California, USA

Abstract Cigarette smoking represents a major health problem in the United States. Although most cigarette smokers express a desire to quit, only about 14 to 49% will be successful after 6 or more months of treatment. An improved understanding of the acute and chronic effects of smoking on brain function may lead to more efficacious pharmacological and behavioral treatments for smoking dependence. Many research groups have utilized functional brain imaging to examine the effects of tobacco exposure on brain activity. Acute administration of nicotine and cigarette smoking itself have been found to increase activity in the prefrontal cortex, thalamus, and visual system; reduce global brain activity; and increase dopamine (DA) release in the ventral striatum/nucleus accumbens. Chronic tobacco exposure lead to an α β overall up-regulation of 4 2 nicotinic acetylcholine receptors (nAChRs) across brain regions (other than thalamus), and reduced monoamine oxidase (MAO) A and B levels in the basal ganglia. Functional brain imaging studies of cigarette craving and withdrawal, too, demonstrate important changes in brain activity. Taken together, current research suggests that smoking enhances neurotransmission through cortico-basal ganglia-thalamic circuits by either direct stimulation of nAChRs, indirect stimulation through DA release of MAO inhibition, or a combination of these, and perhaps, other factors. The purpose of this review is to provide a summary of current functional brain imaging studies of tobacco use and dependence, and use this information to develop a greater understanding of brain function in smokers.

Introduction uptake into the brain; brain activity responses following acute nicotine/cigarette administration; effects of pharmacologic smoking Cigarette smoking represents a major health issue in the United cessation treatment on brain activity; functional imaging of nicotinic States, and smoking cessation continues to be a difficult challenge. acetylcholine receptors; brain dopamine responses to nicotine and According to a recent survey, roughly 23% of Americans reported smoking; functional brain imaging of smoking-related cue-reactivity; smoking cigarettes [1], and while most smokers express a desire to quit functional brain imaging of cigarette withdrawal; relevance of [2], only a small minority will be successful without treatment. Even other receptors, neurotransmitter systems, and genetics to nicotine after 6 months or more of effective treatment, only approximately 14 to dependence; and future directions. 49% of smokers will achieve abstinence [3-8]. Due to the considerable health risks [9,10] and high societal costs [11,12] attributed to smoking, Nicotine Uptake into the Brain more efficacious smoking cessation treatments are urgently needed. In Numerous studies [16-18] have shown that the effects of many combination with other areas of research, functional brain imaging drugs, including nicotine, vary in relation to the rate of rise of the offers great potential for uncovering both molecular targets and brain drug’s concentration in the brain. Specifically, for drugs with addictive circuits that mediate the acute effects of smoking and the chronic potential, it is thought that faster rates of rise are associated with more effects of nicotine dependence. Knowledge of the effects of smoking on pronounced hedonic effects, thereby increasing the likelihood of brain function may lead to the creation of improved pharmacological eventual drug dependence [19,20]. Some recent studies [21,22] have and behavioral smoking cessation interventions. utilized positron emission tomography (PET) and [(11)C] nicotine to Four main imaging modalities have been utilized in functional help elucidate the cerebral kinetics of smoked nicotine. brain imaging studies of tobacco use and dependence: (1) functional In one recent study [21], PET scans of the brain were obtained in magnetic resonance imaging (fMRI), (2) positron emission 11 healthy smokers following single puffs of [(11)C] nicotine-infused tomography (PET), (3) single photon emission computed tomography cigarettes. Investigators found that a single puff was associated with a (SPECT), and (4) autoradiography. Researchers have used each of “rise time”, or the time in seconds for the [(11)C] nicotine concentration these modalities to determine the effects of acute and chronic cigarette curve to rise from 20% to 80% of its maximal value, of 11-69 seconds, smoking on brain function and smoking-related behaviors. For this and was less than 15 seconds for most patients. Noting that this rise review, the MEDLINE database was searched using keywords for each time is similar to that reported for smoked cocaine [23], the authors of the four modalities listed above cross-referenced with the words conclude that the cerebral kinetics of smoked nicotine contribute to “tobacco,” “nicotine,” and “cigarette.” Only data driven functional dependence in smokers. imaging studies were included in this review, and relevant studies from reference lists within papers found on MEDLINE were also included. In order to examine brain activity responses to acute and chronic smoking *Corresponding author: Arthur L. Brody, UCLA, Department of Psychiatry & in a cohesive fashion, this review will discuss studies of both nicotine Biobehavioral Sciences, 300 UCLA Medical Plaza, Suite 2200, Los Angeles, CA and cigarettes, while acknowledging that cigarette smoke contains 90095, USA, Tel: 310-268-4778; Fax: 310-206-2802; E-mail: [email protected] thousands of constituents other than nicotine [13,14]. Additionally, Received December 12, 2011; Accepted January 23, 2012; Published January because blood flow and metabolism are closely linked under normal 25, 2012 conditions [15], functional imaging techniques that measure each of Citation: Storage SS, Brody AL (2012) Functional Brain Imaging of Tobacco these are combined under the general heading of brain activity. Exposure in Humans. J Addict Res Ther S2:003. doi:10.4172/2155-6105.S2-003 The goal of this review is to provide a comprehensive summary Copyright: © 2012 Storage SS, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits of current findings from functional brain imaging studies of tobacco unrestricted use, distribution, and reproduction in any medium, provided the use and dependence. Topics covered in this review include: nicotine original author and source are credited.

J Addict Res Ther Tobacco Addiction ISSN:2155-6105 JART, an open access journal Citation: Storage SS, Brody AL (2012) Functional Brain Imaging of Tobacco Exposure in Humans. J Addict Res Ther S2:003. doi:10.4172/2155-6105. S2-003

Page 2 of 10

A similarly designed study performed by Rose and colleagues smoking, the most common findings are relative increases in activity provides additional information [22]. In this study, 13 dependent in the prefrontal cortex (including the dorsolateral prefrontal cortex, smokers and 10 non-dependent smokers were imaged using PET while and inferior frontal, medial frontal, and orbitofrontal gyri) [26,35,36], smoking [(11)C]nicotine-loaded cigarettes. The authors found that, thalamus [26,36-40], and visual system [26,37-39]. Additionally, a Xe because of slower nicotine washout from the lungs, dependent smokers 133 inhalation study reported increases in frontal lobe and thalamic had a slower rate of nicotine accumulation in the brain than observed blood flow in smokers who smoked a cigarette [41]. Of these studies, in non-dependent smokers. This study, therefore, adds to the preceding those involving humans examined cigarette smokers, while those study by indicating that rate of nicotine accumulation in the brain involving animals used non-dependent rats, with strong concordance alone is not enough to explain dependency on smoked nicotine. It is of findings between each set of studies. While this group of studies clear that the link between nicotine’s kinetics in the brain and smoking demonstrate specific regional activation with cigarette smoking or behavior will be an important topic for future studies to clarify further. nicotine administration, they also imply that activation of cortico- Brain Blood Flow and Metabolic Responses Following basal ganglia-thalamic brain circuits [42] mediates the subjective effects of smoking. Zubieta et al. [43] conducted a15 O-PET study using Acute Nicotine/Cigarette Administration nicotine and denicotinized cigarettes in 19 smokers who were abstinent A fair number of functional brain imaging studies have examined of smoking for 12 hours before PET. In this study, investigators acute effects of nicotine administration or cigarette smoking compared discovered increases in the regional cerebral blood flow (rCBF) in the with a placebo or control state (Table 1). Nicotine and cigarette smoking visual cortex and cerebellum, and reductions in rCBF in the anterior have been reported to alter the activity of a wide array of brain regions; cingulate, right hippocampus, and ventral striatum. Cigarette craving however, several global and regional discoveries have been replicated, in chronic smokers also correlated with rCBF in the right hippocampus, allowing for general conclusions about the acute effects of nicotine or a region involved in associating environmental cues with drugs, and in smoking on brain activity [24]. left dorsal anterior cingulate, an area implicated in drug craving and One common finding is that cigarette smoking [25] and nicotine relapse to drug-seeking behavior. administration [26,27] result in decreased global brain activity. Since regional activity was normalized to whole brain activity in Furthermore, smokers who smoke cigarettes ad lib prior to SPECT at least some of these studies, and whole brain activity has been found scanning (including the morning of scanning) have reduced global to decrease with nicotine or cigarette administration, the regional brain activity compared to both former smokers and non-smokers [28]. findings presented above may represent either increased regional These findings are generally supported by studies using transcranial activity or, possibly, less of a decrease in regional activity than in other Doppler ultrasound or the Xe 133 inhalation method to measure brain areas. Regional decreases in activity are generally not seen with responses to smoking, with some [29-32], but not all [33,34], studies nicotine or cigarette administration, though at least two studies found showing diminished cerebral blood flow. relatively decreased activity in the amygdala (left [35] and right [40]). In studies examining regional activity responses to nicotine or In summary, both reduced global activity as well as increased regional

Authors Subjects Method Intervention Results a) Animal Studies Marenco et al. [156] Rats- chronically nic ex- 2-deoxy-D-[1-14C] glu- SC nic (0.4 mg/kg) vs. saline ↑ thal, superior colliculus in chronically exposed; ↑ thal, posed vs. nic naive cose autoradiography superior colliculus, medial habenula and dorsal lateral geniculate in nic naive London et al. [38, 39] Rats 2-deoxy-D-[1-14C]glu- SC nic (0.1 to 1.75 mg/kg) ↑ nicotine rich regions, including thal, cereb, visual cose autoradiography system, others b) Human Studies Staley et al. [86] 16 smokers 5 IA-SPECT Recent abstinence ↑ Striatum, Parietal cortex, frontal cortex, anterior cin- 16 non-smokers gulated, temporal cortex, occipital cortex, cerebellum Zubieta et al. [43] 19 smokers 15O-PET Nicotine containing versus ↓global blood flow denicotinized cigarettes Stapleton et al. [27] 4 smokers; 2 non-smokers 2 FDG-PETs IV nic (1.5 mg) versus placebo ↓ global and most regions studied (Fully quantified) Yamamoto et al. [25] 10 smokers 99mTc-ECD SPECT Cigarette vs. abstinence ↓ global blood flow Rose et al. [35] 34 smokers 15O-PET Cigarette vs. no nic control ↑ L frontal factor (incl prefrontal and ACC), ↓ L amyg conditions rCBF Zubieta et al. [40] 18 smokers 15O-PET Nic nasal spray vs. pepper spray ↑ anterior thal; ↓ L ant temp and R amyg Domino et al. [26] 11 smokers FDG-PET Nic nasal spray vs. pepper spray Small ↓ global; ↑ L IFG, L PC, R thal, visual cortex; ↓ normalized L ins and R inf occ ctx Domino et al. [37] 18 smokers 15O-PET Nic nasal spray vs. pepper spray ↑ thal, pons, visual cortex, cereb Stein et al. [36] 16 smokers fMRI IV nic (0.75- 2.25 mg/70 kg wt) ↑ R NAc and bilateral amyg, cingulate, frontal lobes, vs. placebo thal, others Rourke et al. [28] 8 smokers; 8 former smok- iodine-123 iodoamphet- Smokers smoked the morning of ↓ cortical uptake of IMP (a measure of blood flow) in ers; 17 non-smokers amine (IMP) SPECT the scan; other groups did not current smokers compared to other groups All regional changes represent normalized activity, unless otherwise stated. SC = subcutaneous; nic = nicotine; thal = thalamus; cereb = cerebellum; SPECT = single photon emission computed tomography; fMRI = functional magnetic resonance imaging; IV = intravenous; R = right; L = left; NAc = nucleus accumbens; amyg = amygdala; FDG = 18F-fluorodeoxyglucose; PET = positron emission tomography; IFG = inferior frontal gyrus; PC = posterior cingulate; ins = insula; inf occ ctx = inferior occipital cortex; ant = anterior; temp = temporal lobe; ACC = anterior cingulate cortex

Table 1: Functional brain imaging studies of nicotine or cigarette administration.

Page 3 of 10

Author Subjects Method Abstinence Period Results 1 day (n=7), 1 week (n=17), 2 Compared to non-smokers, beta(2)*-nAChR availability in smoker Cosgrove et al. [88] 19 smokers; 20 non-smokers SPECT, 5-IA weeks (n=7), 4 weeks (n=11), and striatum, cortex, and cerebellum same after 1 day abstinence, ↑ 6-12 weeks (n=6) after 1 week abstinence, same at 4 and 6-12 weeks abstinence 7 male smokers; 7 male non- ↑ total brain distribution volume of 2-FA in smokers, most promi- Wüllner et al. [157] PET, 2-FA none smokers nently in cerebellum and brainstem Binding potential of nAChRs in smokers ↓ 33.5% +/- 10.5% after 10 male smokers; 6 males 4 hours (n=5), 10 days (n=5), and Mamede et al. [85] SPECT, 5-IA 4 hours abstinence, ↑ 25.7% +/- 9.2% after 10 days abstinence, non-smokers 21 days (n=5) and ↓ to nonsmoker level after 21 days abstinence Compared to non-smokers, recently abstinent smokers had ↑ Staley et al. [86] 16 smokers; 16 non-smokers SPECT, 5-IA 7 days 5-IA uptake in striatum, parietal cortex, frontal cortex, anterior cingulate, temporal cortex, occipital cortex and cerebellum SPECT = single-photon emission computed tomography; 5-IA = (S)-5-[(123)I]iodo-3-(2-azetidinylmethoxy)pyridine; nAChR = nicotinic acetylcholine receptor; PET = posi- tion emission tomography; 2-FA = 2-[(18)F]fluoro-3-(2(S)azetidinylmethoxy)pyridine

Table 2: Up-regulation of alpha4beta2* nicotinic acetylcholine receptors in chronic smokers and following acute, but not prolonged, abstinence.

Author Subjects Method/Task Intervention Results ↑ activation during “crave” condition in LACC, medial fMRI/smoking vs. neutral “allow yourself to crave” Hartwell et al. [121] 32 smokers prefrontal cortex, left middle cingulate gyrus, bilateral cues vs. “resist craving” posterior cingulate gyrus, and bilateral precuneus Smokers with higher FTND scores showed ↑ activa- 17 non-smoking problem gamblers; fMRI/gambling, smoking- Goudriaan et al. tion in VMPFC, rostral ACC, insula, and middle/supe- 18 non-gambling smokers; 17 non- related, and neutral none [123] rior temporal gyrus while watching smoking-related gambling non-smoking controls pictures pictures compared to patients with lower FTND scores Pre-quit vs. extended (52 Smoking cue induced ↑ activity during abstinence in fMRI/smoking-related vs. +/- 11 days) abstinence subcortical caudate nucleus and prefrontal, primary Janes et al. [125] 13 smokers neutral images aided by nicotine re- somatosensory, temporal, parietal, occipital, and placement therapy posterior cingulate cortices. Post-exercise ↓ activity in caudate nucleus, orbito- Janse Van Rensburg fMRI/smoking-related vs. frontal cortex, parietal lobe, parahippocampal, and 10 smokers Exercise vs. sitting et al. [126] neutral images fusiform gyrus and ↑ activity in “default” regions compared to controls ↑ reactivity to cues in right anterior cingulate and OFC McClernon et al. fMRI/smoking-related vs. in patients with higher FTND scores; ↑ reactivity in left 30 smokers none [124] neutral images hippocampus and left OFC in males; ↑ reactivity in cuneus and left superior temporal gyrus in females ↑ activation during “resist” condition in left dorsal fMRI/smoking-related vs. ACC, PCC, and precuneus; ↓ activation during “resist” Brody et al. [122] 42 smokers Crave vs. resist craving neutral images condition in cuneus bilaterally, right postcentral gyrus, left lateral occipital gyrus fMRI = functional magnetic resonance imaging; FTND = Fagerström Test for Nicotine Dependence; VMPFC = ventromedial prefrontal cortex; ACC = anterior cingulate cortex; OFC = orbitofrontal cortex; PCC = posterior cingulate cortex

Table 3: Functional brain imaging studies of smoking-related cue reactivity.

Author Subjects Method/Task Intervention Results 24-h abstinence vs. ad libitum Abstinence increased Stroop BOLD response in right middle frontal and rostral Froeliger et al. [127] 17 smokers fMRI/Stroop smoking anterior cingulate gyri ↑ activation in postcentral gyrus, insula, and frontal and parietal cortices in ab- fMRI/wheel of 24-h abstinence vs. ad libitum Addicott et al. [128] 13 smokers stinent condition during choice selection; ↑ activation in frontal pole, insula, and fortune smoking paracingulate cortex in abstinent condition during reward anticipation Abstinence plus nicotine patch vs. Withdrawal associated with ↓ activity in left and right temporal poles and left Sweet et al. [129] 12 smokers fMRI/2-Back abstinence plus placebo patch medial frontal gyrus fMRI = functional magnetic resonance imaging; BOLD = blood oxygenation level dependent

Table 4: Functional brain imaging studies of nicotine withdrawal. activity in the prefrontal cortex, thalamus, and visual system are among metabolism [46] and activity in brain regions mediating cue-induced some of the findings that have been replicated in functional brain craving [47,48]. imaging studies of nicotine and cigarette administration. A recent study [46] utilized (18)F-fluorodeoxyglucose-positron Effects of Pharmacologic Smoking Cessation Treatment emission tomography (FDG-PET) to examine the effects of 8 weeks on Brain Blood Flow and Metabolic Activity of treatment with bupropion HCl, practical group counseling (PGC), Both bupropion hydrochloride, an atypical antidepressant, and or pill placebo on brain function. In this study, 54 tobacco-dependent varenicline, a partial agonist at α4β2 nicotinic acetylcholine receptors, cigarette smokers underwent resting FDG-PET scanning both before have been shown to be efficacious additions to the pharmacologic and after an 8-week intervention. Costello and colleagues found that smoking cessation armamentarium [3,8,44,45]. Although a relatively smokers treated with either bupropion HCl or PGC (compared to new area of research, some studies have begun to investigate how placebo-treated smokers) showed a reduction in glucose metabolism these smoking cessation treatments alter both resting cerebral glucose in the posterior cingulate gyrus, with PGC having a greater effect than

Page 4 of 10 bupropion HCl. This study supports the idea that bupropion HCl hours post-challenge. Additionally, patients reported a significant functions as a smoking cessation aid in part by reducing activity in decrease in withdrawal symptoms following inhaler use. While these the default mode network of the brain, similar to what is seen when findings are similar to those in the PET study previously outlined performing a goal-oriented task. [77], the slightly different results may be accounted for by different radiotracers and imaging modalities used. Of note, smoking a low (0.6 Studies have also examined how treatments affect activity in brain mg nicotine) or de-nicotinized cigarette (0.05 mg nicotine) results in regions mediating cue-induced craving. Culbertson and colleagues 79% or 26% α β nAChR occupancy, respectively, demonstrating that [47] performed an 8-week randomized, double-blind, before-after 4 2 nicotine inhalation during smoking appears to be solely responsible for placebo-controlled trial on 30 nicotine-dependent smokers to assess receptor occupancy, with other factors having little or no effect [79]. alterations in regional brain activation in response to smoking-related Taken together, these studies demonstrate that smoking may alleviate cues from before to after treatment with bupropion HCl. Participants withdrawal by maintaining nAChRs in a nicotine-bound state and that receiving bupropion HCl showed reduced activation in the left ventral relatively small amounts of inhaled cigarette smoke lead to significant striatum, right medial orbitofrontal cortex, and bilateral anterior nAChR occupancy. cingulate cortex after treatment while actively resisting craving. A study using varenicline as the smoking cessation treatment yielded Exposure to secondhand smoke (SHS), too, can result in significant similar results. An arterial spin-labeled perfusion fMRI study scanned α4β2 nAChR occupancy in the brain [80]. In a recent study, tobacco- 22 non-abstinent, non-treatment-seeking smokers during rest and dependent cigarette smokers (n = 11) and non-smoking controls who during exposure to smoking cues before and after 3 weeks of treatment were exposed to SHS on at least a monthly basis (n = 13) underwent with either varenicline or placebo [48]. Varenicline administration two 2-FA PET scanning sessions. During these sessions, participants reduced smoking cue-elicited activity in the ventral striatum and sat in the passenger’s seat of a car for 1 hour and were exposed to either medial orbitofrontal cortex. These results are remarkably similar moderate SHS (produced by a smoker who smoked 4 to 6 cigarettes in to those observed in bupropion HCl studies, suggesting that similar the driver’s seat of the car) or no SHS. Exposure to SHS led to an average mechanisms mediate the effects of both medications to improve 19% occupancy of brain α4β2 nAChRs, and smokers experienced an patients’ ability to resist cue-induced craving. average 23% increase in craving following SHS exposure. These data may explain a contributing factor as to why children exposed to SHS Functional Imaging of Nicotinic Acetylcholine are more likely to become teenage cigarette smokers, and adult smokers Receptors (Nachrs) exposed to more sources of SHS are less likely to initiate or maintain Brain nicotinic acetylcholine receptors (nAChRs) are ligand- abstinence. gated ion channels consisting of α and β subunits [49,50]. Because Chronic cigarette smoking leads to up-regulation of nAChRs stimulation of nAChRs is closely associated with the effects of smoking, in brain (Table 2). Human postmortem tissue studies show that an important and evolving area of research is labeling these receptors chronic smokers have an increased number of nAChRs compared to using functional brain imaging. Of the many nAChR subtypes that non-smokers [81,82], while former smokers have nAChR densities have been discovered in the mammalian brain, the heteromeric α β 4 2 that are similar to non-smokers [81]. Furthermore, many laboratory receptor is the most common subtype and the homomeric α , the next 7 animal studies demonstrate up-regulation of nAChRs in response to most common [51]. Receptors containing the α subunit are reported 4 chronic nicotine administration [83,84]. In addition, recent studies to be central to the mediation of nicotine-induced reward, tolerance, [85,86] using single photon emission computed tomography (SPECT) and sensitization [52], while those containing the β subunit have been 2 or positron emission tomography (PET) demonstrate that the up- shown to be functionally significant in nicotine self-administration regulation of β -containing nAChRs found in smokers normalizes [53,54]. Animal studies have revealed that nicotinic acetylcholine 2 to levels of non-smokers in roughly three [85,87] to four weeks or receptors are located throughout the brain, with nAChR density greatest longer [88]. Calculations in one of these studies [87] demonstrate in the thalamus and descending in the following order: thalamus, basal that levels of β -containing nAChRs are within a few percent of non- ganglia, cerebral cortex, hippocampus, and cerebellum [55-65]. 2 smoker levels by four weeks of abstinence. In another of these studies 18 The radiotracers 2-[ F]F-A-85380, or simply 2-FA, and related [86], β2-containing nAChR levels did not correlate with the severity of compounds [66-68] are being used for PET imaging, while the Nicotine Dependence, severity of nicotine withdrawal, or the desire to radiotracer 5-[123/125I]iodo- A85380, or 5-I-A, is being used for SPECT smoke, indicating perhaps that the presence or absence of nicotine may α β imaging [69-71] of 4 2 nAChRs. Studies in both humans and non- primarily account for the up-regulation of nAChRs found in smokers. human primates have researched nAChR distribution with these radiotracers and have demonstrated regional densities similar to those Brain Dopamine Responses to Nicotine and Smoking found in the animal work referenced above [66,72-76]. The brain dopamine (DA) reward pathway serves as a common A recent 2-FA PET study [77] of human cigarette smokers found conduit for the positive reinforcement associated with addictive drugs that smoking only one to two puffs of a cigarette led to 50% occupancy [89,90]. Many laboratory animal studies have shown that DA release in the ventral striatum (VST)/nucleus accumbens (NAc) accounts for of brain α4β2 nAChRs with the occupancy lasting for at least 3.1 hours. Consistent with this finding, smoking a full cigarette led to the reinforcing properties of nicotine [89,90]. Using nicotine dosages 88% occupancy and was associated with reduced cigarette craving. A that generally simulated human cigarette smoking, both lesion [91] and recent 5-I-A SPECT study utilizing nicotine inhalers produced similar microdialysis [92-95] studies of rats indicate that nicotine-induced DA results [78]. In this study, 13 tobacco smokers were imaged after release is most pronounced in the VST/NAc. In fact, it is stronger in this undergoing either a nicotine inhaler (n = 9) or tobacco cigarette (n = area than the DA release observed in other related structures receiving 4) challenge. Participants receiving nicotine inhalers had an average dopaminergic input, including the dorsal striatum [95]. Chronic cigarette exposure has been found to up-regulate D and D receptor 55.9 ± 6.4% occupancy of β2 nAChRs, compared to 67.6 ± 14.1% 1 2 for those receiving a cigarette, and this occupancy lasted two to five mRNA in the VST [96], and acute cigarette and nicotine exposure has

Page 5 of 10 been observed to up-regulate DA transporter mRNA in the substantia craving.” During the crave condition, increased activation was nigra and ventral tegmental area (VTA) [97]. Furthermore, in vitro observed in the left anterior cingulate cortex (LACC), left middle studies have reported increased DA release in the VST following cingulate gyrus, medial prefrontal cortex, bilateral precuneus, and nicotine administration [98-102]. bilateral posterior cingulate gyrus. These areas are associated with decision-making, episodic memory, and attention. During the resist Functional brain imaging studies have provided an exciting condition, increased activation was observed in the LACC and areas of opportunity to substantiate and further develop these laboratory the prefrontal cortex. Investigators could only draw clear distinctions findings related to the DA system. Studies in both non-human between the crave and resist groups after factoring in the specific primates and humans have repeatedly demonstrated striatal DA strategies participants used to resist the urge to smoke, suggesting release following a cigarette or nicotine challenge [103-108], with that craving and resisting the urge to smoke are intimately linked. In most of these studies utilizing PET and 11C-raclopride (a radiotracer a similar fMRI study of forty-two tobacco-dependent smokers, Brody that specifically binds the D /D DA receptor) to illustrate DA release 2 3 et al. [122] exposed participants to one of three conditions: smoking through 11C-raclopride displacement. These, along with other studies cues while being allowed to crave, smoking cues while resisting craving, have described a wide range of DA concentration change. For example, and matched neutral cues. Subjects in the smoking cue resist condition two studies [106,107] found that nicotine produced less 11C-ralcopride demonstrated increased activation in the LACC, posterior cingulate displacement than amphetamine, while other studies have reported cortex, and precuneus when compared to those in the smoking cue crave that nicotine-induced DA release is of similar magnitude to that caused condition, providing further evidence that resisting the urge to smoke by other drugs of addictive potential [93]. Additionally, associations involves activation of limbic brain regions. Additionally, participants between 11C-raclopride displacement and the subjective hedonic in the smoking cue resist condition had decreased activation in the left effects of smoking have been demonstrated [109,110], though these lateral occipital gyrus, right postcentral gyrus, and cuneus bilaterally, studies did not find an overall difference between the smoking and suggesting that resisting the urge to smoke is also accompanied by a non-smoking conditions. A more recent study demonstrated that relative deactivation of primary sensory and motor cortices. tobacco-dependent smokers receiving regular cigarettes exhibited a significantly greater reduction in ventral striatal11 C-ralcopride binding Recent studies have also explored the idea that individual factors potential and greater improvement in mood when compared to those including differences in nicotine dependence, withdrawal symptoms, receiving a denicotinized cigarette [103]. Interestingly, this decrease and gender influence brain cue reactivity [123,124]. Specifically, studies in binding potential following nicotine administration does not seem demonstrate that patients with higher Fagerström Test of Nicotine to be seen in non-smokers, perhaps reflecting enhanced DA release in Dependence (FTND) scores show increased reactivity to smoking- smokers [111]. Disparities between these studies may be explained in related cues in the right anterior cingulate and orbitofrontal cortices part by different methodologies (e.g. cigarette smoking versus nicotine [124] as well as the ventromedial prefrontal cortex, insula, and middle/ administration) and technical complexities in performing such superior temporal gyrus [123]. Male smokers exposed to smoking- research. related cues show increased reactivity in the left hippocampus and left orbitofrontal cortex, while females show increased reactivity in the Other functional imaging studies of the DA system have reported cuneus and left superior temporal gyrus [124]. These studies suggest increased 18F-DOPA uptake (a marker for increased DA turnover) that individual factors play a role in cue reactivity, and that smoking [112], decreased D1 receptor density [113], both decreased 18F-DOPA cessation therapies attempting to reduce cue reactivity should consider uptake and D1 receptor density [114], and no alterations [115] in these variables. dopamine transporter binding in smokers. More recent studies have also demonstrated reduced availability of D2/D3 DA receptors in Smoking-related cue reactivity may change depending on smoking nicotine-dependent smokers as compared to non-smokers [116]. status. A 2009 fMRI study exposed 13 tobacco-dependent smokers to smoking-related versus neutral cues prior to a smoking cessation In summary, there is a great body of evidence that cigarette attempt, and again after 52 ± 11 days of abstinence aided by nicotine smoking and nicotine administration result in activation of the replacement therapy [125]. Smoking-related cues induced increased brain DA mesolimbic pathway, resulting in increased DA turnover activity during abstinence in the subcortical caudate nucleus and and release in the VST/NAc. Since dopaminergic input to the NAc prefrontal, primary somatosensory, temporal, parietal, occipital, and modulates neurotransmission through cortico-basal ganglia-thalamic posterior cingulate cortices. Therefore, fMRI smoking cue reactivity circuitry [117], increases in DA concentration following smoking may is increased in some brain regions during extended abstinence, explain some of the clinical effects of cigarette use. perhaps contributing to continued relapse vulnerability. Interestingly, Functional Brain Imaging of Smoking-Related Cue exercise has been shown to reduce cigarette craving and cue-related Reactivity activity in the caudate nucleus, orbitofrontal cortex, parietal lobe, parahippocampal gyrus, and fusiform gyrus, shifting activation towards Dependent cigarette smokers experience craving for cigarettes structures associated within the brain default mode network [126]. minutes after their last cigarette, and this craving intensifies over the next 3 to 6 hours of abstinence [118,119]. Compared to neutral cues, Functional Brain Imaging of Cigarette Withdrawal smoking-related cues reliably enhance craving during this period Three recent studies have examined abstinence-induced changes [120], and functional brain imaging of this craving reveals important in dependent smokers using fMRI (Table 4) [127-129]. In Froeliger information (Table 3). and colleagues’ 2011 fMRI study, 17 smokers underwent imaging Hartwell et al. [121] examined the neural correlates of craving while performing an affective Stroop task, once following 24-h and resisting craving in nicotine dependent smokers. In this study, abstinence and once following ad libitum smoking [127]. They found 32 nicotine-dependent smokers underwent fMRI scanning while that smoking abstinence increased Stroop blood-oxygenation-level- viewing smoking-related and neutral cues. While viewing these cues, dependent response in both the rostral anterior cingulate and right participants were instructed to “allow yourself to crave” or “resist middle frontal gyri. Additionally, withdrawal-induced negative affect

Page 6 of 10 correlated with decreased activation in frontoparietal regions during depressed mood experienced by heavy smokers during withdrawal the processing of negative emotional information, while, during [142]. negative emotional Stroop trials, negative affect predicted increased Other recent studies have begun to link genetic variability at the activation in frontal regions. The authors conclude that the increased chromosomal region encoding nicotinic acetylcholine receptors activity in the frontal executive network observed during abstinence (CHRNA4) with differential susceptibilities to nicotine dependence may signify a requirement to recruit additional executive functions to [133,134]. Remarkably, these studies demonstrate that subjects meet task demands. possessing rare CHRNA4 variants are less likely to respond to smoking Another 2011 fMRI study also examined effects of acute nicotine cues or recall smoking-related memories and may be protected abstinence on executive function [128]. In this study, 13 smokers were against nicotine dependence. Additional studies of this type are sure scanned following 24-h of abstinence and ad libitum smoking. During to add important insight into tobacco addiction and may reveal new scanning, participants performed a “wheel of fortune” decision- approaches to smoking cessation therapy. making task with probabilistic monetary outcomes. During choice selection, participants in the abstinent condition exhibited slower Relevance of Tobacco Smoke Constituents Other Than reaction times and increased activation in the insula, postcentral gyrus, Nicotine in Tobacco Smoke and frontoparietal cortices than those in the ad libitum condition. Throughout this review, nicotine and tobacco studies have been During reward anticipation, participants in the abstinent condition discussed together; however, it is important to consider that the showed increased neural activation in the insula, frontal pole, and effects of smoked tobacco may include those of the thousands of other paracingulate cortex compared to those in the ad libitum condition. constituents of tobacco smoke, as well as behavioral factors (such as the Taken together, these results demonstrate that smoking withdrawal feel, taste, and smell of a cigarette) [13,14]. For example, Bacher and may lead to increased recruitment of frontal, parietal, and insular colleagues have investigated the role of harman, a substance in cigarette cortical areas during tasks requiring executive function. smoke known to inhibit MAO-A [143-145]. In their PET study, 24 Sweet et al. [129] examined the effects of nicotine withdrawal on healthy non-smokers and 24 otherwise healthy smokers were scanned verbal working memory (VWM) and associated changes in brain following administration of harmine labeled with carbon-11. Healthy activity. Twelve smokers underwent a 2-Back VWM challenge during controls underwent scanning once, while smokers were imaged after two fMRI sessions. Participants did not smoke prior to each session but acute withdrawal and after active cigarette smoking. In participants did apply a nicotine patch before one session and a placebo patch before who were heavy smokers (defined as ≥25 cigarettes per day), MAO-A the other in a counterbalanced fashion. Withdrawal was associated density was increased in the prefrontal and anterior cingulate cortices with decreased activity in the left medial frontal gyrus and left and right during withdrawal when compared to both active smoking and healthy temporal poles, regions associated with the default network. These non-smoking controls. Interestingly, the difference in MAO-A density results point to reduced default activity during withdrawal, perhaps in the prefrontal and anterior cingulate cortices between withdrawal compensating for disrupted neural processing. and heavy active smoking states correlated with a reduction in plasma harman concentrations in these regions. This decrease in plasma Relevance of Other Receptors, Neurotransmitter harman level, and associated increase in MAO-A binding, may Systems, and Genetics to Nicotine Dependence contribute to withdrawal-induced depressed mood. Interestingly, some studies have implicated other receptors, While acknowledging studies such as these, this review included neurotransmitter systems, and genetics as playing important roles nicotine and tobacco studies for completeness, and because nicotine in nicotine’s effect on the brain. Specifically, mu-opioid receptor is the component of cigarette smoke most intimately linked to tobacco availability [130], inhibition of cerebral aromatase [131], inhibition of dependence [146]. Furthermore, nicotine inhalation during smoking cerebral monoamine oxidase [132], and variations in the chromosomal appears to be solely responsible for nAChR occupancy [79], which is region encoding nAChRs [133,134] may contribute to tobacco presumed to mediate feelings of reward [89], improved attentional addiction. performance [147], reduced anxiety and irritability [148], and Monoamine oxidases (MAOs) catalyze serotonin, dopamine, and improved reaction times [149] following cigarette smoking. Therefore, norepinephrine [135,136], and some have suggested that the increase while nicotine is the most well-studied constituent of tobacco smoke, in monoamine availability following MAO inhibition may contribute emerging brain imaging technologies will likely focus on the influence to some of the clinical effects of smoking [136]. Fowler and colleagues of both nicotine and other factors on the brain mediation of tobacco have demonstrated that, when compared to non-smokers and former dependence. smokers, current smokers have average reductions of 30 and 40% for MAO A and B [135]. These findings were subsequently replicated in Future Directions more recent PET studies [132]. Importantly, these reductions are the New radioligands targeting nAChRs are currently in development. result of chronic smoking behavior as opposed to smoking a single The radiotracers 2-FA, 6-FA, and 5-I-A, which have affinity to bind cigarette [137-139], and are not as pronounced as the reductions seen α β to the 4 2 nAChR subtype, are available, and other radiotracers are with antidepressant MAO inhibitors [140]. Peripheral MAO A and B in development for this receptor subtype [150,151]. There is a need, levels were also shown to be reduced in smokers when compared to however, for radioligands that have affinity for other subtypes of non-smokers [141]. Monoamine oxidase inhibition may enhance the nicotinic receptors, including the α7 subtype, which is the second most rewarding aspects of smoking by both increasing dopamine availability abundant in humans. Some groups have recently begun to develop and improving mood and anxiety [135,136]. A very recent study and characterize such radiotracers [152-154]. Future research will α β demonstrated increases in prefrontal and anterior cingulate cortex likely continue to focus on developing radiotracers for imaging 4 2 MAO A binding during tobacco withdrawal, leading the researcher nAChR in the thalamus with faster kinetics than 2-FA, 6-FA, and α β group to hypothesize that this phenomenon may contribute to the 5-I-A. Additionally, radiolabeled 4 2 nAChR antagonists may prove

Page 7 of 10 beneficial for developing a greater understanding of receptor binding intravenous and intranasal heroin self-administration by morphine-maintained and, ultimately, for creating pharmacological agents for smoking humans. Psychopharmacology (Berl) 143: 327-338. cessation [154,155]. Continued imaging studies with pharmacologic 21. Berridge MS, Apana SM, Nagano KK, Berridge CE, Leisure GP, et al. smoking cessation agents like varenicline may provide more (2010) Smoking produces rapid rise of [11C]nicotine in human brain. Psychopharmacology (Berl) 209: 383-394. α β information about the role of the 4 2 nicotinic acetylcholine receptor in nicotine dependence. 22. Rose JE, Mukhin AG, Lokitz SJ, Turkington TG, Herskovic J, et al. (2010) Kinetics of brain nicotine accumulation in dependent and nondependent References smokers assessed with PET and cigarettes containing 11C-nicotine. Proc Natl Acad Sci U S A 107: 5190-5195. 1. Balluz L, Ahluwalia IB, Murphy W, Mokdad A, Giles W, et al. (2004) Surveillance for certain health behaviors among selected local areas--United States, 23. Volkow ND, Ding YS, Fowler JS, Wang GJ, Logan J, et al. (1995) Is Behavioral Risk Factor Surveillance System, 2002. MMWR Surveill Summ. 53: methylphenidate like cocaine? Studies on their pharmacokinetics and 1-100. distribution in the human brain. Arch Gen Psychiatry 52: 456-463.

2. Fiore MC, Bailey WC, Cohen SJ, Dorfman SF, Goldstein MG, et al. (2000) 24. Sharma A, Brody AL (2009) In vivo brain imaging of human exposure to nicotine Treating Tobacco Use and Dependence. Clinical Practice Guideline. US and tobacco. Handb Exp Pharmacol: 145-171. Department of Health and Human Services. Public Health Service, Rockville, MD. 25. Yamamoto Y, Nishiyama Y, Monden T, Satoh K, Ohkawa M (2003) A study of the acute effect of smoking on cerebral blood flow using 99mTc-ECD SPET. 3. Holmes S, Zwar N, Jimenez-Ruiz CA, Ryan PJ, Browning D, et al. (2004) Eur J Nucl Med Mol Imaging 30: 612-614. Bupropion as an aid to smoking cessation: a review of real-life effectiveness. Int J Clin Pract 58: 285-291. 26. Domino EF, Minoshima S, Guthrie SK, Ohl L, Ni L, et al. (2000) Effects of nicotine on regional cerebral glucose metabolism in awake resting tobacco 4. Killen JD, Fortmann SP, Davis L, Strausberg L, Varady A (1999) Do smokers. Neuroscience 101: 277-282. heavy smokers benefit from higher dose nicotine patch therapy? Exp Clin Psychopharm 7: 226-233. 27. Stapleton JM, Gilson SF, Wong DF, Villemagne VL, Dannals RF, et al. (2003) Intravenous nicotine reduces cerebral glucose metabolism: A preliminary 5. Killen JD, Fortmann SP, Schatzberg AF, Hayward C, Sussman L, et al. (2000) study. Neuropsychopharmacology 28: 765-772. Nicotine patch and paroxetine for smoking cessation. J Consult Clin Psych 68: 883-889. 28. Rourke SB, Dupont RM, Grant I, Lehr PP, Lamoureux G, et al. (1997) Reduction in cortical IMP-SPET tracer uptake with recent cigarette consumption in a young 6. Hughes JR, Lesmes GR, Hatsukami DK, Richmond RL, Lichtenstein E, et al. group of healthy males. San Diego HIV Neurobehavioral Research Center. Eur (1999) Are higher doses of nicotine replacement more effective for smoking J Nucl Med 24: 422-427. cessation? Nic Tobacco Res 1: 169-174. 29. Cruickshank JM, Neildwyer G, Dorrance DE, Hayes Y, Patel S (1989) Acute 7. Jorenby DE, Leischow SJ, Nides MA, Rennard SI, Johnston JA, et al. (1999) Effects of Smoking on Blood-Pressure and Cerebral Blood-Flow. J Hum A controlled trial of sustained-release bupropion, a nicotine patch, or both for Hypertens 3: 443-449. smoking cessation. N Engl J Med 340: 685-691. 30. Kubota K, Yamaguchi T, Abe Y, Fujiwara T, Hatazawa J, et al. (1983) Effects of 8. Hurt RD, Sachs DP, Glover ED, Offord KP, Johnston JA, et al. (1997) A Smoking on Regional Cerebral Blood-Flow in Neurologically Normal Subjects. comparison of sustained-release bupropion and placebo for smoking cessation. Stroke 14: 720-724. N Engl J Med 337: 1195-1202. 31. Kubota K, Yamaguchi T, Fujiwara T, Matsuzawa T (1987) Effects of Smoking 9. Mokdad AH, Marks JS, Stroup DF, Gerberding JL (2004) Actual causes of on Regional Cerebral Blood-Flow in Cerebral Vascular-Disease Patients and death in the United States, 2000. JAMA 291: 1238-1245. Normal Subjects. Tohoku J Exp Med 151: 261-268.

10. Bartal M (2001) Health effects of tobacco use and exposure. Monaldi Arch 32. Rogers RL, Meyer JS, Shaw TG, Mortel KF, Hardenberg JP, et al. (1983) Chest Dis 56: 545-554. Cigarette-Smoking Decreases Cerebral Blood-Flow Suggesting Increased Risk for Stroke. JAMA 250: 2796-2800. 11. Leistikow BN, Martin DC, Milano CE (2000) Estimates of smoking-attributable deaths at ages 15-54, motherless or fatherless youths, and resulting Social 33. Kodaira K, Fujishiro K, Wada T, Maie K, Satoi T, et al. (1993) A study on Security costs in the United States in 1994. Prev Med 30: 353-360. cerebral nicotine receptor distribution, blood flow, oxygen consumption, and other metabolic activities--a study on the effects of smoking on carotid and 12. Leistikow BN, Martin DC, Milano CE (2000) Fire injuries, disasters, and costs cerebral artery blood flow. Yakubutsu Seishin Kodo 13: 157-165. from cigarettes and cigarette lights: a global overview. Prev Med 31: 91-99. 34. Terborg C, Birkner T, Schack B, Witte OW (2002) Acute effects of cigarette 13. Baker RR, Massey ED, Smith G (2004) An overview of the effects of tobacco smoking on cerebral oxygenation and hemodynamics: a combined study with ingredients on smoke chemistry and toxicity. Food Chem Toxicol S53-S83. near-infrared spectroscopy and transcranial Doppler sonography. J Neurol Sci 205: 71-75. 14. Fowles J, Dybing E (2003) Application of toxicological risk assessment principles to the chemical constituents of cigarette smoke. Tob Control 12: 424- 35. Rose JE, Behm FM, Westman EC, Mathew RJ, London ED, et al. (2003) PET 430. studies of the influences of nicotine on neural systems in cigarette smokers. Am J Psychiatry 160: 323-333. 15. Paulson OB (2002) Blood-brain barrier, brain metabolism and cerebral blood flow. Eur Neuropsychopharmacol 12: 495-501. 36. Stein E, Pankiewicz J, Harsch HH, Cho JK, Fuller SA, et al. (1998) Nicotine- induced limbic cortical activation in the human brain: A functional MRI study. 16. Ferrario CR, Shou M, Samaha AN, Watson CJ, Kennedy RT, et al. (2008) Am J Psychiatry 155: 1009-1015. The rate of intravenous cocaine administration alters c-fos mRNA expression and the temporal dynamics of dopamine, but not glutamate, overflow in the 37. Domino EF, Minoshima S, Guthrie S, Ohl L, Ni L, et al. (2000) Nicotine effects striatum. Brain Res 1209: 151-156. on regional cerebral blood flow in awake, resting tobacco smokers. Synapse 38: 313-321. 17. Nelson RA, Boyd SJ, Ziegelstein RC, Herning R, Cadet JL, et al. (2006) Effect of rate of administration on subjective and physiological effects of intravenous 38. London ED, Connolly RJ, Szikszay M, Wamsley JK, Dam M (1988) Effects of cocaine in humans. Drug Alcohol Depend 82: 19-24. nicotine on local cerebral glucose utilization in the rat. J Neurosci 8: 3920-3928.

18. Samaha AN, Yau WY, Yang P, Robinson TE (2005) Rapid delivery of nicotine 39. London ED, Dam M, Fanelli RJ (1988) Nicotine enhances cerebral glucose promotes behavioral sensitization and alters its neurobiological impact. Biol utilization in central components of the rat visual system. Brain Res Bull 20: Psychiatry 57: 351-360. 381-385.

19. Abreu ME, Bigelow GE, Fleisher L, Walsh SL (2001) Effect of intravenous 40. Zubieta J, Lombardi U, Minoshima S, Guthrie S, Ni L, et al. (2001) Regional injection speed on responses to cocaine and hydromorphone in humans. cerebral blood flow effects of nicotine in overnight abstinent smokers. Biol Psychopharmacology (Berl) 154: 76-84. Psychiatry 49: 906-913.

20. Comer SD, Collins ED, MacArthur RB, Fischman MW (1999) Comparison of 41. Nakamura H, Tanaka A, Nomoto Y, Ueno Y, Nakayama Y (2000) Activation of

Page 8 of 10

fronto-limbic system in the human brain by cigarette smoking: evaluated by a 64. London ED, Connolly RJ, Szikszay M, Wamsley JK (1985) Distribution of CBF measurement. Keio J Med 1: A122-A124. cerebral metabolic effects of nicotine in the rat. Eur J Pharmacol 110: 391-392.

42. Alexander GE, Crutcher MD, DeLong MR (1990) Basal ganglia-thalamocortical 65. Clarke PB, Pert C, Pert A (1984) Autoradiographic distribution of nicotine circuits: parallel substrates for motor, oculomotor, “prefrontal” and “limbic” receptors in rat brain. Brain Res 323: 390-395. functions. Prog Brain Res 85: 119-146. 66. Chefer SI, Horti AG, Koren AO, Gundrisch D, Links JM, et al. (1999) 2-[18F] 43. Zubieta JK, Heitzeg MM, Xu Y, Koeppe RA, Ni L, et al. (2005) Regional F-A-83580: a PET radioligand for alpha4beta2 nicotinic acetylcholine receptors. cerebral blood flow responses to smoking in tobacco smokers after overnight Neuroreport 10: 2715-2721. abstinence. Am J Psychiatry 162: 567-577. 67. Horti AG, Scheffel U, Koren AO, Ravert HT, Mathews WB, et al. (1998) 2-[F-18] 44. Grassi MC, Enea D, Ferketich AK, Lu B, Pasquariello S, et al. (2011) fluoro-A-85380, an in vivo tracer for the nicotinic acetylcholine receptors. Nucl Effectiveness of varenicline for smoking cessation: a 1-year follow-up study. J Med Biol 25: 599-603. Subst Abuse Treat 41: 64-70. 68. Koren AO, Horti AG, Mukhin AG, Gundisch D, Kimes AS, et al. (1998) 2-, 5-, 45. Cahill K, Stead LF, Lancaster T (2011) Nicotine receptor partial agonists for and 6-halo-3-(2(S)-azetidinylmethoxy)pyridines: Synthesis, affinity for nicotinic smoking cessation. Cochrane Database Syst Rev. acetylcholine receptors, and molecular modeling. J Med Chem 41: 3690-3698.

46. Costello MR, Mandelkern MA, Shoptaw S, Shulenberger S, Abrams A, et al. 69. Mukhin AG, Gundisch D, Horti AG, Koren AO, Tamagnan G, et al. (2000) (2010) Effects of Tobacco Dependence Treatments on Resting Brain Glucose 5-iodo-A-85380, an alpha 4 beta 2 subtype-selective ligand for nicotinic Metabolism. Neuropsychopharmacology 35: 605-612. acetylcholine receptors. Mol Pharmacol 57: 642-649.

47. Culbertson CS, Bramen J, Cohen MS, London ED, Olmstead RE, et al. (2011) 70. Horti AG, Koren AO, Lee KS, Mukhin AG, Vaupel DB, et al. (1999) Effect of bupropion treatment on brain activation induced by cigarette-related Radiosynthesis and preliminary evaluation of 5-[123/125I]iodo-3-(2(S)- cues in smokers. Arch Gen Psychiatry 68: 505-515. azetidinylmethoxy)pyridine: a radioligand for nicotinic acetylcholine receptors. Nucl Med Biol 26: 175-182. 48. Franklin T, Wang Z, Suh JJ, Hazan R, Cruz J, et al. (2011) Effects of varenicline on smoking cue-triggered neural and craving responses. Arch Gen Psychiatry 71. Chefer SI, Horti AG, Lee KS, Koren AO, Jones DW, et al. (1998) In vivo imaging 68: 516-526. of brain nicotinic acetylcholine receptors with 5-[123I]iodo-A-85380 using single photon emission computed tomography. Life Sci 63: PL355-360. 49. Hogg RC, Raggenbass M, Bertrand D (2003) Nicotinic acetylcholine receptors: from structure to brain function. Rev Physiol Biochem Pharmacol 147: 1-46. 72. Chefer SI, London ED, Koren AO, Pavlova OA, Kurian V, et al. (2003) Graphical analysis of 2-[F-18]FA binding to nicotinic acetylcholine receptors in rhesus 50. Court JA, Martin-Ruiz C, Graham A, Perry E (2000) Nicotinic receptors in monkey brain. Synapse 48: 25-34. human brain: topography and pathology. J Chem Neuroanat 20: 281-298. 73. Fujita M, Ichise M, van Dyck CH, Zoghbi SS, Tamagnan G, et al. (2003) 51. Wu J, Liu Q, Yu K, Hu J, Kuo YP, et al. (2006) Roles of nicotinic acetylcholine Quantification of nicotinic acetylcholine receptors in human brain using [I-123]5- receptor beta subunits in function of human alpha4-containing nicotinic I-A-85380 SPET. Eur J Nucl Med Mol Imaging 30: 1620-1629. receptors. J Physiol 576: 103-118. 74. Kimes AS, Horti AG, London ED, Chefer SI, Contoreggi C, et al. (2003) 2-[18F] 52. Perry DC, Xiao Y, Nguyen HN, Musachio JL, vila-Garcia MI, et al. (2002) F-A-85380: PET imaging of brain nicotinic acetylcholine receptors and whole Measuring nicotinic receptors with characteristics of alpha4beta2, alpha3beta2 body distribution in humans. FASEB J 17: 1331-1333. and alpha3beta4 subtypes in rat tissues by autoradiography. J Neurochem 82: 468-481. 75. Fujita M, Seibyl JP, Vaupel DB, Tamagnan G, Early M, et al. (2002) Whole- body biodistribution, radiation absorbed dose, and brain SPET imaging with 53. Epping-Jordan MP, Picciotto MR, Changeux JP, Pich EM (1999) Assessment [123i]5-i-A-85380 in healthy human subjects. Eur J Nucl Med Mol Imaging 29: of nicotinic acetylcholine receptor subunit contributions to nicotine self- 183-190. administration in mutant mice. Psychopharmacology (Berl) 147: 25-26. 76. Valette H, Bottlaender M, Dolle F, Guenther I, Fuseau C, et al. (1999) Imaging 54. Picciotto MR, Zoli M, Rimondini R, Lena C, Marubio LM, et al. (1998) central nicotinic acetylcholine receptors in baboons with [F-18]fluoro-A-85380. Acetylcholine receptors containing the beta2 subunit are involved in the J Nucl Med 40: 1374-1380. reinforcing properties of nicotine. Nature 391: 173-177. 77. Brody AL, Mandelkern MA, London ED, Olmstead RE, Farahi J, et al. (2006) 55. Davila-Garcia MI, Houghtling RA, Qasba SS, Kellar KJ (1999) Nicotinic receptor Cigarette smoking saturates brain alpha4beta2 nicotinic acetylcholine binding sites in rat primary neuronal cells in culture: characterization and their receptors. Arch Gen Psychiatry 63: 907-915. regulation by chronic nicotine. Brain Res Mol Brain Res 66: 14-23. 78. Esterlis I, Mitsis EM, Batis JC, Bois F, Picciotto MR, et al. (2011) Brain beta2*- 56. Villemagne V, Horti A, Scheffel U, Ravert H, Finley P, et al. (1997) Imaging nicotinic acetylcholine receptor occupancy after use of a nicotine inhaler. Int J nicotinic acetylcholine receptors with fluorine-18-FPH, an epibatidine analog. J Neuropsychopharmacol 14: 389-398. Nucl Med 38: 1737-1741. 79. Brody AL, Mandelkern MA, Costello MR, Abrams AL, Scheibal D, et al. 57. Davila-Garcia MI, Musachio J, Perry D, Xiao Y, Horti A, et al. (1997) [125I]IPH, (2009) Brain nicotinic acetylcholine receptor occupancy: effect of smoking a an epibatidine analog, binds with high affinity to neuronal nicotinic cholinergic denicotinized cigarette. Int J Neuropsychopharmacol 12: 305-316. receptors. J Pharmacol Exp Ther 282: 445-451. 80. Brody AL, Mandelkern MA, London ED, Khan A, Kozman D, et al. (2011) Effect 58. London ED, Scheffel U, Kimes AS, Kellar KJ (1995) In vivo labeling of nicotinic of secondhand smoke on occupancy of nicotinic acetylcholine receptors in acetylcholine receptors in brain with [3H]epibatidine. Eur J Pharmacol 278: R1- brain. Arch Gen Psychiatry 68: 953-960. 2. 81. Breese CR, Marks MJ, Logel J, Adams CE, Sullivan B, et al. (1997) Effect 59. Perry DC, Kellar KJ (1995) [3H]Epibatidine labels nicotinic receptors in rat of smoking history on [3H]nicotine binding in human postmortem brain. J brain: An autoradiographic study. J Pharmacol Exp Ther 285: 1030-1034. Pharmacol Exp Ther 282: 7-13.

60. Cimino M, Marini P, Fornasari D, Cattabeni F, Clementi F (1992) Distribution 82. Benwell ME, Balfour DJK, Anderson JM (1988) Evidence that tobacco smoking of nicotinic receptors in cynomolgus monkey brain and ganglia: localization increases the density of (-)-[3H]nicotine binding sites in human brain. J of alpha 3 subunit mRNA, alpha-bungarotoxin and nicotine binding sites. Neurochem 50: 1243-1247. Neuroscience 51: 77-86. 83. Zhang X, Tian JY, Svensson AL, Gong ZH, Meyerson B, et al. (2002) Chronic 61. Pabreza LA, Dhawan S, Kellar KJ (1991) [3H]Cytisine binding to nicotinic treatments with tacrine and (-)-nicotine induce different changes of nicotinic cholinergic receptors in brain. Mol Pharmacol 39: 9-12. and muscarinic acetylcholine receptors in the brain of aged rat. J Neural Transm 109: 377-392. 62. Broussolle EP, Wong D, Fanelli RJ, London ED (1989) In vivo specific binding of [3H]-nicotine in the mouse brain. Life Sci 44: 1123-1132. 84. Yates SL, Bencherif M, Fluhler EN, Lippiello PM (1995) Up-regulation of nicotinic acetylcholine receptors following chronic exposure of rats to 63. Pauly JR, Stitzel JA, Marks MJ, Collins AC (1989) An autoradiographic analysis mainstream cigarette smoke or alpha 4 beta 2 receptors to nicotine. Biochem of cholinergic receptors in mouse brain. Brain Res Bull 22: 453-459. Pharmacol 50: 2001-2008.

Page 9 of 10

85. Mamede M, Ishizu K, Ueda M, Mukai T, Iida Y, et al. (2007) Temporal change Comparative effects of methamphetamine and nicotine on the striatal [C-11] in human nicotinic acetylcholine receptor after smoking cessation: 5IA SPECT raclopride binding in unanesthetized monkeys. Synapse 45: 207-212. study. J Nucl Med 48: 1829-1835. 108. Dewey SL, Brodie JD, Gerasimov M, Horan B, Gardner EL, et al. (1999) A 86. Staley JK, Krishnan-Sarin S, Cosgrove KP, Krantzler E, Frohlich E, et al. (2006) pharmacologic strategy for the treatment of nicotine addiction. Synapse 31: Human tobacco smokers in early abstinence have higher levels of beta2* 76-86. nicotinic acetylcholine receptors than nonsmokers. J Neurosci 26: 8707-8714. 109. Montgomery AJ, Lingford-Hughes AR, Egerton A, Nutt DJ, Grasby PM (2007) 87. Mukhin AG, Kimes AS, Chefer SI, Matochik JA, Contoreggi CS, et al. (2008) The effect of nicotine on striatal dopamine release in man: A [11C]raclopride Greater nicotinic acetylcholine receptor density in smokers than in nonsmokers: PET study. Synapse 61: 637-645. a PET study with 2-18F-FA-85380. J Nucl Med 49: 1628-1635. 110. Barrett SP, Boileau I, Okker J, Pihl RO, Dagher A (2004) The hedonic 88. Cosgrove KP, Batis J, Bois F, Maciejewski PK, Esterlis I, et al. (2009) beta2- response to cigarette smoking is proportional to dopamine release in the Nicotinic acetylcholine receptor availability during acute and prolonged human striatum as measured by positron emission tomography and [(11)C] abstinence from tobacco smoking. Arch Gen Psychiatry 66: 666-676. raclopride. Synapse 54: 65-71.

89. Leshner AI, Koob GF (1999) Drugs of abuse and the brain. Proc Assoc Am 111. Takahashi H, Fujimura Y, Hayashi M, Takano H, Kato M, et al. (2008) Phys 111: 99-108. Enhanced dopamine release by nicotine in cigarette smokers: a double-blind, randomized, placebo-controlled pilot study. Int J Neuropsychopharmacol 11: 90. Koob GF (1992) Drugs of abuse: anatomy, pharmacology and function of 413-417. reward pathways. Trends Pharmacol Sci 13: 177-184. 112. Salokangas RK, Vilkman H, Ilonen T, Taiminen T, Bergman J, et al. (2000) 91. Corrigall WA, Franklin KB, Coen KM, Clarke PB (1992) The mesolimbic High levels of dopamine activity in the basal ganglia of cigarette smokers. Am dopaminergic system is implicated in the reinforcing effects of nicotine. J Psychiatry 157: 632-634. Psychopharmacology (Berl) 107: 285-289. 113. Dagher A, Bleicher C, Aston JAD, Gunn RN, Clarke PBS, et al. (2001) 92. Sziraki I, Lipovac MN, Hashim A, Sershen H, Allen D, et al. (2001) Differences Reduced dopamine D1 receptor binding in the ventral striatum of cigarette in nicotine-induced dopamine release and nicotine pharmacokinetics between smokers. Synapse 42: 48-53. Lewis and Fischer 344 rats. Neurochem Res 26: 609-617. 114. Krause KH, Dresel SH, Krause J, Kung HF, Tatsch K, et al. (2002) Stimulant- 93. Pontieri FE, Tanda G, Orzi F, Di Chiara G (1996) Effects of nicotine on the like action of nicotine on striatal dopamine transporter in the brain of adults nucleus accumbens and similarity to those of addictive drugs. Nature 382: 255- with attention deficit hyperactivity disorder. Int J Neuropsychopharmacol 5: 257. 111-113. 94. Damsma G, Day J, Fibiger HC (1989) Lack of tolerance to nicotine-induced 115. Staley JK, Krishnan-Sarin S, Zoghbi S, Tamagnan G, Fujita M, et al. (2001) Sex dopamine release in the nucleus accumbens. Eur J Pharmacol 168: 363-368. differences in [123I]beta-CIT SPECT measures of dopamine and serotonin transporter availability in healthy smokers and nonsmokers. Synapse 41: 275- 95. Di Chiara G, Imperato A (1988) Drugs abused by humans preferentially 284. increase synaptic dopamine concentrations in the mesolimbic system of freely moving rats. Proc Natl Acad Sci U S A 85: 5274-5278. 116. Fehr C, Yakushev I, Hohmann N, Buchholz HG, Landvogt C, et al. (2008) Association of low striatal dopamine d2 receptor availability with nicotine 96. Bahk JY, Li S, Park MS, Kim MO (2002) Dopamine D1 and D2 receptor mRNA dependence similar to that seen with other drugs of abuse. Am J Psychiatry up-regulation in the caudate-putamen and nucleus accumbens of rat brains by 165: 507-514. smoking. Prog Neuropsychopharmacol Biol Psychiatry 26: 1095-1104. 117. Haber SN, Fudge JL (1997) The primate substantia nigra and VTA: integrative 97. Li S, Kim KY, Kim JH, Park MS, Bahk JY, et al. (2004) Chronic nicotine and circuitry and function. Crit Rev Neurobiol 11: 323-342. smoking treatment increases dopamine transporter mRNA expression in the rat midbrain. Neurosci Lett 363: 29-32. 118. Jarvik ME, Madsen DC, Olmstead RE, Iwamoto-Schaap PN, Elins JL, et al. (2000) Nicotine blood levels and subjective craving for cigarettes. Pharmacol 98. Rowell PP, Carr LA, Garner AC (1987) Stimulation of [3H]dopamine release by Biochem Behav 66: 553-558. nicotine in rat nucleus accumbens. J Neurochem 49: 1449-1454. 119. Schuh KJ, Stitzer ML (1995) Desire to smoke during spaced smoking intervals. 99. Connelly MS, Littleton JM (1983) Lack of stereoselectivity in ability of nicotine Psychopharmacology (Berl) 120: 289-295. to release dopamine from rat synaptosomal preparations. J Neurochem 41: 1297-1302. 120. Carter BL, Tiffany ST (1999) Meta-analysis of cue-reactivity in addiction research. Addiction 94: 327-340. 100. Marien M, Brien J, Jhamandas K (1983) Regional release of [3H]dopamine from rat brain in vitro: effects of opioids on release induced by potassium, 121. Hartwell KJ, Johnson KA, Li X, Myrick H, LeMatty T, et al. (2011) Neural nicotine, and L-glutamic acid. Can J Physiol Pharmacol 61: 43-60. correlates of craving and resisting craving for tobacco in nicotine dependent smokers. Addict Biol 16: 654-666. 101. Westfall TC, Grant H, Perry H (1983) Release of dopamine and 5-hydroxytryptamine from rat striatal slices following activation of nicotinic 122. Brody AL, Mandelkern MA, Olmstead RE, Jou J, Tiongson E, et al. (2007) cholinergic receptors. Gen Pharmacol 14: 321-325. Neural substrates of resisting craving during cigarette cue exposure. Biol Psychiatry 62: 642-651. 102. Sakurai Y, Takano Y, Kohjimoto Y, Honda K, Kamiya HO (1982) Enhancement of [3H]dopamine release and its [3H]metabolites in rat striatum by nicotinic 123. Goudriaan AE, de Ruiter MB, van den Brink W, Oosterlaan J, Veltman DJ drugs. Brain Res 242: 99-106. (2010) Brain activation patterns associated with cue reactivity and craving in abstinent problem gamblers, heavy smokers and healthy controls: an fMRI 103. Brody AL, Mandelkern MA, Olmstead RE, Allen-Martinez Z, Scheibal D, et al. study. Addict Biol 15: 491-503. (2009) Ventral striatal dopamine release in response to smoking a regular vs a denicotinized cigarette. Neuropsychopharmacology 34: 282-289. 124. McClernon FJ, Kozink RV, Rose JE (2008) Individual differences in nicotine dependence, withdrawal symptoms, and sex predict transient fMRI-BOLD 104. Brody AL, Mandelkern MA, Olmstead RE, Scheibal D, Hahn E, et al. (2006) responses to smoking cues. Neuropsychopharmacology 33: 2148-2157. Gene variants of brain dopamine pathways and smoking-induced dopamine release in the ventral caudate/nucleus accumbens. Arch Gen Psychiatry 63: 125. Janes AC, Frederick B, Richardt S, Burbridge C, Merlo-Pich E, et al. (2009) 808-816. Brain fMRI reactivity to smoking-related images before and during extended smoking abstinence. Exp Clin Psychopharmacol 17: 365-373. 105. Brody AL, Olmstead RE, London ED, Farahi J, Meyer JH, et al. (2004) Smoking-induced ventral striatum dopamine release. Am J Psychiatry 161: 126. Janse Van Rensburg K, Taylor A, Hodgson T, Benattayallah A (2009) Acute 1211-1218. exercise modulates cigarette cravings and brain activation in response to smoking-related images: an fMRI study. Psychopharmacology (Berl) 203: 106. Marenco S, Carson RE, Berman KF, Herscovitch P, Weinberger DR (2004) 589-598. Nicotine-induced dopamine release in primates measured with [C-11] raclopride PET. Neuropsychopharmacology 29: 259-268. 127. Froeliger B, Modlin L, Wang L, Kozink RV, McClernon FJ (2011) Nicotine withdrawal modulates frontal brain function during an affective Stroop task. 107. Tsukada H, Miyasato K, Kakiuchi T, Nishiyama S, Harada N, et al. (2002) Psychopharmacology (Berl).

Page 10 of 10

128. Addicott MA, Baranger DA, Kozink RV, Smoski MJ, Dichter GS, et al. 143. Bacher I, Houle S, Xu X, Zawertailo L, Soliman A, et al. (2011) Monoamine (2012) Smoking withdrawal is associated with increases in brain activation oxidase A binding in the prefrontal and anterior cingulate cortices during acute during decision making and reward anticipation: a preliminary study. withdrawal from heavy cigarette smoking. Arch Gen Psychiatry 68: 817-826. Psychopharmacology (Berl) 219: 563-573. 144. Breyer-Pfaff U, Wiatr G, Stevens I, Gaertner HJ, Mundle G, et al. (1996) 129. Sweet LH, Mulligan RC, Finnerty CE, Jerskey BA, David SP, et al. (2010) Elevated norharman plasma levels in alcoholic patients and controls resulting Effects of nicotine withdrawal on verbal working memory and associated brain from tobacco smoking. Life Sci 58: 1425-1432. response. Psychiatry Res 183: 69-74. 145. Spijkerman R, van den Eijnden R, van de Mheen D, Bongers I, Fekkes D 130. Ray R, Ruparel K, Newberg A, Wileyto EP, Loughead JW, et al. (2011) Human (2002) The impact of smoking and drinking on plasma levels of norharman. Mu Opioid Receptor (OPRM1 A118G) polymorphism is associated with brain Eur Neuropsychopharmacol 12: 61-71. mu-opioid receptor binding potential in smokers. Proc Natl Acad Sci U S A 108: 9268-9273. 146. Henningfield JE, Fant RV (1999) Tobacco use as drug addiction: the scientific foundation. Nicotine Tob Res 2: S31-35. 131. Biegon A, Kim SW, Logan J, Hooker JM, Muench L, et al. (2010) Nicotine blocks brain estrogen synthase (aromatase): in vivo positron emission 147. Newhouse PA, Potter A, Singh A (2004) Effects of nicotinic stimulation on tomography studies in female baboons. Biol Psychiatry 67: 774-777. cognitive performance. Curr Opin Pharm 4: 36-46.

132. Leroy C, Bragulat V, Berlin I, Gregoire MC, Bottlaender M, et al. (2009) 148. West R, Shiffman S (2001) Effect of oral nicotine dosing forms on cigarette Cerebral monoamine oxidase A inhibition in tobacco smokers confirmed with withdrawal symptoms and craving: a systematic review. Psychopharmacology PET and [11C]befloxatone. J Clin Psychopharmacol 29: 86-88. (Berl) 155: 115-122.

133. Xie P, Kranzler HR, Krauthammer M, Cosgrove KP, Oslin D, et al. (2011) 149. Ernst M, Matochik JA, Heishman SJ, Van Horn JD, Jons PH, et al. (2001) Rare nonsynonymous variants in alpha-4 nicotinic acetylcholine receptor gene Effect of nicotine on brain activation during performance of a working memory protect against nicotine dependence. Biol Psychiatry 70: 528-536. task. Proc Natl Acad Sci U S A 98: 4728-4733.

134. Janes AC, Smoller JW, David SP, Frederick BD, Haddad S, et al. (2011) 150. Hillmer AT, Wooten DW, Moirano JM, Slesarev M, Barnhart TE, et al. (2011) Association between CHRNA5 genetic variation at rs16969968 and brain Specific alpha4beta2 nicotinic acetylcholine receptor binding of [F-18]nifene in reactivity to smoking images in nicotine dependent women. Drug Alcohol the rhesus monkey. Synapse 65: 1309-1318. Depend 120: 7-13. 151. Gao Y, Ravert HT, Holt D, Dannals RF, Horti AG (2007) 6-Chloro-3-(((1-[11C] 135. Fowler JS, Logan J, Wang GJ, Volkow ND (2003) Monoamine oxidase and methyl)-2-(S)-pyrrolidinyl)methoxy)-5-(2-fluoropyridi n-4-yl)pyridine ([11C] cigarette smoking. Neurotoxicology 24: 75-82. JHU85270), a potent ligand for nicotinic acetylcholine receptor imaging by positron emission tomography. Appl Radiat Isot 65: 947-951. 136. Berlin I, Anthenelli RM (2001) Monoamine oxidases and tobacco smoking. Int J Neuropsychopharmacol 4: 33-42. 152. Sakata M, Wu J, Toyohara J, Oda K, Ishikawa M, et al. (2011) Biodistribution and radiation dosimetry of the alpha7 nicotinic acetylcholine receptor ligand 137. Fowler JS, Logan J, Wang GJ, Volkow ND, Telang F, et al. (2005) Comparison [11C]CHIBA-1001 in humans. Nucl Med Biol 38: 443-448. of monoamine oxidase a in peripheral organs in nonsmokers and smokers. J Nucl Med 46: 1414-1420. 153. Deuther-Conrad W, Fischer S, Hiller A, Nielsen EO, Timmermann DB, et al. (2009) Molecular imaging of alpha7 nicotinic acetylcholine receptors: design 138. Fowler JS, Wang GJ, Volkow ND, Franceschi D, Logan J, et al. (2000) and evaluation of the potent radioligand [18F]NS10743. Eur J Nucl Med Mol Maintenance of brain monoamine oxidase B inhibition in smokers after Imaging 36: 791-800. overnight cigarette abstinence. Am J Psychiatry 157: 1864-1866. 154. Pomper MG, Phillips E, Fan H, McCarthy DJ, Keith RA, et al. (2005) Synthesis 139. Fowler JS, Wang GJ, Volkow ND, Franceschi D, Logan J, et al. (1999) and biodistribution of radiolabeled alpha 7 nicotinic acetylcholine receptor Smoking a single cigarette does not produce a measurable reduction in brain ligands. J Nucl Med 46: 326-334. MAO B in non-smokers. Nicotine Tob Res 1: 325-329. 155. Horti AG, Villemagne VL (2006) The quest for Eldorado: development of 140. Fowler JS, Volkow ND, Logan J, Wang GJ, MacGregor RR, et al. (1994) Slow radioligands for in vivo imaging of nicotinic acetylcholine receptors in human recovery of human brain MAO B after L-deprenyl (Selegeline) withdrawal. brain. Curr Pharm Des 12: 3877-3900. Synapse 18: 86-93. 156. Marenco T, Bernstein S, Cumming P, Clarke PBS (2000) Effects of nicotine 141. Fowler JS, Logan J, Wang GJ, Volkow ND, Telang F, et al. (2003) Low and chlorisondamine on cerebral glucose utilization in immobilized and freely- monoamine oxidase B in peripheral organs in smokers. Proc Natl Acad Sci U moving rats. Br J Pharmacol 129: 147-155. S A 100: 11600-11605. 157. Wullner U, Gundisch D, Herzog H, Minnerop M, Joe A, et al. (2008) Smoking 142. Bacher I, Houle S, Xu X, Zawertailo L, Soliman A, et al. (2011) Monoamine upregulates alpha4beta2* nicotinic acetylcholine receptors in the human brain. oxidase A binding in the prefrontal and anterior cingulate cortices during acute Neurosci Lett 430: 34-37. withdrawal from heavy cigarette smoking. Arch Gen Psychiatry 68: 817-826.

This article was originally published in a special issue, Tobacco Addiction handled by Editor(s). Dr. Carolyn J. Heckman, University of Iowa, USA.

J Addict Res Ther Tobacco Addiction ISSN:2155-6105 JART, an open access journal