Molecular Psychiatry (2009) 14, 653–667
& 2009 Nature Publishing Group All rights reserved 1359-4184/09 $32.00
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FEATURE REVIEW
Constitutional mechanisms of vulnerability and resilience
to nicotine dependence
N Hiroi1,2 and D Scott2
1
Department of Psychiatry and Behavioral Sciences, Laboratory of Molecular Psychobiology, Albert Einstein College of
Medicine, Bronx, NY, USA and 2Dominick P. Purpura Department of Neuroscience, Albert Einstein College of Medicine, Bronx,
NY, USA
The core nature of nicotine dependence is evident in wide variations in how individuals
become and remain smokers. Individuals with pre-existing behavioral traits are more likely to
develop nicotine dependence and experience difficulty when attempting to quit. Many
molecular factors likely contribute to individual variations in the development of nicotine
dependence and behavioral traits in complex manners. However, the identification of such
molecules has been hampered by the phenotypic complexity of nicotine dependence and the
complex ways molecules affect elements of nicotine dependence. We hypothesize that
nicotine dependence is, in part, a result of interactions between nicotine and pre-existing
behavioral traits. This perspective suggests that the identification of the molecular bases of
such pre-existing behavioral traits will contribute to the development of effective methods for
reducing smoking dependence and for helping smokers to quit.
Molecular Psychiatry (2009) 14, 653–667; doi:10.1038/mp.2009.16; published online 24 February 2009
Keywords: smoking; addiction; knockout mice; translational model; comorbidity; genetic
susceptibility
Introduction
According to a recent estimate, 1.3 billion individuals
or one-fifth of the global population smokes. Tobacco
smoking poses a grave health hazard, with half of the
continuing smokers being expected to die prematurely due to tobacco-related diseases.1 Cigarette
smoking is one of the most persistent types of
substance dependence, comparable to cocaine dependence. A survey of 10 343 daily smokers and 107 daily
cocaine users aged 12 years or older revealed that
75% of smokers and 72% of daily cocaine users try to
cut down on their use. However, 80% of smokers and
66% of daily cocaine users feel unable to cut down on
their use, despite their efforts. The majority of daily
smokers (85%) and daily cocaine users (63%) feel
they are dependent, and 37% of daily smokers and
49% of daily cocaine users feel sick when they stop or
cut down on the use of the drug.2
Antidepressants and some forms of nicotine replacement therapy increase tobacco cessation rates.3,4
However, the majority of quitters relapse, despite the
use of these aids or even a combination of these aids.
More effective tobacco cessation treatments depend
Correspondence: Dr N Hiroi, Department of Psychiatry and
Behavioral Sciences, Laboratory of Molecular Psychobiology,
Albert Einstein College of Medicine, 1300 Morris Park Avenue,
Bronx, NY 10461, USA.
E-mail: [email protected]
Received 22 September 2008; revised 2 January 2009; accepted 22
January 2009; published online 24 February 2009
upon a more complete understanding of the mechanisms underlying dependence. Although chemicals
other than nicotine might contribute to the development of continued smoking,5 evidence suggests that
nicotine is a major determinant of dependence. When
switched to denicotinized cigarettes, smokers consume
fewer denicotinized cigarettes within 1 week.6 Smoking
denicotinized cigarettes causes smokers to experience
withdrawal symptoms.7 Conversely, nicotine replacement therapy reduces withdrawal symptoms and the
urge to smoke in smokers during abstinence.8 Nicotine
replacement also increases the success of cessation
efforts.4 Varenicline, a partial nicotinic receptor agonist,9 increases the success rates of long-term smoking
cessation efforts.10 Nicotine alone is sufficient to
sustain self-administration behavior in humans.11
In this review, we discuss the difficulty in defining
nicotine dependence, individual variation in smoking
and pre-existing traits for smoking. We also discuss
potential molecular correlates of individual susceptibility to nicotine dependence in humans and experimental animals. We propose a hypothetical framework
to better understand nicotine dependence and discuss
its implications for future research directions.
Many definitions of nicotine dependence
The clinical definition of nicotine dependence
depends on the measure that is used. The Fagerström
Test for Nicotine Dependence (FTND) and the
Diagnostic and Statistical Manual (DSM)-III or
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N Hiroi and D Scott
654
DSM-IV-Revised are commonly used for studies of
nicotine dependence. Both measures define nicotine
dependence in terms of behavioral and clinical
manifestations. The FTND is a revised version of the
earlier Fagerström Tolerance Questionnaire. As the
name indicates, this scale assumes that physical
dependence, including withdrawal and tolerance,
motivates compulsive smoking. It assesses the degree
of dependence on a continuous scale.12
The DSM focuses on salient behavioral and physiological features of smoking. These features include (1)
impaired control over use, (2) use greater than
intended, (3) withdrawal, (4) use despite harm and
problems and (5) tolerance. DSM criteria not readily
applicable to nicotine dependence are (6) large
amounts of time spent obtaining, using and recovering from the substance and (7) forgoing other
activities to use the substance.13 Each item of the
DSM is judged to be present or absent, and overall
dependence is categorically judged to be present or
absent if a smoker meets three or more of these criteria
at any time during a 12-month period. This diagnosis
is useful for reliably determining the prevalence of
smoking. However, a shortcoming of the DSM-based
diagnosis is that it does not take into account the
gradual development of smoking. Even when a
smoker is nearing the threshold of a diagnostic cutoff,
he would be judged as non-dependent. Moreover, a
single diagnosis does not reveal the combinations of
the multidimensional symptoms that are present. At
different stages of smoking, smokers might exhibit
distinct sets of characteristics or more of one
particular symptom. Grouping smokers into a single
‘dependent’ group ignores the potential heterogeneity
among these individuals.
Not surprisingly, the FTND and DSM do not
correlate well. The FTND defines smoking on a
continuous dimension and has no clear-cut point
that divides dependent and non-dependent individuals. Cutoffs can be arbitrarily set to divide nondependent and dependent smokers or to define low,
medium or high levels of dependence. However, no
matter how a cutoff is set, the FTND-defined nicotine
dependence does not agree well with nicotine
dependence defined by the DSM-III-R-based scale.14
The FTND is a better predictor of smoking cessation
than the DSM-III-R.15,16
Whether nicotine dependence should be categorically defined as a state or a continuous process and
whether nicotine dependence involves a single
process or multiple processes are matters of debate.17
The Wisconsin Inventory of Smoking Dependence
Motives (WISDM-68) was developed to comprehensively capture the multidimensional reasons for
smoking on a continuous scale.18 This inventory
includes the following potential motives for smoking:
a strong emotional attachment to smoking and
cigarettes (that is, affiliative attachment); smoking
without awareness or intention (that is, automaticity);
smoking among all options despite constraints
or negative consequences (that is, behavioral choice-
Molecular Psychiatry
melioration); smoking to enhance cognitive functioning (that is, cognitive enhancement); frequent urge,
inability to ignore urge to smoke and intensified and
intolerable nature of urge to smoke during abstinence
(that is, craving); strong impact of smoking-associated
cues on urge to smoke and smoking (that is, cue
exposure-associative processes); a sense of loss
of volitional control over smoking (that is, loss of
control); the ability of smoking to improve mood, lift a
‘down’ mood, relieve irritability and increase the
ability to cope with stress (that is, negative reinforcement); the desire to smoke to experience pleasure or
to enhance an already positive feeling or experience
(that is, positive reinforcement); social stimuli or
contexts that either model or invite smoking (that is,
social-environmental goads); the need to experience
the sensory and gustatory effects of smoking (that is,
taste and sensory properties); the need to smoke
increasing amounts over time or the ability to smoke
large amounts without acute toxicity (that is, tolerance); and use of cigarettes to control body weight or
appetite (that is, weight control).
This test is likely to uncover distinct underlying
motives for various aspects of smoking. Variation in
how much one smokes is correlated with tolerance,
loss of control, craving, automaticity, behavioral
choice-melioration, affiliative attachment, cognitive
enhancement, cue exposure-associative processes and
negative reinforcement; the number of cigarettes
smoked is less correlated with positive reinforcement,
weight control, taste and sensory properties and
social-environmental goads.18 Relapse also can be
predicted by some of these motives. Smokers subjectively feel that they relapse because they automatically smoke without thinking about it (that is,
automaticity), they smoke to enhance cognitive function (that is, cognitive enhancement), they smoke to
alleviate stress or withdrawal (that is, negative
reinforcement) and their social environments are
conducive to smoking (that is, social-environmental
goads).18 In a follow-up study, tolerance, automaticity,
social-environmental goads and craving were found
to be predictive of abstinence.16
Many behavioral and physiological features are
potentially related to the mechanisms underlying
nicotine dependence. The symptomatic complexity
challenges the assumption that a single mechanism
governs the many aspects of nicotine dependence.
This raises the question as to how to model
‘dependence’ as a whole and whether such an attempt
is a reasonable endeavor. In addition, imposing an
artificial division between dependent and nondependent individuals is conceptually limiting.
Smoking is more appropriately characterized by
the degree of dependence on a continuous,
multidimensional scale.
Myth of the average smoker
The interindividual variation in nicotine intake is
large. Among smokers aged 18 or older in the United
Constitutional mechanisms of nicotine dependence
N Hiroi and D Scott
States, the majority (64%) consume between 5 and 24
cigarettes per day. A sizable population of smokers
(23%) smoke only on some days or smoke 1–4
cigarettes per day. Heavy smokers who smoke at least
25 cigarettes per day make up 12% of the total
population of smokers.19
These different levels of smoking represent a crosssection of how individuals’ smoking habits change
over a lifetime. Most smokers initiate smoking during
adolescence, and their smoking habits change
through distinct trajectories into adulthood. Although
there is inconsistency among studies regarding how
many trajectories exist, prospective studies have
identified four primary trajectories: (1) persistent
low-level smoking, (2) early initiation of smoking
with rapid progression to heavy, persistent smoking,
(3) early initiation of smoking with slow progression
to moderate smoking and eventual cessation, (4) later
initiation of smoking with progression to moderate to
heavy smoking.20–36 Those who become persistent,
heavy smokers comprise approximately one-third of
those who have ever tried cigarettes.
Like adolescent smokers, adult smokers show
various trajectories. Among college students examined over a course of 4 years, light smokers quit
(45%), became occasional (35%) or daily smokers
(20%). The majority of those who were daily smokers
at baseline quit or reduced smoking (54%). The
remaining individuals became low-level smokers
(6%) or increased their daily smoking (27%).37
Among adults over 24 years old who have smoked
for at least 5 years, 37% of daily low-level smokers
(pfive cigarettes per day) quit, 36% retain the same
level of smoking, 21% increase their smoking to more
than five cigarettes per day and 6% become occasional smokers over a period of 2 years.38
Light or intermittent smokers are often in transition
to either quitting or becoming regular smokers.
However, a subpopulation of intermittent and light
smokers remains at this level for more than 20 years
without changing their smoking status.39 Even after
smoking tens of thousands of cigarettes over 20 years,
these smokers, dubbed ‘chippers’, do not experience
craving, mood disturbance, reduced arousal, or sleep
disturbance.40 Chippers feel the urge to smoke only in
settings where they usually smoke, such as in settings
related to relaxation, socializing, eating and drinking
alcohol; they do not feel the urge to smoke or
experience positive feelings upon smoking outside
of their usual smoking settings.41–43
The intensity and time course of withdrawal
symptoms following quitting differs from individual
to individual. Some individuals experience intense
withdrawal immediately following the onset of
abstinence, with the symptoms gradually or quickly
waning. Others experience a rebound in withdrawal
symptoms later.44,45 Lapses are highly correlated
with the individual time course of withdrawal
intensity,46 and lapsers have higher levels of withdrawal symptoms (for example, negative affect) than
abstainers.44
There is also heterogeneity in nicotine dependence
among smokers. During adolescence, different
smoking trajectories are correlated with different
levels of nicotine dependence. Adolescents whose
smoking rates rapidly escalate tend to develop
stronger nicotine dependence, with 95% becoming
dependent (as defined by the International Statistical
Classification of Diseases and Related Health Problems or ICD). In contrast, only 12% of non-progressing, low-intensity adolescent smokers become
nicotine dependent, whereas 79% of both slow and
moderate smoking escalators become dependent.30
Similarly, by early adulthood, 51% of early stable
smokers meet the FTND-defined criteria for nicotine
dependence, compared to 26% of late stable smokers
and 5% of low-level smokers.47 However, individual
smokers with different trajectories during adolescence might eventually reach similar levels of
nicotine dependence by the time they reach
adulthood.35
Individual smokers markedly differ in the trajectory
of smoking, rate of smoking, relapse timing, withdrawal and nicotine dependence. The mechanisms of
nicotine dependence need to explain the reasons for
this variation.
655
Pre-existing conditions for smoking progression
The individual variation in nicotine dependence
raises the question as to what may be unique about
those who are more vulnerable to nicotine dependence. One way of viewing this variation is that it
simply reflects the amount of nicotine exposure. That
is, the more one is exposed to nicotine, the more
likely they will develop dependence. According to
this explanation, any person who is exposed to a
sufficient amount of nicotine will develop dependence. However, this view cannot adequately explain
why chippers maintain smoking without developing
dependence and why only one-third of novice light
smokers increase their level of smoking.
Evidence suggests that those susceptible to heavy
smoking are not simply individuals who happened to
be exposed to large amounts of nicotine. Longitudinal
studies have shown that individuals with higher
levels of novelty/sensation seeking tend to have a
greater susceptibility to smoking and nicotine dependence.33,48–55 Novelty seeking is ‘a heritable tendency
toward intense exhilaration or excitement in response
to novel stimuli or cues for potential rewards or
potential relief of punishment, leading to frequent
exploratory activity in pursuit of potential rewards’.56
Sensation seeking is ‘a trait by which an individual
seeks varied, novel, complex and intense sensations
and experiences and is willing to take physical,
social, legal and financial risks for the sake of such
experiences’.57 These two scales are highly correlated.58 If a cigarette is perceived as a novel object
during adolescence, then novelty/sensation seeking
could easily manifest itself as initiation of smoking.
However, because novelty seeking might not necessaMolecular Psychiatry
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N Hiroi and D Scott
656
rily be a predictor for sustained smoking,55 this
behavioral trait may not influence all aspects of
nicotine dependence.
Novelty seeking predicts the onset of disruptive
behaviors, such as oppositional defiant disorder and
conduct disorder. These behavioral traits also are
associated with susceptibility to nicotine dependence.52 The presence of conduct disorder in childhood and adolescence is a strong predictor of daily
smoking and DSM-defined nicotine dependence.55,59–61
Such traits are likely to contribute to poor choices
despite negative future consequences (that is, behavioral choice-melioration).18
Novelty seeking also predicts the future incidence
of attention-deficit hyperactivity disorder (ADHD).52
Longitudinal studies have shown that ADHD predicts
progression to regular smoking and nicotine dependence.59,62–67 ADHD symptoms of inattention68,69
and hyperactivity/impulsivity60 are associated with
smoking and nicotine dependence, although these
two classes of symptoms might contribute to nicotine
dependence during different developmental periods.70 Because nicotine improves attention in
smokers with ADHD71 and cognitive/behavioral inhibition in non-smoking adolescents with ADHD,72–76
negative reinforcement might underlie nicotine
dependence in smokers with ADHD.68
Pre-existing conditions that may lead a person to
smoke not only include motivational and behavioral
traits, but also include more pathological conditions.
Although smoking withdrawal might cause anxiety
and depression-like symptoms, the opposite can
also be true. The presence of depressive disorders
and some forms of anxiety disorders may predict
the likelihood that a person will initiate smoking
and develop dependence.77,78 However, it is unclear if
there is a causal relationship between depressed
mood or anxiety and various aspects of nicotine
dependence.79
Genetic origin of variation in nicotine dependence
and pre-existing traits
Multiple factors likely contribute to individual variation in pre-existing behavioral traits and susceptibility and resilience to nicotine dependence.
Environmental factors are thought to contribute to
variation in nicotine dependence. However, the
precise identification of the environmental factors is
difficult, and such factors might not exert as robust an
influence as genetic factors.80 Twin studies have
consistently shown that heritable factors account for
a substantial amount of the variance in susceptibility
to smoking initiation, quantity, persistence, regular
use, dependence and cessation.81–87 However, heritability estimates vary depending upon the particular
aspect of smoking and the definition of dependence.
Different genetic factors appear to affect smoking
initiation, regular use and nicotine dependence
(as defined by the FTND) as well as DSM-IV-defined
nicotine withdrawal.80,88
Molecular Psychiatry
Although it is clear that there is a genetic influence
on nicotine dependence, the exact genes that contribute to dependence have not been clearly delineated.
Genome-wide linkage analyses have implicated
almost all chromosomes in various aspects of smoking. However, the involvement of each locus has not
been consistently demonstrated. Several factors are
thought to contribute to this problem. First, studies
have used different criteria, including the Fagerström
Tolerance Questionnaire, number of cigarettes
smoked per day, maximum number of cigarettes
smoked in any 24-h period, age at which the first
cigarette was smoked, FTND, cessation, frequency,
withdrawal severity and DSM. These different measures have led to the identification of linkages to
different chromosomes within the same population
sample. For example, linkage was found on chromosome 5 when smoking quantity was used as a
criterion, chromosome 6 with FTND, chromosome 7
with a DSM-based continuous scale, chromosome 8
with a dichotomous DSM classification, chromosome
16 with cessation and chromosome 19 with smoking
frequency.89 Second, different population bases show
different linkage loci even when the same measures
are used. Linkage with FTND scales are located
on chromosomes 9, 10, 11 and 13 in an AfricanAmerican sample but on chromosomes 4 and 9 in a
sample from Americans of European origin.90,91
A genome-wide association study found that alleles
in the neurexin 1 and the b3 nicotinic receptor genes
may be associated with FTND-defined nicotine
dependence.92 However, another genome-wide association study, examining far more SNPs, identified a
different set of genes that were associated with both
nicotine and other substance dependence.93 By contrast, a number of genes have been found to be
consistently associated with smoking cessation in
three different sample populations.94 Some of these
genes encode proteins that are involved in cell
adhesion and cell signaling.
Association studies examining individual candidate genes have uncovered variants of many monoamine-related genes that might contribute to smoking
initiation, persistence, cessation, consumption and
therapeutic response (see refs. 95–99 for reviews).
Associations between specific genes and variation
in behavioral traits have also been examined. Polymorphisms in the dopamine D4 receptor have been
implicated in novelty/sensation seeking, and polymorphisms in the serotonin transporter have been
linked to anxiety-related traits.100 Although some
studies do not support the association between D4
receptor alleles and novelty/sensation seeking, the
association is more consistent in subjects under 35
years old.101 Like genes associated with nicotine dependence, variants in monoamine-related
genes have been reported to be associated with
susceptibility to ADHD. These genes include the
dopamine transporter, dopamine D4 receptor, tryptophan hydroxylase 2, phenylethanolamine N-methyltransferase, adrenergic b2 receptor and monoamine
Constitutional mechanisms of nicotine dependence
N Hiroi and D Scott
oxidase A (MAOA).102 The serotonin receptor 2A,
adrenergic a2A receptor, adrenergic a2C receptor,
phenylethanolamine N-methyltransferase, catecholO-methyltransferase, serotonin transporter and
MAOA have been reported to be associated with
conduct disorder, oppositional defiant disorder or
antisocial behavior.103–105
In some cases, human association studies are
difficult to replicate. Many reasons are likely to
contribute to this problem, but the following are
some of the potential reasons relevant to the gene side
of association. First, the impact of each gene on
nicotine dependence or novelty/sensation seeking
is thought to be small. A meta-analysis could
potentially reveal an overall trend in a large number
of studies but might overestimate the impact of a
gene allele on smoking and associated behavioral traits. This is because meta-analyses are affected
by publication bias; more studies with positive
associations are published than those with no
association and more significant measures are
reported than those that are less or not significant even within individual studies.106 Second,
reported gene alleles might not be the genuine
source of phenotypic variation. Rather, allelic
association with a phenotype could reflect the
impact of other gene alleles that are linked to the
reported gene alleles. Third, the phenotypic expression of a single gene allele may be influenced
by alleles in other genes that differ in different ethnic
groups.
A problem at the phenotypic side of correlation is
that the scales used to categorize phenotypes might
not match genetic influences perfectly. For example,
categorizing nicotine dependence and pre-existing
behavioral traits using self-reported questionnaires
may not fit well with the way single genes influence
behavior. If a specific gene affects only a specific
element/aspect of nicotine dependence or preexisting behavioral traits, the overall association
between gene polymorphisms and traits could fail
to reach significance. Another complicating factor
is that variance of each motive for smoking is large
and thus each smoker might have a unique set of
motives for smoking.18 Moreover, various subscales
of novelty/sensation seeking do not necessarily
correlate with each other, and thus what is globally
defined as novelty/sensation seeking might contain
more than one psychological process.107 In mice,
behaviors in various behavioral tasks that involve
novel elements do not necessarily co-vary with
genetic background, suggesting a complex influence
of genetic factors on behaviors in response to novel
stimuli.108,109
Different elements of nicotine dependence and
behavioral traits might have non-identical, albeit
partially overlapping, genetic bases. The reproducibility of human association studies might be improved if they focused on associations between single
genes and distinct elements of nicotine dependence
and behavioral traits.
Phenotypic refinement: translational models of
nicotine dependence
657
Experimental animals provide a complementary
approach to precisely characterize genetic mechanisms of nicotine dependence independently of the
subjective assessment of smokers. The ultimate value
of rodent models lies in their ability to predict
nicotine dependence in humans, but the translation
of rodent data into human studies and vice versa must
be done cautiously. Caution must be used when
translating animal data to humans, particularly in
terms of highly subjective processes such as craving,
urge and pleasure, as there are no unequivocal,
objective ways to measure these psychological
processes in rodents.
Another limitation of rodent models of nicotine
dependence is that they are not designed to mimic the
entire process of nicotine dependence. Ironically, this
limitation may be advantageous in identifying behavioral elements that might be affected by molecules.
Models that focus on specific, distinct aspects of
nicotine dependence are advantageous when testing
underlying mechanisms. A single molecule may not
contribute equally to all elements of nicotine dependence, and distinct molecules may affect different
elements of nicotine dependence. Feature-specific
models are less likely to be contaminated by mechanistically heterogeneous processes and thus will allow
us to tease apart distinct mechanisms.
Three paradigms are widely used to determine the
role of molecules in nicotine dependence using
knockout (KO) mice: self-administration, conditioned
place preference and withdrawal. Because mice
cannot reliably or robustly establish intravenous
self-administration, the oral route has been used to
evaluate how much nicotine a mouse consumes.
Nicotine consumption has a clear counterpart in
smokers. Each smoker has a unique optimal blood
nicotine concentration.110–112 The amount of nicotine
taken in during smoking is the best predictor of
relapse in humans.15 ‘Tolerance’, as defined in the
WISDM-68 inventory, essentially characterizes how
heavily one consumes nicotine.18
Cue reactivity or cue exposure-associative
processes have been examined using the placeconditioning paradigm in mice. This Pavlovian conditioning
procedure
assesses
an
animal’s
approach, termed conditioned place preference
(CPP), toward sensory cues that are associated with
a substance that has dependence potential.113–115 Cue
reactivity is a prominent element of nicotine dependence in humans. Non-nicotine cues that are associated with smoking (for example, smoking
paraphernalia and smoking-association sensory cues
and context) contribute to relapse in ex-smokers and
to persistent smoking in smokers.116,117 Cue reactivity
correlates with the amount of smoking during early,
developing stages of nicotine dependence, as well as
in late stages of dependence.18 Cue reactivity is
established through Pavlovian conditioning.118 When
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N Hiroi and D Scott
658
neutral cues are paired with smoking under Pavlovian
experimental conditions, new sensory cues acquire
the ability to induce urge within only a few trials.119
Individuals differ in the way they react to these cues
during relapses.120
In humans, withdrawal symptoms of nicotine
dependence are divided into two major classes:
somatic and affective withdrawal. During abstinence,
smokers experience somatic symptoms, including
insomnia, difficulty concentrating, restlessness,
decreased heart rate, increased appetite and weight
gain.121 Affective withdrawal includes feelings of
depression, heightened anxiety, increased irritability
or anger and frustration.122,123 Smokers report that
avoidance of withdrawal is one of the subjective
motives for heavy smoking and relapse (that is,
negative reinforcement).18 Because a reliable method
to demonstrate affective withdrawal signs has not
been developed in mice until recently,124,125 somatic
signs have been used widely to evaluate withdrawal
in mice. Somatic withdrawal symptoms in mice
include paw tremor, head shaking, scratching, body
tremor, teeth chatter, ptosis, backing and jumping.
Other possible contributors to smoking are difficult
to model in experimental animals. For example, it is
not feasible to establish that a mouse considers
nicotine to be a ‘friend’ (affiliative attachment) or
makes decisions in light of future negative consequences (behavioral choice-melioration). The latter is
not a simple choice between a drug and other
reinforcers but reflects a complex cognitive process
that compares the immediate value of smoking with
future reinforcers in the presence of other reinforcers
and constraints on cigarettes. Determining whether
animals feel that they have lost control over their
behavior (loss of control) or whether they act without
being aware (automaticity) is not feasible. Similarly,
although craving may be an underlying motive, it is
not possible to unequivocally attribute the cause of
behavioral alterations to this subjective feeling in
experimental animals.
A systematic comparison between preclinical and
clinical studies is difficult for several reasons. Rodent
models focus on specific elements of nicotine dependence, whereas human association studies use more
global definitions of nicotine dependence. A future
challenge is to increase the translationability of
animal and human studies by focusing on specific
elements of human nicotine dependence, as exemplified in the WISDM-68. For example, examining the
association between subjective feelings and activities
of specific brain regions during exposure to smokingrelated cues in humans with specific genetic
alleles would provide a human equivalent of rodent
cue reactivity, as measured in CPP and withdrawalassociated conditioned place aversion (CPA).
Moreover, a better understanding of the functional
consequences of gene alleles (for example, expression
and activity levels of proteins) in humans would be
essential for comparing mouse KO studies to human
studies.
Molecular Psychiatry
Multiple molecules for distinct aspects of nicotine
dependence
Complex behaviors, including dependence-related
behaviors, are thought to be influenced by multiple
genes. Rodent quantitative trait loci for complex
behavioral traits generally suggest that the average
percentage of total phenotypic variance that is
explained by each sequence variant is 5% or less.126
Such a small effect is difficult—if not impossible—to
detect.
The constitutive, complete deletion of genes using
KO mice provides a unique opportunity to assess the
maximum potential impact of a single gene on
behavior. Another advantage of constitutive genetic
manipulation is that it is expected to induce developmental and compensatory alterations. From the
susceptibility perspective, secondary alterations
originating from a single gene deletion do not limit
interpretation and should not be considered a
contaminant, because any molecular alteration would
be expected to have some effects on related molecules
and developmental processes in the human brains, as
well as in the mouse brains.127–130 Developmental
alterations cannot be recapitulated by pharmacological means that are applied to adult or even
adolescent rodents.
Evidence suggests that both shared and distinct
molecular bases exist for elements of nicotine dependence. Both nicotine CPP and somatic withdrawal are
reduced in mice that are defective for preproenkephalin131 or the m-opioid receptor.132 Other molecules
influence some but not all models of nicotine
dependence. Genetic deletion of the cannabinoid
CB1 receptor or adenosine A2A receptor attenuates
nicotine CPP but not somatic withdrawal signs.133,134
Mice deficient for the nicotinic acetylcholine
receptor subtype b2 do not show withdrawal-induced
CPA, but are normal in somatic withdrawal signs;
a5 subunit KO mice show the opposite pattern of
phenotypes.124 As the impact of single genes
on elements of nicotine dependence would be
difficult to detect in a model that incorporates many
aspects of dependence symptoms, rodent models
that focus on specific elements of nicotine dependence likely are the most effective models for
understanding the genetic determinants of nicotine
dependence.
Distinct molecular mechanisms might also exist for
different phases of exposure to nicotine. Mice
deficient for the transcription factor FosB are impaired in behavioral alterations that are induced by
repeated or prolonged exposure to nicotine in
voluntary nicotine intake, nicotine CPP and nicotine-induced motor suppression, but these mice
respond normally to acute single nicotine exposure.109 Concomitant with the behavioral effects of
FosB deletion, FosB proteins increase in the brain of
wild-type mice following repeated injections of
nicotine, but not after a single, acute nicotine
exposure.109
Constitutional mechanisms of nicotine dependence
N Hiroi and D Scott
Gene variation is likely to influence nicotine
dependence through many molecular pathways. First,
molecules may influence nicotine dependence
through direct involvement in signaling cascades
activated by nicotine (Figure 1, circles). The nicotinic
acetylcholine receptor is one such example (Figure 1,
green circle).124,135–137 Alternatively, even if they are
not part of a cascade that is directly activated by
nicotine, other molecules still could influence nicotine dependence either by influencing the molecular
cascades activated by nicotine (Figure 1, triangle) or
independently of the nicotine-activated cascades
(Figure 1, star). Specific examples of these factors
are discussed below.
The pleiotropic action of these genes raises the
question of whether molecules exist that are selectively involved in the development of nicotine
dependence. Lack of behavioral selectivity does not
necessarily indicate that the dependence phenotype
in a KO mouse is a contaminant of some general
behavioral abnormality. Instead, such lack of behavioral selectivity could provide a means to explore a
causal relationship between pre-existing behavioral
traits and substance dependence. In more general
terms, it is difficult to assume that the organisms have
evolved, during their evolutionary history, to express
molecules that are selectively designed to respond to
addictive substances.
Pleiotropy of nicotine dependence and pre-existing
behavioral traits
Indirect influence of molecular variation on
nicotine dependence
Why is there an association between nicotine dependence and pre-existing traits? One plausible biological explanation is that some molecules commonly
affect both nicotine dependence and pre-existing
behavioral traits.138 This phenomenon, called pleiotropy, could be one of the underlying mechanisms of
nicotine dependence. Although human association
studies have not provided genes that clearly exert
pleiotropic effects on nicotine dependence and preexisting traits, animal studies have provided a few
examples.
FosB is induced along the mesencephalic dopaminergic systems and other limbic brain regions by
nicotine and other addictive substances in rodents
(see Figure 1, red circle).109,139 FosB is also induced in
limbic and other brain regions by external stimuli that
evoke stress and alter affect in rodents.140,141 FosB KO
mice are impaired in nicotine intake and CPP, and
also are abnormal in behavioral traits related to tasks
in which stress levels are considered high.109 Another
transcription factor, cAMP-response element binding
protein (CREB), has been implicated in behaviors
relevant to learning, depression and anxiety, as well
as nicotine dependence.142–144 These transcription
factors could have a common influence on elements
of nicotine dependence and pre-existing behavioral
traits.
Constitutive levels of molecules and their activities
that are not regulated by nicotine nonetheless could
influence smoking and relapses (Figure 1, triangle or
star). Nicotine at physiological concentrations does
not reliably alter the activity of MAOA, but the
constitutive level of MAOA nevertheless might affect
smoking in humans and behavioral responses to
nicotine in mice.
The activity levels of MAOA vary widely among
individuals. In cultured skin fibroblasts, individual
responses range from extremely low, almost undetectable, levels to levels 30-fold higher.145–149 Differences in MAOA activity of up to seven-fold have been
noted in postmortem tissues of the human frontal
cortex.149 These individual differences in MAOA
activity exist at ages before smoking usually
starts.145,149,150
The genetic origin for variance in MAOA activities
is poorly understood. High levels of MAOA activities
are associated with either a T allele, compared to a C
allele, at position 1460 in exon 14 or with either 3.5
and 4 repeats, compared to other repeat numbers, at
the variable number tandem repeat in the promoter
region of the human MAOA gene.146,151–153 However,
the impact of these polymorphisms on MAOA
activity is weak and no known single alleles or their
haplotypes adequately account for the large interindividual differences in basal MAOA activity.146,149,151–153 A PET study also demonstrated that
MAOA alleles are not strongly correlated with MAOA
activity in vivo.154
The weak impact of genetic alleles on MAOA
activities might be one of the reasons why association
studies of human MAOA and nicotine dependence
have not been consistent. Some studies have shown a
positive association between the high-activity alleles
and an increased risk of nicotine dependence,155–157
but other studies have failed to confirm this association.158,159 These studies have many procedural
differences, including the gender, age and other
characteristics of the sample population and the
definition of dependence, which make direct comparisons difficult.
Figure 1 Possible effects of molecular variation on the
development of nicotine dependence. The degree of
nicotine dependence may be determined by molecular
variation in the cascades that are activated directly (green
circle) or indirectly (gray and red circles) by nicotine, by
molecular variation that indirectly affects nicotine-regulated molecular cascades (triangle), or by variation in
molecules that influence the degree of dependence independently of these cascades (star).
659
Molecular Psychiatry
Constitutional mechanisms of nicotine dependence
N Hiroi and D Scott
660
Constitutive Maoa-deficient mice are impaired in
nicotine intake and nicotine CPP.160 This effect cannot
be generalized to the isoenzyme MAOB in mice, as
constitutive Maob-deficient mice exhibit normal
nicotine intake.161 Although species differences
should be taken into account in generalizing this
finding to humans,162 constitutively high and low
MAOA activities might confer susceptibility and
resilience, respectively, to levels of nicotine intake
and cue reactivity in smokers.
Although it still is possible that some unidentified
alleles within MAOA or in other genes influence
MAOA activities, non-genetic, environmental factors
also might alter MAOA activities. Tobacco smoke
contains chemicals that inhibit MAOA,163–166 and
brain MAOA levels are reduced in smokers.167
Simultaneous, irreversible inhibition of both MAOA
and MAOB by non-selective MAOA/B inhibitors (for
example, tranylcypromine or phenelzine) increases
nicotine self-administration in rats.168,169 Clorgyline,
an irreversible MAOA inhibitor, also promotes nicotine self-administration in rats.169,170 These studies in
rats suggest that MAO activities have an inhibitory
effect on nicotine intake. However, this possibility is
inconsistent with the report that the MAOA inhibitor
moclobemide does not increase smoking and rather
has some subjective beneficial effects on reducing
smoking.171 Similarly, none of the MAOB inhibitors
tested so far lead to increased smoking; rather, they
result in reduced smoking and increased cessation
rates.172–174
These studies with Maoa KO mice and pharmacological inhibition of MAOA in rats should not be
compared directly. First, the developmental impact of
constitutive deletion of MAOA expression on the
behavioral effects of nicotine likely occurs through
processes different from acute or semi-chronic
pharmacological inhibition of MAOA during adulthood. In fact, the constitutive inactivation of MAOA
and the pharmacological inhibition of MAOA by
clorgyline induce many different and even opposite
effects on various behaviors in mice. For example,
acoustic startle response is reduced in Maoa KO mice,
compared to wild-type mice, but is either unaffected
or slightly potentiated by clorgyline in a dosedependent manner in mice.175 Second, many MAO
inhibitors lack selectivity and exert a myriad of
effects. It is unclear what actions of these drugs
influence nicotine-regulated behaviors in rats. The
non-selective MAOA/B inhibitor tranylcypromine
inhibits CYP2A6, the principle enzyme responsible
for metabolizing nicotine into cotinine.176 Tranylcypromine and clorgyline inhibit monoamine uptake in
various brain regions.177–180 This action of these
inhibitors is likely to contribute to the potentiation
of nicotine self-administration, as a dopamine transporter inhibitor has been shown to enhance nicotineinduced behavior.181 Clorgyline also binds to the
s-opioid receptor.182–184 This is problematic because
the s-opioid receptor is involved in some behavioral
actions of nicotine.185
Molecular Psychiatry
Constitutional basis for nicotine dependence
Exposure to nicotine does not necessarily result in
smoking. Even after smoking has become established,
individuals exhibit varying degrees of nicotine
dependence. Individuals who develop dependence
are not necessarily those who happened to be exposed
to a large amount of nicotine for a long period of time;
those who develop nicotine dependence often exhibit
pre-existing traits. Human and mouse studies suggest
that molecular variation provides a basis for both
pre-existing behavioral traits and susceptibility and
resilience to elements of nicotine dependence.
One way to understand the complex picture of
nicotine dependence is to hypothesize that nicotine
acts to direct pre-existing behavioral traits toward
nicotine or to provide some beneficial effects for the
host (Figure 2). According to this constitutional view,
nicotine dependence is determined in part by preexisting molecular variation that provides a basis for
quantitative variance in behavioral traits. However,
pre-existing traits are unlikely to be all-or-none
determinants for nicotine dependence; it is more
probable that they probabilistically increase the
chances of developing nicotine dependence.
Pre-existing traits may confer susceptibility through
various modalities. Smoking may become a target of
some pre-existing behavioral traits (see Figure 2,
redirected target mode). Compared to other age
groups, adolescents tend to seek novel sensations
and cigarettes and smoking might be perceived as
novel. A pre-existing automatic and stereotypical
behavioral pattern also might be directed toward
smoking. A possible gene that contributes to behavioral choice-melioration, a condition in which
smokers are unwilling to give up cigarettes even
when faced with negative consequences (for example,
illness), is an allele linked to the dopamine D2
receptor. Healthy volunteers with the A1 allele are
impaired in their general ability to learn from negative
consequences.186 The A1 allele linked to the dopamine D2 receptor gene is associated with current
smoking, as well.96
In other instances, nicotine may be perceived as
therapeutic for an individual’s pre-existing motivational or affective defects (see Figure 2, defect repair
mode). Nicotine may induce this effect by normalizing negative affective states. Alternatively, nicotine
may induce some subjective effects that counteract
negative affective states. Affective abnormalities such
as depressive symptoms, high levels of anxiety and
altered stress reactivity exist before smoking starts in
a subpopulation of smokers.77 The ability of antidepressants to reduce smoking and aid smoking
cessation187 is consistent with this mode. Alternatively, molecular variation may independently influence pre-existing behavioral traits and nicotine
dependence (see Figure 2, independent influence).79
The plasticity-based dependence model posits that
addictive substances induce behavioral dependence
(that is, addiction) because they cause pathologically
Constitutional mechanisms of nicotine dependence
N Hiroi and D Scott
661
Figure 2 Three possible modes of the influence of molecular variation on nicotine dependence. Molecular variation, which
involves altered levels or function of a molecule, is caused by genetic variants or non-genetic factors such as developmental
anomalies or environmental factors. Molecular variation could increase tendencies toward novelty seeking affiliative
attachment, loss of control, cue reactivity, decision-making deficits and automaticity. After exposure, nicotine could serve as
a new target for these traits (re-directed target mode). Alternatively, molecular variation could set a basal tone of affect (for
example, negative affect, depression, anxiety and stress vulnerability). Nicotine then could provide a ‘therapeutic’ or ‘repair’
function and may potentiate the intensity of negative reinforcement (defect repair mode). Molecular variation also could
independently influence behavioral traits and susceptibility or resilience to nicotine dependence (shared, independent
influence).
persistent molecular and cellular alterations that, in a
normal form, serve to establish long-term associative
memories.188 Rodent studies have provided an ample
body of evidence that addictive substances, including
nicotine, modulate many molecules that normally
subserve learning-related events in the rodent
brain.188–190 The plasticity-based hypothesis of addiction/dependence provides a plausible explanation as
to why nicotine consolidates cue reactivity or promotes self-administration, but it does not explain why
such processes widely differ among individuals.
The ultimate evidence would be to demonstrate
that such plastic alterations actually occur in the
brains of heavy smokers, but not in chippers or nonsmokers, as a causal event for the development of
nicotine dependence. Needless to say, it is technically
difficult to demonstrate drug-induced molecular
alterations as a causal event in humans. Demonstration of altered levels or activities of molecules in the
postmortem brains of current and former smokers,
compared to non-smokers, could suggest that such
alterations are induced by smoking and are longlasting. However, equally plausible is an alternative
interpretation that pre-existing molecular levels or
activities increase the probability of initiating smoking. Levels or activities of molecules that are different
in smokers than in former smokers and non-smokers
could be equally interpreted as a suggestion that
former smokers were able to quit because they lacked
the pre-existing molecular substrates for addiction or
that nicotine only transiently induces these molecular
alterations in former smokers. Functional imaging
might provide an alternative, reliable way to obtain
correlative evidence that altered responsiveness of
regions in the brain predates or follows the initiation
of drug exposure in both humans and experimental
animals.191
Setting the dividing line between smokers and
non-smokers is another difficult issue in determining
the molecular correlates of nicotine dependence in
humans. Artificially drawing a line between smokers
and non-smokers would create a barrier to revealing
the underlying mechanisms. ‘Smokers’ may include
heterogeneous samples, if distinct molecular substrates exist for heavy smokers, moderate smokers and
chippers. Similarly, it is important to consider that
non-smokers might include a combination of individuals with and without susceptibility factors. Nicotine dependence develops only if nicotine is available
and one initiates smoking. Even if one is burdened
with many susceptibility factors, nicotine dependence will not develop unless smoking is initiated.
‘Non-smokers’ might be heterogeneous and may
not serve as a reliable control. Unless initial exposure to nicotine is equal among smokers and
non-smokers, the molecular basis for susceptibility
to nicotine dependence will be difficult to identify.
This point is well illustrated by the seminal study
Molecular Psychiatry
Constitutional mechanisms of nicotine dependence
N Hiroi and D Scott
662
that demonstrated that the genetic contribution to
tobacco consumption was more prominently revealed
when historical social restrictions in Sweden changed
to allow more women to smoke.192
One possible difficulty associated with the constitutional hypothesis is that cue reactivity or cue
exposure-associative processes occur only after
exposure to nicotine and cues, and therefore, these
processes cannot be a pre-existing trait. However,
pre-existing molecular variation could potentially
influence the response to nicotine, the general
capability to form cue association or both. Consistent
with this possibility, smokers with the A1 allele of the
dopamine D2 receptor exhibit stronger cue-induced
cravings than those without the allele, even though
these two genotype groups are indistinguishable in
the number of cigarettes smoked per day, years of
smoking and levels of nicotine dependence.193 This
study suggests that pre-existing molecular variation
could selectively affect the capability of cue reactivity
without altering the direct effects of nicotine. Moreover, inbred rat strains that differ in susceptibility to
behavioral alterations induced by nicotine exhibit
differences in basal levels of many molecules in the
brain, suggesting that pre-existing molecular variation
could alter the behavioral effects of nicotine.194–196
Alternatively, both pre-existing molecular variation
and induced alterations might determine the ultimate
degree of dependence.
Individual variations in the susceptibility to dependence and pre-existing traits are not unique to
nicotine dependence and are also seen with stimulants, opiates and alcohol dependence.138,197–200 However, any given molecule could exert different effects
in response to diverse addictive substances. For
example, the constitutive absence of FosB or CREB
renders mice more sensitive to cocaine, but less
sensitive to nicotine in the place-conditioning paradigm.109,143,201,202
A future challenge is to evaluate how each
molecule contributes to pre-existing traits and the
susceptibility and resilience to substance dependence. Such an endeavor will hopefully result in
the identification of appropriate molecular targets for
medication to more effectively prevent substance
dependence disorders.
Acknowledgments
This article is dedicated to the memory of T Klein,
who inspired the first author’s research direction. We
thank Drs TB Baker and ME Piper for sharing
unpublished data and Drs Justin Cho and Soh
Agatsuma for their critical comments on an early
draft of this article. The preparation of this article was
supported by Grants R01 DA013232 and R01
DA024330 from the National Institute on Drug Abuse
(NIH). The content is solely the responsibility of the
authors and does not necessarily represent the official
views of the National Institute on Drug Abuse or the
National Institutes of Health.
Molecular Psychiatry
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