Tobacco and Positron-Emission Tomography (PET) of the Dopaminergic System: A Review of Human Studies

C H A P T E R

14 Tobacco and Positron-Emission Tomography (PET) of the Dopaminergic System: A Review of Human Studies Chidera C. Chukwueke*, Bernard Le Foll† †

*Department of Pharmacology and Toxicology, University of Toronto, Toronto, ON, Canada Translational Addiction Research Laboratory, Centre for Addiction and Mental Health, Toronto, ON, Canada

Abbreviations BPND D1/D2/D3 DA Denic MDD Nic PET

binding potential (nondisplaceable) dopamine receptor subtype 1/2/3 dopamine denicotinized cigarette major depressive disorder nicotinized cigarette positron-emission tomography

14.1 TOBACCO SMOKING AND THE DOPAMINERGIC SYSTEM As tobacco smoking is the leading cause of preventable mortality in the United States (Surgeon General, 2014), there is a significant need to better understand the mechanisms that maintain smoking in order to improve treatment. Nicotine, the psychoactive ingredient in tobacco, is thought to exert its rewarding and reinforcing effects through modulation of dopamine (DA) neurotransmission (Di Chiara, 2000). The advent of positronemission tomography (PET) currently makes it possible to assess DA activity in vivo in humans in response to nicotine use.

14.1.1 Positron-Emission Tomography With earlier iterations of this technology dating back to the 1950s, PET imaging has evolved to be capable of producing high-resolution images used to assess neurochemical brain activity (Portnow, Vaillancourt, & Okun, 2013). PET scanners reconstruct images of spatial density by detecting photons or gamma rays produced

Neuroscience of Nicotine https://doi.org/10.1016/B978-0-12-813035-3.00014-9

from the use of positron-emitting radiotracer. By employing radiotracers that bind to receptors of interest, PET imaging allows the assessment of regional receptor density and neurotransmitter fluctuation. This is done by measuring the radiotracer binding potential (BP), which has been defined as the ratio of Bmax (receptor density) to KD (radiotracer equilibrium dissociation constant) (Mintun, Raichle, Kilbourn, Wooten, & Welch, 1984). As radiotracer binding affinity is the inverse of KD, BP can be seen as the product of receptor density and radiotracer affinity. In PET studies, BPND refers to the ratio of specifically bound radiotracer to nondisplaceable radiotracer in tissue at equilibrium. Used frequently in reference tissue methods, BPND compares the concentration of radiotracer in receptor-rich with that in receptor-free regions. In PET studies investigating tobacco smoker’s brain activity, BPND provides an indirect measure of neurotransmission and receptor availability. By examining the difference between radiotracer BPND before and after an acute challenge (e.g., smoking a cigarette), changes in DA neurotransmitter concentration are inferred as a result of increased challenge-induced competition between radiotracer and endogenous neurotransmitter. Therefore, in comparison to a baseline BPND value, observed decreases in BPND following an acute challenge are thought to reflect an increase in DA concentration (while increases in BPND likewise reflect neurotransmitter decrease). On the other hand, receptor availability can be observed by comparing baseline BPND between smokers and nonsmokers. This design infers regional receptor availability under stable baseline conditions, whereby differences between

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14. TOBACCO AND POSITRON-EMISSION TOMOGRAPHY (PET) OF THE DOPAMINERGIC SYSTEM: A REVIEW OF HUMAN STUDIES

groups may reflect neuroadaptive changes in response to chronic tobacco use. In this chapter, we will review studies that use PET to assess the effects of tobacco smoking or nicotine on DA activity in humans.

14.1.2 Dopamine DA has been implicated in drug addiction (Volkow, Wang, Fowler, & Tomasi, 2012), therefore necessitating the evaluation of its role in tobacco dependence. Like most substances of abuse, tobacco smoking increases extracellular DA concentration, particularly in the striatum (Brody, Mandelkern, et al., 2009). Drug-elicited DA concentration is also generally associated with the drug’s rewarding effects (Volkow et al., 2012). This review focuses on nicotine PET studies analyzing DA synthesis, neurotransmission, and DA receptor (e.g., subtypes D1, D2, and D3) availability inferred by using radiotracers that have distinct regional BPND and receptor affinities. DA activity in the striatum is indirectly measured using radiotracers [11C]-raclopride and [18F]-fallypride for D2 activity and [11C]-SCH 23390 for D1 activity. Furthermore, this chapter reviews extrastriatal D3 activity measured with [11C]-(+)-PHNO, cortical D2 activity measured with [11C]-FLB-457, and DA synthesis measured with [18F]-fluorodopa. Though the studies reviewed here utilize various radiotracers, some methodological commonalities exist. First, some studies assess DA release by examining the difference between radiotracer BPND before and after acute nicotine administration. As explained above, DA release is indirectly measured by inferring that challenge-induced changes in radiotracer BPND proportionally reflect challenge-induced changes in DA concentration. Second, some studies compare baseline BPND between chronic and nonsmokers to assess DA receptor levels in response to long-term nicotine use. However, it is important to note that, with this design, it remains difficult to ascertain whether observed differences in BPND reflect preexisting neural configurations or whether they are consequences of nicotine use.

14.2 PET STUDIES IN HUMAN SMOKERS 14.2.1 [11C]-Raclopride DA release. [11C]-raclopride, a D2/D3 receptor antagonist with modest preference for striatal D2 over D3 (Lammertsma & Hume, 1996), has been a primary radiotracer used in PET studies investigating nicotine-related D2 activity. Studies using this tracer (Table 14.1) have demonstrated DA release in the ventral striatum of smokers who did, compared to those who did not, smoke

a regular cigarette during an outdoor midscan break (Brody et al., 2004). A double-blind, randomized, placebo-controlled study confirmed DA release following nicotine gum consumption in the ventral striatum of smokers, but not nonsmokers (Takahashi et al., 2008). More recent reports exhibit smoking-induced DA release in the dorsal striatum (Weinstein et al., 2016). These studies provide multimodal evidence in support of nicotine-induced DA release. Sex differences have also been reported in studies using [11C]-raclopride (Cosgrove et al., 2014) and with different radiotracers (Brown et al., 2012; Okita, Petersen, et al., 2016). With [11C]-raclopride, male smokers displayed DA release in the ventral striatum, while females displayed faster smoking responses in the dorsal striatum following smoking a regular cigarette (Cosgrove et al., 2014). This report adds differential sex-specific regional and temporal DA responses to nicotine. By contrast, some studies have reported no DA release following either regular cigarette smoking in a scanner or intranasal nicotine administration (Barrett, Boileau, Okker, Pihl, & Dagher, 2004; Montgomery, LingfordHughes, Egerton, Nutt, & Grasby, 2007). Though using the same radiotracer, these results may be attributable to discrepant methodology. Studies supporting nicotine-induced DA release typically show this in the ventral striatum (Brody et al., 2004; Takahashi et al., 2008) and more recently in the dorsal striatum (Weinstein et al., 2016), though this may be exemplified more ventrally in males, while females display timecourse sensitive DA responses in the dorsal region (Cosgrove et al., 2014). However, nicotine administration inconsistently induces apparent DA release (Barrett et al., 2004; Montgomery et al., 2007). This inconsistency in the literature might suggest that nicotine-induced DA release is sensitive to the route of nicotine administration (e.g., smoking vs nasal spray), the smoking methods (e.g., outdoors vs in a scanner), or other factors (e.g., withdrawal in smokers and multiple chemicals in tobacco) that exist in these studies. It should be noted that because of small sample sizes and the lack of systematic control of some factors in most of these studies, it is difficult to conclude on the influence of those factors at this point. Nicotinized vs denicotinized cigarettes. To elucidate the specific contribution of nicotine on DA release, studies have employed a nicotinized (nic; containing regular amounts of nicotine) versus denicotinized (denic; containing significantly reduced amounts of nicotine, i.e., almost no nicotine) cigarette paradigm. This paradigm is beneficial in that smoking a denic cigarette allows us to examine the effects of smoking cues (i.e., the act of smoking minus nicotine delivery) on DA activity, if a proper control condition is tested. Studies employing this paradigm have produced relatively consistent results. One study showed that smokers

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14.2 PET STUDIES IN HUMAN SMOKERS

TABLE 14.1

[11C]-Raclopride Studies

Authors

Subjects

Wiers et al. (2017)

Objective

Intervention

Results/conclusion

Eight current smokers (7.4 Evaluate the effect of smoking cigarettes per day), status on baseline D2 receptor 10 ex-smokers, and availability and DA release 18 nonsmokers

Retrospectively analyzed data of subjects who underwent one PET scan after either placebo or methylphenidate injection

Smokers displayed significantly lower receptor levels, while ex-smokers did not differ from nonsmokers. No significant different in DA release between current smokers and nonsmokers after methylphenidate injection

Weinstein et al. (2016)

10 Smokers smoking 21 cigarettes/day on average

Assessed the association between pretreatment cigarette use and smokinginduced DA release using [11C]-raclopride

One PET scan on the seventh week of bupropion treatment where subjects smoked during a midscan break in a different room

Smoking-induced DA release in caudate and putamen

Cosgrove et al. (2014)

16 Smokers (eight males, eight females)

Examined the differential effects of smoking between males and females using [11C]-raclopride

One PET scan where subjects smoked one or two cigarettes while in the scanner

Found significant right ventral striatum activation in males and none in females. Females displayed faster responses to smoking in the dorsal putamen

Albrecht et al. (2013) 81 Total subjects. 34 nontreatment-seeking alcoholics. 21 social drinking smokers. 26 social drinking nonsmokers

N/A Conducted a retrospective study using [11C]-raclopride PET data to examine the differential contribution of alcohol and tobacco in chronic comorbid use in striatal DA concentration

Domino et al. (2013) 17 Males smoking a mean of 18.5 cigarettes/day

Investigated the effects of plasma nicotine concentration on mood and DA release by comparing nicotinized with denicotinized cigarettes and using [11C]-raclopride

Found lower binding in smoking groups compared to the nonsmoking group in the dorsal striatum and primarily in the dorsal putamen. No differences were found in the ventral striatum

Two PET scans, the first after smoking denicotinized cigarettes and the second after smoking nicotinized cigarettes

Denicotinized cigarettes released DA in the right caudate and putamen, while nicotinized cigarettes released DA in the whole striatum

Domino et al. (2012) 20 Male smokers smoking Examined the modulating role 15–40 cigarettes/day of the OPRM1 A118G polymorphism on DA release following smoking a nicotinized vs a denicotinized cigarette using [11C]raclopride

Two PET scans. First, after smoking two denicotinized cigarettes, then again after smoking two nicotinized cigarettes

Those with the G allele displayed greater nicotineinduced DA release in the right caudate and ventral pallidum when compared to individuals with homozygous AA alleles

Brody, Mandelkern, et al. (2009)

62 Dependent smokers smoking 24.2 cigarettes/ day

Compared smoking-induced DA release using [11C]raclopride in nicotinized with that in denicotinized cigarettes

One PET scan during which they smoked either a nicotinized or a denicotinized cigarette

Both cigarette types relieved craving; however, only nicotinized cigarettes increased DA release in the ventral striatum and improved mood

Brody, Olmstead, et al. (2009)

56 Smokers smoking 24.7 cigarettes/day with and without MDD

Used [11C]-raclopride to examine smoking-induced DA release between smokers with and without depressive episodes

One PET scan during which subjects smoked a regular cigarette

In comparison to MDD
, MDD+ subjects showed heightened smoking-induced DA release. Greater smokinginduced DA release was associated with greater prescan depression and anxiety levels

Busto et al. (2009)

17 MDD+/
smokers, smoking an average of 16.65 cigarettes/day, compared to 21 MDD+/
nonsmokers

Compared the effects of an acute amphetamine challenge across healthy controls and depressed subjects with or without tobacco dependence using [11C]-raclopride

Two PET scans, a baseline scan, then a scan following oral administration of amphetamine

Smokers, but not MDD+ subjects, showed lower binding at baseline. MDD+ smokers displayed the greatest amphetamineinduced decreases in binding Continued

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TABLE 14.1

[11C]-Raclopride Studies—cont’d

Authors

Subjects

Objective

Intervention

Results/conclusion

Takahashi et al. (2008)

Six smokers smoking over 15 cigarettes/day compared to six nonsmokers

A double-blind, randomized, placebo-controlled study that investigated the differences in [11C]-raclopride binding between smokers and nonsmokers using nicotine gum

Two PET scans. Both scans were done, while the subject chewed either a nicotine or placebo gum throughout the scan

Nicotine gum elicited significantly lower binding when compared to placebo in the striatal region of smokers but not nonsmokers. Striatal binding correlated with degree of nicotine dependence

Scott et al. (2007)

Six smokers smoking a mean of 16.7 cigarettes/ day compared to six age and sex matched nonsmokers

Examined the effects of nicotinized vs denicotinized cigarette smoking on D2 and μ-opioid receptors using [11C]raclopride and [11C]carfentanil

One PET scan. During the scan, subjects were sequentially injected with both radiotracers in a counterbalanced manner. Smokers smoked the denicotinized cigarette during the first half of the scan and smoked the nicotinized cigarette during the second half

Smokers did not display a significant difference in D2 binding compared to nonsmokers. Nicotinized cigarettes resulted in lower D2/D3 binding compared to nicotinized cigarettes in the left ventral basal ganglia

Montgomery et al. (2007)

10 Smokers smoking a mean of 10.9 cigarettes/ day

Determined the effect of nicotine administration via nasal spray on DA release by using [11C]-raclopride

One PET scan with nicotine nasal spray administration midscan

No significant difference in binding between pre- and postnicotine administration. Found several associations between nicotine-induced changes in mood and dorsal striatal binding

Brody et al. (2006)

45 Smokers smoking 23.9 cigarette/day

Examined the genetic variability involved in smoking-induced DA release using [11C]-raclopride

One PET scan under either a smoking condition or a nonsmoking condition

Found associations between specific genetic polymorphisms and greater smoking-induced DA release

Barrett et al. (2004)

10 Male smokers smoking Assessed DA activity in an average of response to acute cigarettes 18 cigarettes/day smoking using [11C]raclopride, as well as associations to nicotine craving and the hedonic effects of smoking

Two PET scans under a smoking condition, where subjects smoked cigarettes repeatedly while in the scanner, and a nonsmoking condition where they did not smoke

No significant difference in DA binding between smoking and the nonsmoking condition; however, the hedonic effects of smoking were significantly correlated with DA binding in the dorsal striatum

Brody et al. (2004)

20 Smokers smoking at least 15 cigarettes/day

One PET scan where half the subjects underwent a smoking condition while the other half underwent a control condition

Smoking condition resulted in significant reductions in binding in the ventral striatum that was associated with reductions in self-reported craving

Assessed the effect of nicotine administration via regular cigarette on DA release using [11C]-raclopride

This table outlines the subjects, objectives, and conclusions of nicotine PET studies that use the radiotracer [11C]-raclopride. DA, dopamine; MDD +/
, major depressive disorder positive or negative; PET, positron-emission tomography.

(N ¼ 6) exhibited DA release in the ventral striatum after smoking a nic cigarette compared to a denic cigarette (Scott et al., 2007). These findings were replicated in another study with a much larger sample (N ¼ 62; Brody, Mandelkern, et al., 2009). Interestingly, another study assessing DA release in response to nic versus denic smoking confirmed nic-induced DA release, though in the whole striatum (i.e., ventral and dorsal), while also

showing a denic-induced DA release in the right dorsal striatum (Domino et al., 2013). Collectively, these studies provide further evidence to support smoking-induced DA release. Potentially, while nicotine itself may contribute to smoking-induced DA release in the ventral striatum, DA release in the dorsal striatum may be attributable to smoking cues. The drug addiction literature supports this view as ventral striatal

14.2 PET STUDIES IN HUMAN SMOKERS

DA release has been linked to drugs rewarding and reinforcing effects while dorsal striatal DA release has been implicated in habit learning and exposure to drug-associated cues (Volkow, Fowler, Wang, Baler, & Telang, 2009; Volkow et al., 2012). Subjective correlates. Subjective measures of craving, mood regulation, and nicotine dependence severity have been reported in relation to nicotine-induced DA activity. Smoking-induced mood changes and hedonic effects have been reported to correlate with DA release in the dorsal striatum (Barrett et al., 2004; Montgomery et al., 2007). On the other hand, studies correlate ventral striatal DA release to the reduction of subjective craving scores and mood improvements (Brody et al., 2004; Brody, Mandelkern, et al., 2009; Takahashi et al., 2008). Also, subjective measures of nicotine dependence severity are reported to correlate with the ventral striatal DA release (Scott et al., 2007; Takahashi et al., 2008) and baseline dorsal striatum DA receptor availability (Montgomery et al., 2007), making the regional distinctions less clear. While more research is needed to distinguish regional contribution in nicotine dependence, these results do support the idea that both regions play an important role in behavioral components of addiction (Volkow et al., 2012). Nicotine and depression. Tobacco dependence may occur in the context of comorbid major depressive disorder (MDD). In studies using [11C]-raclopride, smokers with past depressive episodes displayed greater smokinginduced DA release compared to those without (Brody, Olmstead, et al., 2009). On the other hand, smokers with MDD showed blunted amphetamine challenge-induced DA response compared to nonsmokers with or without MDD (Busto et al., 2009). Clear differences in the study design may account for the discrepant results. However, it is plausible that in smokers with comorbid mental health issues, the administration of the substance of dependence (e.g., nicotine for smokers) stimulates an overactive DA response while a less familiar substance (e.g., amphetamine for smokers) produces a weakened response as has been previously reported (Parsey et al., 2001). Altogether, it is clear that comorbid existence of MDD and nicotine dependence dysregulates the DA system more than any one disorder alone. Genetic variation. Studies examining genetic variability in smokers using [11C]-raclopride have shown an association to various genetic polymorphisms (Brody et al., 2006; Domino et al., 2012). According to these studies, carriers of the minor G allele of the μ-opioid receptor and genes associated with low resting DA tone (ninerepeat allele of the dopamine transporter, Val/Val genotype of the catechol-O-methyltransferase enzyme, and seven-repeat allele of the D4 receptor) show greater magnitudes of smoking-induced DA release. These studies recruited a majority male population, thus warranting further research. Though far from conclusive, genetic

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variability may be able to account for a significant portion of individual differences in smoking-induced DA release. Receptor availability. Studies assessing receptor availability changes in tobacco dependence using [11C]raclopride have produced mixed results. While earlier studies show no difference in baseline receptor availability in smokers versus nonsmokers (Scott et al., 2007; Takahashi et al., 2008), more recent studies challenge these findings. Studies show that smokers with comorbid alcohol use and depressive issues have presented lower D2 receptor availability compared to nonsmokers (Albrecht, Kareken, & Yoder, 2013; Busto et al., 2009). This finding has recently been supported as Wiers et al. (2017) found lower D2 receptor availability in current smokers compared to nonsmokers using a retrospective study design. In this study, ex-smokers did not differ from nonsmokers in D2 receptor availability, suggesting that periods of abstinence may normalize receptor levels. While these reports are inconsistent, addiction-induced DA receptor downregulation is well documented (Volkow et al., 2009) and is seen in nicotine PET studies using different radiotracers (Dagher et al., 2001; Fehr et al., 2008; Yasuno et al., 2007), therefore supporting the narrative that tobacco dependence does indeed reduce DA receptor availability with the possibility of restoration upon abstinence. Interestingly, a recent study negatively correlated daily cigarette use with DA release in the dorsal striatum, suggesting neuroadaptive tolerance to smoking (Weinstein et al., 2016); however, these findings are preliminary.

14.2.2 [18F]-Fallypride Nicotine PET studies have utilized [18F]-fallypride (Table 14.2), a high-affinity D2 radioligand (Riccardi et al., 2008, 2005), to assess D2/3 receptor availability in striatal and extrastriatal areas. [18F]-Fallypride research shows lower D2 receptor availability in the dorsal striatum of smokers but not nonsmokers (Fehr et al., 2008). However, sex differences complicates this finding as studies reports lower dorsal striatum D2 availability in male smokers (Brown et al., 2012) in combination with higher midbrain D2 availability, positively correlated with dorsal striatal D2 availability, in female smokers (Okita, Petersen, et al., 2016). This indicates an underactive DA system in nicotine dependence where males experience more DA receptor downregulation than females. [18F]-Fallypride studies have confirmed associations between the DA system and craving, cigarette use, and dependence severity. Research positively correlates craving with ventral striatal receptor availability but negatively correlates craving with the anterior cingulate and inferior temporal cortex (Fehr et al., 2008). Furthermore, one study shows lower D2 availability in the ventral striatum correlated with higher cigarette use and dependence severity (Okita, Mandelkern, & London, 2016),

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TABLE 14.2

[18F]-Fallypride Studies

Authors

Subjects

Objective

Intervention

Results/conclusion

Okita, Mandelkern, et al. (2016)

20 Nondependent smokers

Correlated [18F]-fallypride binding to both daily cigarette smoking and nicotine dependence

One PET scan

Lower binding in the ventral striatum correlated with higher cigarette use. Higher dependence scores correlated with lower binding in the whole striatum (ventral and dorsal striatum). This suggests a downregulation of DA receptors as cigarette use escalates and dependence develops

Okita, Petersen, et al. (2016)

18 Smokers smoking 5–20 cigarettes/day compared to 19 nonsmokers

Assessed sex differences in midbrain DA receptor availability using [18F]fallypride

One PET scan

Female smokers exhibited higher midbrain binding than male smokers. Midbrain binding was positively correlated with striatal binding and negatively correlated with dependence scores

Brown et al. (2012)

19 Light smokers smoking 4–14 cigarettes/day compared to 18 nonsmokers

Investigated sex differences in light smokers vs nonsmokers using [18F]fallypride

One PET scan

Male smokers showed significantly lower D2/D3 receptor availability in the caudate and putamen when compared to females and nonsmokers. Females did not differ from nonsmokers in receptor availability

Fehr et al. (2008)

17 Smokers smoking a mean of 19.5 cigarettes/day compared to 21 nonsmokers

Used [18F]-fallypride to compare D2/D3 receptor availability in striatal and extrastriatal regions between smokers and nonsmokers

Two PET scans, first following regular cigarette consumption and, secondly, following 24-hour abstinence

Smokers displayed lower D2/D3 receptor availability in the putamen, but not in extrastriatal regions, following both regular cigarette consumption and abstinence. This study found correlations between binding in several brain regions and behavioral measures

This table outlines the subjects, objectives, and conclusions of nicotine PET studies that use the radiotracer [18F]-fallypride. DA, dopamine; PET, positron-emission tomography.

while another shows dependence scores negatively correlated with dorsal striatum D2 availability (Okita, Petersen, et al., 2016). This suggests that craving may be differentially mediated by both striatal and extrastriatal areas, and in accordance with [11C]-raclopride research, level of dependence may be related to DA receptor availability in the both striatal regions.

14.2.4 [11C]-(+)-PHNO [11C]-(+)-PHNO is a D2/3 agonist reported to be more sensitive than [11C]-raclopride to acute DA fluctuations (Shotbolt et al., 2012) and is a D3 preferring agonist in extrastriatal areas such as the substantia nigra (Tziortzi et al., 2011). To determine the specific involvement of TABLE 14.3 The [11C]-FLB-457 Study

14.2.3 [11C]-FLB-457 A single study has examined smoking-induced cortical DA release using [11C]-FLB-457 (Table 14.3). [11C]-FLB-457 is a high-affinity D2/3 receptor ligand that shows greater sensitivity to DA changes in cortical areas with low DA receptor density (Narendran et al., 2009). The sole study examining cortical DA transmission shows that smoking a cigarette releases DA primarily in the cingulate cortex (Wing, Payer, Houle, George, & Boileau, 2015). In this study, craving was not correlated with cortical DA release; thus, the role of cortical DA transmission in nicotine craving remains unclear. However, this does add to the literature that smoking a cigarette results in not only striatal DA release but also cortical DA release.

Authors Subjects

Objective

Intervention

Wing et al. (2015)

Examined DA release by tobacco smoking in extrastriatal and cortical brain regions using [11C]FLB-457

Two PET scans. First scan following 16-hour abstinence, the second scan following smoking to satiation

10 Smokers smoking an average of 16 cigarettes/ day

Results/ conclusion Found significant binding reductions in primarily the cingulate gyrus. Greater puff volume correlated with greater binding reductions

This table outlines the subjects, objectives, and conclusions of a nicotine PET study that used the radiotracer [11C]-FLB-457. DA, dopamine; PET, positronemission tomography.

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14.2 PET STUDIES IN HUMAN SMOKERS

D3 in nicotine dependence, studies using [11C]-(+)-PHNO (Table 14.4) suggest that smoking a regular cigarette elevates DA in the limbic (i.e., ventral) striatum and the D3 rich ventral pallidum (Fig. 14.1) (Le Foll et al., 2014). Motivation to smoke, craving, and withdrawal symptoms have been correlated with DA release in the limbic striatum (Le Foll et al., 2014). However, presentation of smoking-related cues alone elicits no detectable DA response in a pilot study (Chiuccariello et al., 2013). At this point, these studies support striatal involvement and indicate the involvement of D3-rich areas (ventral pallidum) in response to smoking but not smokingrelated environmental cues.

14.2.5 [11C]-SCH 23390 Research using [11C]-SCH 23390, a D1 receptor antagonist, to measure D1 receptor availability (Table 14.5) has demonstrated significantly lower D1 receptor availability in the ventral striatum of smokers compared to nonsmokers (Dagher et al., 2001). These findings were

replicated by Yasuno et al. (2007), showing lower ventral striatal D1 receptor availability in smokers that increased following 6 months of abstinence. Yasuno et al. (2007) also negatively correlated ventral striatum D1 receptors with cue-induced craving scores, suggesting an association between lower D1 receptor density and larger craving. These studies suggest that while chronic smoking induces the downregulation of D1 receptors, which is associated with larger craving, this downregulation may be reversible upon abstinence as seen with D2 receptors (Wiers et al., 2017).

14.2.6 [18F]-Fluorodopa Studies investigating DA synthesis capacity using [18F]-fluorodopa in smokers have produced mixed results (Table 14.6). One study reports significantly higher DA activity in the dorsal striatum of male smokers than in nonsmokers (Salokangas et al., 2000), while Bloomfield et al. (2014) found no difference in the whole striatum related to smoking status. These inconsistent results

TABLE 14.4

[11C]-(+)-PHNO Studies

Authors

Subjects

Objective

Intervention

Results/conclusion

Le Foll et al. (2014)

10 Smokers smoking 13.2 cigarettes/ day

Investigated smoking-induced DA release in the striatum, ventral pallidum, and substantia nigra using [11C]-(+)-PHNO

Two PET scans under a smoking and abstinent condition

The smoking condition resulted in significant reductions in binding in the limbic striatum and the ventral pallidum when compared to the abstinent condition. There were also correlations between PHNO binding and smoking behaviors

Chiuccariello et al. (2013)

18 Smokers smoking 18.2 cigarettes/ day

Investigated DA release by presentation of smoking cue vs neutral cue using [11C]-(+)-PHNO

One PET scan with smoking cue vs neutral cue (visual and tactile components)

No significant difference in DA levels in any brain region between smoking and neutral cue presentation

This table outlines the subjects, objectives, and conclusions of nicotine PET studies that use the radiotracer [11C]-(+)-PHNO. DA, dopamine; PET, positron-emission tomography.

FIG. 14.1 [11C]-(+)-PHNO binding in response to cigarette smoking. T-statistical overlaid average T1 MRI showing clusters of significantly reduced [11C]-(+)-PHNO BPND after smoking a cigarette. Greatest decreases in [11C]-(+)-PHNO BPND cluster in the ventral part of the striatum and in the area that corresponds to the ventral pallidum. For visualization purposes, the image is threshold at a P < .05 uncorrected. Adapted from Le Foll et al. (2014).

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TABLE 14.5

[11C]-SCH23390 Studies

Authors

Subjects

Objective

Intervention

Results/conclusion

Yasuno et al. (2007)

18 Smokers smoking at least 15 cigarettes/day vs 12 nonsmokers

Used [11C]-SCH23390 studies to investigate binding levels in D1 receptors in smokers vs nonsmokers during regular cigarette consumption and after months of abstinence

Subjects underwent one PET scan at baseline and subjects who achieved abstinence underwent subsequent PET scans

Smokers showed significantly lower D1 receptor binding than nonsmokers. D1 receptor binding in the bilateral nucleus accumbens increased after 3 and 6 months of abstinence. Finally, there was a significant negative correlation in the nucleus accumbens between smoking-induced brain activation, craving scores, and D1 receptor binding

Dagher et al. (2001)

11 Smokers smoking a mean of 19.4 cigarettes/day compared to 18 nonsmokers

Examined D1 receptor density in smokers vs nonsmokers using [11C]SCH23390 studies

Two PET scans, one following overnight abstinence and the other during regular smoking rates

Smokers displayed significantly less D1 receptor binding than nonsmokers in the whole striatum; however, there was no difference in D1 receptor binding between overnight abstinence and regular smoking

This table outlines the subjects, objectives, and conclusions of nicotine PET studies that use the radiotracer [11C]-SCH23390. DA, dopamine; PET, positron-emission tomography.

TABLE 14.6

[18F]-Fluorodopa

Authors

Subjects

Objective

Intervention

Results/conclusion

Bloomfield et al. (2014)

15 Smokers (average of 8.1 cigarettes/day) matched against 15 nonsmokers

Compared DA synthesis in smokers with nonsmokers using [18F]fluorodopa

One PET scan; smokers were abstinent for 3 hours prior to scanning

Found no associations in any striatal region between DA synthesis and smoker status, daily cigarette use or sex

Salokangas et al. (2000)

Nine smokers smoking 19.8 cigarettes/day compared to 10 nonsmokers

Examined whether dopamine synthesis in the basal ganglia differs between smokers and nonsmokers using [18F]-fluorodopa

One PET scan

Smokers showed increased DA synthesis in the putamen and the caudate, especially in the right caudate and left putamen

This table outlines the subjects, objectives, and conclusions of nicotine PET studies that use the radiotracer [18F]-fluorodopa. DA, dopamine; PET, positron-emission tomography.

may be a result of discrepant sample populations. Salokangas et al. (2000) used only male heavy smokers, while Bloomfield et al. (2014) recruited both male and female moderate smokers. Therefore, it is plausible that dopamine synthesis may be altered in heavy smokers but not moderate smokers.

14.3 CONCLUSION Using various radiotracers, PET studies have elucidated much about the nicotine-DA relationship. Firstly, nicotine administration seems to elicit DA release in striatal (both ventral and dorsal), cortical (primarily the cingulate cortex), and D3-rich (the ventral pallidum) areas. Though nicotine itself may be a major contributor to DA release, smoking-related cues may also play an important role. Nicotine-induced DA release has not been consistently reported, however, and may be sensitive to route

of nicotine administration, smoking method, and other factors. Furthermore, nicotine-induced DA release may differ between sexes, across various genetic polymorphisms, and within comorbid disorders. Secondly, chronic tobacco use results in a downregulation of D1 and D2 receptors, though this may be reversible for upon abstinence. As with DA release, downregulation of DA receptors may also be experienced differently between sexes. DA synthesis may also be compromised as nicotine dependence develops, though this may affect heavier users more severely. Finally, DA activity is regionally correlated with several smoking behaviors. Craving seems related to ventral striatal DA activity and receptor (D1 and D2) availability, though possibly also related to cortical regions. Mood changes and the pleasurable effects of smoking may be related to the dorsal striatum, while dependence severity may be related to activity in both striatal regions. These behaviors and tobacco dependence as a whole are

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effectively combatted with pharmacotherapy such as varenicline and bupropion. Interestingly, bupropion (Brody et al., 2010) and varenicline (Di Ciano et al., 2016) appear to affect DA transmission differently. As tobacco dependence continues to be a considerable clinical issue, more research is needed to understand the complex tobacco-DA relationship. Overall, very limited PET studies have been conducted in this area, and we know very little on DA synthesis and how receptors evolve over time. There is clearly a need for more and larger studies. It would be important to delineate the impact of smoking on DA transmission in different brain areas and to explore the role of individual factors into the variability of the signal that is measured. Better understanding how subjects respond to drugs used clinically would also provide a better understanding of the mechanism of action of those drugs in human smokers.

MINI-DICTIONARY OF TERMS Acute challenge The administration of a substance in order to elicit a measurable change on a defined parameter. Binding potential A measure of a radiolabeled ligand’s binding ability. This measure is typically a combination of receptor availability and ligand affinity. Denicotinized cigarette A cigarette that contains a significantly reduced amount of nicotine, typically for research purposes. Dorsal striatum A brain region that is part of the subcortical basal ganglia. This area typically consists of the caudate nucleus and the putamen. Induced dopamine release A measure of the change in dopamine concentration elicited by a substance or action. For example, smoking-induced dopamine release is the release of dopamine following smoking. Limbic striatum Similar to the ventral striatum and sometimes used interchangeably by authors. This brain area refers to the subdivisions of the striatum that receives neuronal projections from limbic structures (e.g., amygdala and hippocampus). Nicotinized cigarette A cigarette that contains regular concentrations of nicotine. This cigarette is similar to commercially bought cigarettes but may also be produced specifically for research purposes. Receptor availability The density or amount of receptors, in a defined brain region, to which ligand binding is possible. Smoking-related cue This refers to stimuli associated with smoking. For example, pictures of a cigarette or lighter or the smell of cigarette smoke. Ventral striatum A brain region that is part of the subcortical basal ganglia. This area typically includes the nucleus accumbens.

Key Facts of Radiotracers in PET Scans • Radiotracers used in PET scans are positron-emitting chemical ligands that bind to receptors of interest. • There are many radiotracers with different affinities to several receptors. • They allow the indirect measure of neurotransmitter concentration by competing with endogenous neurotransmitter for receptor binding.

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• Radiotracers allow to get a measure of receptor density by the estimation of BPND when the measures are done at rest. Summary Points • This chapter reviews human dopamine (DA) activity in nicotine dependence using positron-emission tomography (PET). • PET employs different radiotracers to assess DA neurotransmission in different brain regions and the availability of different receptor subtypes in vivo. • Research shows that tobacco administration increase DA levels in the striatum, D3-rich extrastriatal areas, and cortical areas. • There have been some inconsistent reports on the ability of tobacco to elevate DA levels. • Sex and genetic variability may influence those effects. • Chronic tobacco use downregulates DA receptors, and this may be reversible after a period of abstinence. • There are several tobacco-related phenotypes that are associated with DA changes: withdrawal, craving, mood changes, and dependence severity. • Future research should focus on elucidating the mechanistic underpinnings of individual variability as it relates to acute neurotransmission and neuroadaptive changes in response to chronic tobacco use for the improvement of treatment.

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