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Smokingtoself-medicateattentionalandemotionaldysfunctions

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Review

Smoking to self-medicate attentional and emotionaldysfunctions

Jean-G. Gehricke, Sandra E. Loughlin, Carol K. Whalen, Steven G. Potkin,James H. Fallon, Larry D. Jamner, James D. Belluzzi, Frances M. Leslie

Received 3 April 2007; accepted 3 August 2007

Individuals with attentional and emotional dysfunctions are most at risk for smoking initiation and subsequentnicotine addiction. This article presents converging findings from human behavioral research, brain imaging, andbasic neuroscience on smoking as self-medication for attentional and emotional dysfunctions. Nicotine and othertobacco constituents have significant effects on neural circuitry underlying the regulation of attention and affect. Age,sex, early environment, and exposure to other drugs have been identified as important factors that moderate both theeffects of nicotine on brain circuitry and behavior and the risk for smoking initiation. Findings also suggest that theeffects of smoking differ depending on whether smoking is used to regulate attention or affect. Individual differencesin the reinforcement processes underlying tobacco use have implications for the development of tailored smokingcessation programs and prevention strategies that include early treatment of attentional and emotional dysfunctions.

Introduction

Smoking prevalence rates in the general population

have shown a steady decline in recent years because

of increased efforts of anti-smoking campaigns and

smoking bans in many states. However, overall

smoking prevalence rates may have reached a

plateau. Some studies suggest that individuals with

attentional and emotional dysfunctions continue to

smoke at high rates and are less successful with

smoking cessation (Acierno et al., 2000; Beckham,

1999; Beckham et al., 1997; Breslau, 1995; Breslau,

Davis, & Schultz, 2003; de Leon, Diaz, Rogers,

Browne, & Dinsmore, 2002; Dierker, Avenevoli,

Merikangas, Flaherty, & Stolar, 2001; Glassman

et al., 1990; Glassman et al., 1988; Kendler et al.,

1993; Kollins, McClernon, & Fuemmeler, 2005;

Marmorstein & Iacono, 2003; O. F. Pomerleau,

Downey, Stelson, & Pomerleau, 1995; Rohde,

Kahler, Lewinsohn, & Brown, 2004; Sonntag,

Wittchen, Hofler, Kessler, & Stein, 2000;

Upadhyaya, Brady, Wharton, & Liao, 2003). With

the majority of smokers beginning to smoke by age

18 (Johnston, O’Malley, & Bachman, 1998), adoles-

cents with attentional and emotional dysfunctions

also have a higher risk for smoking compared with

those without such problems (Stevens, Colwell,

Smith, Robinson, & McMillan, 2005; J. W. Weiss

et al., 2005; Whalen, Jamner, Henker, & Delfino,

2001; Whalen, Jamner, Henker, Delfino, & Lozano,

2002). Adolescents may self-medicate with tobacco

to regulate negative affect associated with attentional

and emotional dysfunctions (Whalen et al., 2001;

Whalen et al., 2002). The notion that individuals with

specific deficits smoke for purposes of self-

medication (Khantzian, 1997; C. S. Pomerleau,

Marks, & Pomerleau, 2000) is supported by evidence

that nicotine treatment can attenuate dysfunction in

depression (Haro & Drucker-Colin, 2004a, 2004b)

ISSN 1462-2203 print/ISSN 1469-994X online # 2007 Society for Research on Nicotine and Tobacco

DOI: 10.1080/14622200701685039

Jean-G. Gehricke, Ph.D., Steven G. Potkin, M.D., Department of

Psychiatry and Human Behavior; Sandra E. Loughlin, Ph.D., Frances

M. Leslie, Ph.D., Department of Pharmacology; James H. Fallon,

Ph.D., Department of Anatomy and Neurobiology; Carol K. Whalen,

Ph.D., Larry D. Jamner, Ph.D., Department of Psychology and Social

Behavior, University of California, Irvine, Irvine, CA.

Correspondence: Jean-G. Gehricke, Ph.D., Department of

Psychiatry and Human Behavior, D402 Medical Sciences I, Irvine,

CA 92697-1675, USA. Tel: +1 (949) 824-1834; Fax: +1 (949) 824-1811;

E-mail: jgehrick@uci.edu

Nicotine & Tobacco Research Volume 9, Supplement 4 (December 2007) S523–S536

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and attention-deficit/hyperactivity disorder (ADHD;

Levin, Conners, Silva, Canu, & March, 2001).

Individuals with deficits in attention may be

self-medicating with nicotine to improve their atten-

tion (Bekker, Bocker, Van Hunsel, van den Berg, &

Kenemans, 2005; Gehricke, Whalen, Jamner, Wigal,

& Steinhoff, 2006). In contrast, individuals with

affective dysfunctions may be self-medicating to

regulate their emotions (Haro & Drucker-Colin,

2004b).

This review integrates findings from the

Transdisciplinary Tobacco Use Research Center of

the University of California, Irvine (UCI TTURC) in

the context of the existing literature on links between

smoking and attentional and emotional dysfunction.

Attentional and emotional dysfunctions are asso-

ciated with externalizing and internalizing behavior

problems. Externalizing behavior problems include

ADHD, oppositional defiant disorder (ODD), and

conduct disorder (CD). Internalizing behavior pro-

blems, on the other hand, include major depression,

anxiety disorders, and their corresponding subclini-

cal manifestations of negative affect. Externalizing

and internalizing disorders frequently co-occur

(Busch et al., 2002; Jensen et al., 2001; Jensen,

Martin, & Cantwell, 1997; McGough et al., 2005;

Kendall, Brady Verduin, 2001; Kessler et al., 2006),

and such comorbidities may increase the risk for

smoking (Ernst et al., 2006; Marmorstein & Iacono,

2003; Milberger, Biederman, Faraone, Chen, &

Jones, 1997). However, the reinforcing effects of

smoking in externalizing and internalizing disorders

may vary depending on the predominance of atten-

tional or emotional dysfunctions.

We propose a conceptual model (see Figure 1) in

which adolescents with attentional and emotional

dysfunctions may be especially vulnerable to smok-

ing initiation because of corticolimbic dysregulation.

Such dysregulation may, in turn, increase behavioral

drive and reduce behavioral inhibition and control.

The elevated risk of dependence and the greater

difficulty quitting may result, in part, from nicotine-

associated normalization of activity of corticolimbiccircuits that regulate attention and affect. Treatment

of these attentional and emotional dysfunctions and

the resulting normalization of corticolimbic circuits

may reduce the reinforcing effects of smoking and,

thus, may represent tailored smoking cessation

strategies. Such tailored smoking cessation strategies

also may be translated and applied to prevention

programs for at-risk youths (Jamner et al., 2003).

In addition to behavioral therapies and nicotine

replacement therapy, pharmacotherapies (e.g., sti-

mulants, antidepressants) may be used separately, or

in combination, depending on whether the person

smokes to enhance attention, to modulate moods, or

both (Figure 1).

This article reviews the literature relevant to the

notion that smoking may be used to self-medicate for

attentional and emotional dysfunctions. The focus

here is on the associations between smoking,

externalizing disorders, internalizing disorders, nega-

tive affect, and moderating variables such as devel-opmental factors and other tobacco constituents.

Smoking and externalizing behavior problems

Attention-deficit/hyperactivity disorder

ADHD is a frequent diagnosis for symptoms of

inattention, impulsivity, and hyperactivity in chil-

dren, and increasing evidence indicates that, for themajority of affected individuals, the disorder con-

tinues into adulthood (Biederman et al., 1992;

Biederman et al., 1993; Wender, Wolf, &

Wasserstein, 2001; Wilens & Dodson, 2004). It is

Figure 1. Mechanisms of initiation and dependence in individuals with attentional and emotional dysfunctions.

S524 SMOKING TO SELF-MEDICATE ATTENTIONAL AND EMOTIONAL DYSFUNCTIONS

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estimated that ADHD affects approximately 7% of

children (Barbaresi et al., 2004; Barbaresi et al., 2002)

and 2%–6% of adults (Kessler et al., 2006; M. Weiss

& Murray, 2003). In a landmark study, O. F.

Pomerleau and colleagues (1995) reported that adults

with ADHD have elevated smoking prevalence (40%)

and reduced quit rates (29%) compared with the

general population (26% and 48.5%, respectively).

Several other studies have documented relationships

between smoking and ADHD in adolescents

(Barkley et al., 1990; Chilcoat & Breslau, 1999;

Fergusson, Lynskey, & Horwood, 1996; Hartsough

& Lambert, 1987; Lambert & Hartsough, 1998;

Milberger et al., 1997; Riggs, Mikulich, Whitmore,

& Crowley, 1999). These relationships are likely to be

causal because an ADHD diagnosis implies that

some symptoms occur prior to age 7, which means

they always precede the onset of smoking. However,

contradictory findings exist on which aspect of

ADHD (i.e., inattention vs. hyperactivity-

impulsivity) shows stronger relationships with

smoking (Burke, Loeber, & Lahey, 2001; Molina,

Smith, & Pelham, 1999) and whether ADHD subtype

interacts with gender in predicting smoking (Galera,

Fombonne, Chastang, & Bouvard, 2005). A recent

study by Kollins and colleagues (2005), using a

nationally representative sample of young adults,

revealed that the number of retrospectively reported

ADHD symptoms was associated with lifetime

smoking, with each additional ADHD symptom

conferring additional risk for regular smoking.

Hyperactive-impulsive symptoms were found to be

a better predictor of lifetime smoking than were

inattentive symptoms.

Our UCI TTURC used a different approach to

examine links between ADHD and smoking.

Adolescents who were participating in a longitudinal

study of smoking trajectories reported their moods,

contexts, and behaviors (including smoking) twice

each waking hour, across two 4-day recording

intervals. Based on parent ratings, the 153 9th-grade

participants were divided into subgroups with low,

middle, or high levels of ADHD characteristics.

Findings revealed that ADHD characteristics were

associated with an increased risk of smoking and

alcohol consumption as well as elevated rates of

negative affect (Whalen et al., 2002). More specifi-

cally, adolescents with high, in contrast to low,

ADHD symptom levels recorded more negative and

fewer positive moods, lower alertness, and more

tobacco and alcohol use. These findings suggest that,

even at subclinical levels, ADHD characteristics are

associated with behavior patterns and contexts that

may promote unhealthy lifestyle behaviors and

vulnerability to nicotine dependence. A limitation

of the present study was that comorbid ODD and

CD symptoms were not examined.

ADHD comorbidities

Studies have shown that 38%–68% of adolescents

with diagnosed ADHD have comorbid ODD

(Barkley et al., 1991; Barkley et al., 1990;

Biederman, Newcorn, & Sprich, 1991; Fischer et al.,

1990), major depression (Busch et al., 2002; Kessler

et al., 2006), or anxiety disorders (Kessler et al.,

2006). ODD is characterized by a recurrent pattern

of negativism, defiance, disobedience, and hostility to

authority (American Psychiatric Association, 2000).

Although inconsistencies are found across studies,

strong evidence indicates that approximately half of

adolescents with ADHD meet criteria for CD

(Biederman et al., 1991; Jensen et al., 1997), which

is characterized by deceitfulness, rule violations, and

aggressive conduct (American Psychiatric

Association, 2000).

Milberger et al. (1997) examined the role of

comorbidities as predictors of smoking in a study

of 128 children with ADHD and 109 non-ADHD

controls who were assessed at baseline and 4-year

follow-up. Children and adolescents with ADHD

and comorbid mood, conduct, or anxiety disorders

were at higher risk for smoking than were those

without comorbid diagnoses. In particular, CD was

a predictor of smoking independent of ADHD. In

addition, Marmorstein and Iacono (2003) showed

that co-occurrence of CD and major depression in

adolescents was associated with greater nicotine

dependence compared with a single diagnosis of

either CD or major depression. Moreover, in a

longitudinal study (Ernst et al., 2006), aggression was

the strongest predictor of tobacco smoking and

marijuana use in adolescents with and without

ADHD, findings that support Milberger et al.’s

results. Thus negative affect associated with externa-

lizing behavior problems may contribute to an

increased risk for smoking. Unfortunately, little is

known about the reinforcing effects of smoking and

nicotine in ODD and CD. However, some studies

have examined the effects of nicotine on attentional

dysfunctions associated with ADHD.

The effects of nicotine in attentional dysfunctions

A number of research studies have examined the

direct effects of nicotine on ADHD symptoms and

have shown that acute nicotine administration

improves concentration and reduces clinical symp-

toms as well as shortens and homogenizes reaction

times in adult smokers and nonsmokers with ADHD

(Conners et al., 1996; Levin et al., 1996). In one

illustrative study, Levin and colleagues (2001)

randomly assigned adult nonsmokers with ADHD

to one of four 4-week treatment conditions (i.e.,

nicotine patch only, nicotine patch with a fixed dose

of 5-mg/day methylphenidate, methylphenidate only,

NICOTINE & TOBACCO RESEARCH S525

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and placebo). Acute administration of nicotine

improved clinical symptoms of ADHD and self-

reported depression and also increased consistency

on a continuous performance task, compared with

methylphenidate, nicotine in combination with

methylphenidate, or placebo. In contrast, during

the chronic treatment phase, no differences were

found in clinical symptom ratings, but the antide-

pressant effect of nicotine and the improved con-

sistency on the task were still evident. The authors

speculated that the lack of methylphenidate effects

on clinical symptoms may be attributable to a small

sample size and low methylphenidate doses. Nicotine

also has been found to improve response inhibition,

as indicated in a placebo-controlled pilot study of the

effects of nicotine compared with stimulant medica-

tion on cognitive performance in eight adolescents

with ADHD (Potter & Newhouse, 2004). The

results indicated that nicotine affects cognitive–

behavioral inhibition in a manner comparable with

methylphenidate.

Individuals with ADHD may use cigarettes as a

stimulant drug similar to medications such as

methylphenidate or dextroamphetamine and their

long-acting variants Concerta and Adderall, the

medications most commonly prescribed to treat

ADHD (Conners et al., 1996; Levin et al., 1996).

To examine the effects of nicotine and stimulant

medication on ADHD symptoms and moods in the

daily lives of adult smokers with ADHD, Gehricke

and colleagues (2006) studied 10 adult abstinent

smokers with clinically diagnosed ADHD (5 women,

5 men). Subjects participated in a 262 crossover

design with nicotine and placebo patches in the

presence and absence of stimulant medication. All

participants completed four 2-day sequences, each

time under a different nicotine and stimulant

medication condition. ADHD symptoms, moods,

and behaviors were monitored with an electronic

diary that participants completed approximately

every 30 min during waking hours. In addition, heart

rate and blood pressure as indicators of physiological

arousal and cardiac side effects were recorded with

ambulatory monitors. It was hypothesized that

nicotine and stimulant medication would reduce

ADHD symptoms, improve moods, and increase

cardiovascular arousal.

Linear mixed-model analyses of data from the 2-

day recording periods revealed that nicotine patches

reduced ADHD symptoms, compared with placebo

patches. No differences were found between nicotine

with and without stimulant medication. As shown in

Figure 2, nicotine with stimulant medication and

without stimulant medication (nicotine patch only)

and placebo patch with stimulant medication

reduced self-reported difficulty concentrating, com-

pared with placebo patch only, F(3, 27)56.38,

p5.001. The same pattern was found for self-defined

core symptoms such as daydreaming and zoning out,

F(3, 22)55.73, p5.005. When compared with pla-

cebo patch, nicotine also increased diastolic blood

pressure independent of stimulant medication, F(3,

31)53.31, p5.04. This finding contrasts with the

results of an ambulatory monitoring study with

healthy smokers (Khoury et al., 1996), which showed

no significant increases in cardiovascular activity.

It is possible that individuals with ADHD are

more susceptible to cardiovascular side effects of

nicotine. Interestingly, moods were not affected by

nicotine in this sample, perhaps because of the small

sample size. These findings support previous studies

on adults with ADHD in the laboratory (Conners et

al., 1996; Levin et al., 1996) and demonstrate that the

symptom-reducing and arousal-enhancing effects

hold true outside of the clinical or laboratory setting

(i.e., in everyday life). No differences were found

between nicotine and stimulant medication condi-

tions, a pattern that corroborates previous findings

in adolescents (Potter & Newhouse, 2004) and adults

(Levin et al., 2001) and that lends support to the self-

medication hypothesis.

Additional evidence for the self-medication

hypothesis comes from Whalen, Jamner, Henker,

Gehricke, and King (2003), who compared smoking

rates of medicated and nonmedicated adolescents

with ADHD over 2 years in a longitudinal study. The

convergent findings from self-report surveys, electro-

nic diaries, and salivary cotinine showed that

adolescents who received medication for their

ADHD smoked less than their untreated counter-

parts. Although no causal inferences can be drawn

from this study, the findings are ocnsistent with the

concept that early treatment of ADHD may delay or

prevent smoking initiation. Moreover, these findings

suggest that smoking may serve self-regulatory

functioning in adolescents with ADHD.

Summary

The links between smoking and externalizing beha-

vior problems are well documented. The data from

diverse studies are generally consistent with the self-

medication hypothesis and suggest that individuals

with ADHD may smoke to alleviate symptoms

associated with attention deficit, impulsivity, and

hyperactivity. More studies on larger samples are

necessary to assess the differential risks for adoles-

cent smoking initiation that are associated with

ADHD subtypes and with ODD and CD comorbid-

ities. In addition, little is known about the effects of

nicotine on individuals diagnosed with ODD or

CD without ADHD; such information would pro-

vide crucial information about the reinforcing

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mechanisms of nicotine in these populations. More

specifically, it still needs to be determined if

individuals diagnosed during childhood or adoles-

cence with ODD or CD smoke to reduce emotional

dysfunctions such as excessive feelings of anger,

resentment, and hostility.

Smoking and internalizing behavior problems

Major depression

Relationships between smoking and depression

became more prominent when the overall smoking

prevalence rates declined (Murphy et al., 2003).

Several studies have documented a relationship

between smoking and major depression in adults

(Breslau, Kilbey, & Andreski, 1991; de Leon et al.,

2002; Glassman et al., 1990; Kendler et al., 1993) and

adolescents (Brown, Lewinsohn, Seeley, & Wagner,

1996; Fergusson et al., 1996; Marmorstein & Iacono,

2003). Interestingly, a longitudinal study by Dierker

and colleagues (2001), found associations between

reports of tobacco use and mood and anxiety

disorders but not ADHD. Upadhyaya and collea-

gues (2003) found similar results: associations

between smoking and mood disorders and no

associations between smoking and ADHD.

Other longitudinal studies revealed reciprocal

associations between smoking and major depression

in that a history of smoking increased the risk for

major depression and vice versa (Breslau, Peterson,

Schultz, Chilcoat, & Andreski, 1998; Hanna &

Grant, 1999). However, a 21-year longitudinal study

of a birth cohort showed that major depression was

associated with increased rates of smoking and

nicotine dependence but that reciprocal influences

were inconsistent across time (Fergusson, Goodwin,

& Horwood, 2003). The findings of associations

between smoking and major depression suggest that

the neural substrates of smoking and antidepressant

medication may overlap (Quattrocki, Baird,

& Yurgelun-Todd, 2000). Furthermore, tricyclic

antidepressants (Rana et al., 1993; Schofield,

Witkop, Warnick, & Albuquerque, 1981), seroto-

nin-reuptake inhibitors (Fryer & Lukas, 1999a), and

atypical antidepressants such as bupropion (Fryer &

Lukas, 1999b) all have been shown to be noncompe-

titive antagonists of nicotinic receptors. Recent

preclinical findings suggest that nicotinic receptor

inactivation may be essential to the antidepressant

effects of some of these drugs (Caldarone et al.,

2004). Although nicotine does have antidepressant

effects, these may result from agonist-induced

receptor desensitization.

Figure 2. Difficulty concentrating in adult smokers with ADHD under nicotine and stimulant medication conditions.

NICOTINE & TOBACCO RESEARCH S527

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Some studies have shown that nicotine reduces

depression in smokers and nonsmokers with major

depression, a finding that supports the self-

medication hypothesis (Covey, Glassman, & Stetner,

1990, 1997; Cox et al., 2003; Glassman, Covey,

Stetner, & Rivelli, 2001; Haro & Drucker-Colin,

2004b; McClernon, Hiott, Westman, Rose, & Levin,

2006). Thus antidepressant therapy in combination

with nicotine replacement therapy may be a tailored

smoking cessation strategy for smokers with major

depression.

Anxiety disorders

As with the relationship between smoking and

depression, nicotine can have both anxiolytic and

anxiogenic effects (Picciotto, Brunzell, & Caldarone,

2002), depending perhaps on the type and time

course of anxiety disorder and whether nicotine is

administered acutely or chronically. Smoking initia-

tion and prevalence rates are increased in individuals

with post-traumatic stress disorder (PTSD; Acierno

et al., 2000; Beckham, 1999; Beckham et al., 1997;

Breslau et al., 2003), which indicates that nicotine

may act as an anxiolytic in response to developing

PTSD. Supporting evidence for this notion comes

from a study on smoking topography in trauma

survivors with and without PTSD (McClernon et al.,

2005). Most notably, puff volumes were higher in the

PTSD group than in the non-PTSD group.

Similar relationships between smoking and social

phobia have been found in adolescents and young

adults (Sonntag et al., 2000). In contrast, a long-

itudinal study on smoking and psychiatric disorders

found that heavy smoking in adolescence increased

the risk for agoraphobia, generalized anxiety dis-

order, and panic disorder during early adulthood

(Johnson et al., 2000). Thus the anxiogenic effects of

smoking may be caused by chronic exposure to

nicotine. Indirect support for this notion comes from

research using animal models to show that nicotine

exposure in adolescent rats leads to increased

anxiety-like behavior in adulthood (Slawecki,

Gilder, Roth, & Ehlers, 2003). The study’s authors

also proposed that increased anxiety associated with

smoking abstinence may play a role in continued

adolescent tobacco use.

In a review of the animal literature on the effects of

nicotine and nicotinic receptors on anxiety and

depression, Picciotto and colleagues (2002) suggested

that the paradoxical effects of nicotine on anxiety

and depression may be related to the broad expres-

sion of nicotinic acetylcholine receptors (nAChRs)

across many brain areas, the large number of nAChR

subtypes, and the ability of nicotine to activate and

desensitize nAChRs simultaneously. However, direct

support for the self-medication hypothesis for

anxiety was provided by Salin-Pascual and

Basanez-Villa (2003), who showed that transdermal

nicotine administration reduced anxiety in nonsmo-

kers with obsessive–compulsive disorder (OCD).

Although little is known about the relationship

between smoking and OCD, the results indicate that

smoking may serve as a self-medication for those

with elevated levels of anxiety.

Internalizing and externalizing behavior comorbidities

The underlying mechanisms for smoking to self-

medicate externalizing and internalizing behaviors

may involve nicotine-induced regulation of emo-

tional dysfunctions. Studies have shown an associa-

tion between smoking and negative affect such as

depressive or anxious mood (Goodman & Capitman,

2000; Hawkins, Hawkins, & Seeley, 1992; Kandel &

Davies, 1986; Upadhyaya, Deas, Brady, & Kruesi,

2002; Wu & Anthony, 1999). In addition, negative

affect frequently co-occurs with ADHD (Costello,

Mustillo, Erkanli, Keeler, & Angold, 2003; Palacio

et al., 2004; Pliszka, McCracken, & Maas, 1996;

Whalen et al., 2002; Wilens & Dodson, 2004), so that

some individuals with attentional dysfunctions may

smoke to regulate emotion.

Additional evidence of an association between

depressive, anxious, and aggressive dispositions and

smoking in adolescents comes from studies within the

UCI TTURC that used experience sampling methods

to assess smoking in the daily lives of adolescents

with emotional dysfunctions. Whalen and colleagues

(2001) used surveys and electronic diaries to assess

how depressive and aggressive dispositions relate to

smoking and daily moods in 170 adolescents.

Overall, cigarette and alcohol intake were elevated

in adolescents with depressive or aggressive disposi-

tions. Depression in boys, however, appeared to

reduce the risk for smoking associated with externa-

lizing behaviors. Moreover, depression combined

with aggression was associated with diary reports

of anxiety, stress, and fatigue in girls but not in boys.

Similarly, anxiety in adolescents increased the risk of

both smoking urges and tobacco use (Henker,

Whalen, Jamner, & Delfino, 2002). Recent findings

from the longitudinal studies conducted by Jamner

and colleagues on over 330 high school students

confirmed that trait hostility (Cook & Medley, 1954)

is a significant vector of vulnerability for tobacco

uptake in adolescents (Figure 3). Changes in salivary

cotinine levels (4-day mean) between the start of 9th

grade and the end of 11th grade were prospectively

examined in high (n5155) compared with low

(n5172) trait hostile adolescents. Although the two

groups had similar cotinine levels upon enrollment

into the study, the cotinine levels of high-hostile

youth increased significantly over time: 9th gra-

S528 SMOKING TO SELF-MEDICATE ATTENTIONAL AND EMOTIONAL DYSFUNCTIONS

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de53.8¡3.5 ng/ml versus 11th grade521.5¡

8.6 ng/ml. In contrast, cotinine levels among low-

hostile adolescents did not change across this 3-year

period: 9th grade57.4¡3.5 ng/l versus 11th grade5

8.3¡8.5ng/ml; hostility6grade interaction, F(1,

320)510.65; p5.009.

Such associations between smoking and mood

suggest that the addictive properties of nicotine may

stem in part from its potential to enhance mood in

individuals with dysfunctions in emotional regulation

(Jamner, Shapiro, & Jarvik, 1999; Whalen et al.,

2001). Consistent with this notion, it has been

proposed that tobacco may be acting as an anti-

depressant through monoamino oxidase inhibition,

which in turn reduces catabolism of catecholamines

(i.e., serotonin, norepinephrine, and dopamine; see

animal studies discussed later). Such mood-enhan-

cing properties of tobacco may make smoking

particularly rewarding for adolescents with primarily

emotional dysfunctions. Self-medication to reduce

negative affect may be a critical factor that leads to

the initiation of cigarette smoking in adolescents and

maintenance of smoking during adulthood.

Effects of nicotine on emotional dysfunction

Studies that support the self-medication hypothesis

have shown that nicotine reduces depression in

depressive smokers and nonsmokers (Covey et al.,

1990, 1997; Glassman et al., 2001; Haro & Drucker-

Colin, 2004b), anger in high-hostile smokers and

nonsmokers (Jamner et al., 1999), and anxiety in

obsessive–compulsive nonsmokers (Salin-Pascual &

Basanez-Villa, 2003). Further insights into the

underlying brain circuitry of nicotine administration

in emotional dysfunctions come from a brain

imaging study conducted at the UCI TTURC

(Fallon, Keator, Mbogori, & Potkin, 2004). Fluoro

deoxy-glucose positron emission topography (FDG-

PET) was used to measure brain glucose metabolism

in response to nicotine and placebo patches during a

sustained attention task (continuous performance

task [CPT]), which assessed attentional performance

(Conners et al., 1996; Levin et al., 2001; Levin et al.,

1996; Walker, Shores, Trollor, Lee, & Sachdev, 2000),

and a modified anger provocation task (Bushman,

1995). A total of 86 participants were divided into

high- and low-hostility subgroups based on their scores

on the Cook–Medley Hostility Scale (Cook & Medley,

1954). Findings indicated that nicotine reduced global

brain metabolism in high-hostile smokers during anger

provocation, whereas high-hostile nonsmokers showed

the reverse effect. In contrast, nicotine had no

significant effects on brain metabolism in low-hostile

smokers or nonsmokers. These metabolic changes

were not observed when subjects performed the CPT.

These findings suggest that nicotine may have the

strongest effects on brain metabolism in individuals

with dysfunctions in affect regulation (i.e., hostile and

aggressive individuals). However, the central nervous

system effects of nicotine also were shown to differ

between men and women.

Sex differences have been established in smoking

topography, response rates to nicotine replacement

therapies, and sensitivity to nicotine and smoking

cues (Centers for Disease Control and Prevention,

2003; Delfino, Jamner, & Whalen, 2001; National

Institute on Drug Abuse, 2000). The UCI TTURC

(Fallon, Keator, Mbogori, Taylor, & Potkin, 2005)

examined gender differences in brain metabolism in

response to different levels of transdermal nicotine

compared with placebo in 42 women and 77 men

during a CPT and an anger provocation task. More

specifically, 54 nonsmokers received a placebo and a

3.5-mg nicotine patch; 55 smokers received a

placebo, a 3.5-mg nicotine patch, and a 21-mg patch.

Findings suggested that brain metabolism, as mea-

sured by FDG-PET, in response to nicotine com-

pared with placebo, was a function of gender, type of

task, and smoking status. Gender differences were

most apparent under placebo: Compared with males,

female smokers during the CPT and female non-

smokers during anger provocation showed consis-

tently higher brain glucose metabolism in the

prefrontal system, mid and anterior temporal lobe,

language cortices, and related subcortical systems.

These brain regions are primarily responsible for

attention, short-term memory, executive function,

affect regulation, and language. Sex differences were

not observed in brain metabolism patterns in subjects

treated with a nicotine patch. Such findings suggest

that nicotine may decrease gender differences asso-

ciated with task-specific brain metabolism.

Summary

The relationships between smoking and internalizing

behavior problems appear to be dependent on the

Figure 3. Smoking trajectories in high- versus low-hostile adolescents.

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type of emotional dysfunction (depressed, anxious)

and the stage of smoking trajectory (i.e., initiation vs.

dependence). The findings suggest that individuals

start smoking because of problems with emotional

regulation underlying depression, anxiety, and

aggression. However, evidence indicates that smok-

ing also increases the risk for major depression and

anxiety disorders, which seems to suggest that

nicotine, the major psychoactive ingredient in

tobacco smoke, may initially alleviate symptoms

and moods associated with depression and anxiety

but then increase the risk of negative affectivity as the

individual becomes addicted to nicotine. The

increased negative affectivity in dependent smokers

may result in part from nicotine withdrawal experi-

enced between cigarettes. Between-study differences

in the pattern of associations between smoking,

internalizing, and externalizing behaviors may be

related to methods of assessing smoking (e.g., the use

of retrospective self-report measures rather than

salivary cotinine levels).

Our human behavioral and brain imaging studies

used salivary and serum levels to determine nicotine

intake and showed that trait hostility is a significant

vector of vulnerability for tobacco uptake and

susceptibility. In addition, interactions emerged

between type of emotional dysfunction and gender

in the risk for smoking initiation and in brain

metabolic responses to nicotine, findings that require

replication. Finally, to increase understanding of the

complex and paradoxical effects of nicotine in

relation to internalizing problems, studies are needed

on the receptor-activating and -desensitizing effects

of nicotine.

Developmental factors that contribute to the

association between smoking and attentional and

emotional dysfunctions: Evidence from animal studies

Adolescence has been identified as a critical period

for the initiation of alcohol and tobacco use (Chen &

Kandel, 1995; Kandel & Logan, 1984) and is also a

time of active neural remodeling (Huttenlocher,

1990; Pechmann, Levine, Loughlin, & Leslie, 2005).

Among adolescents, those with emotional and

attentional dysfunctions are most likely to start

smoking (Stevens et al., 2005; J. W. Weiss et al.,

2005; Whalen et al., 2001; Whalen et al., 2002) and

also develop psychiatric disorders as they grow older

(Dryman & Eaton, 1991; Erlenmeyer-Kimling &

Cornblatt, 1992; Gosden, Kramp, Gabrielsen,

Andersen, & Sestoft, 2005; Hofstra, van der Ende,

& Verhulst, 2002; Pine, Cohen, Cohen, & Brook,

1999; Wilcox & Anthony, 2004). It has been unclear

whether smoking initiation during adolescence

reflects social influences or an increased biological

sensitivity to the addictive effects of tobacco.

Whereas this question cannot be addressed easily

in human studies, the use of rodents permits a direct

experimental examination of the effects of nicotine

and other tobacco constituents on behavior and the

developing brain. Leslie and colleagues at the UCI

TTURC have used this model to provide evidence

supporting the concept that adolescence is a time of

unique sensitivity to the biological effects of nicotine

(Belluzzi, Lee, Oliff, & Leslie, 2004; Belluzzi, Wang,

& Leslie, 2005; Cao et al., 2007; Leslie et al., 2004;

McQuown, Belluzzi, & Leslie, 2007). In particular,

nicotine has been shown to be more rewarding and

less aversive during early adolescence compared with

adulthood (Vastola, Douglas, Varlinskaya, & Spear,

2002; Adriani & Laviola, 2004; Belluzzi et al., 2004;

Belluzzi et al., 2005; Shram, Funk, Li, & Le, 2006).

This age difference in behavioral response to nicotine

may result, in part, from differential activation of

both central and peripheral stress pathways (Cao

et al., 2007). Two critical domains of the stress

response pathway, the paraventricular nuclei of the

hypothalamus and thalamus, are differentially acti-

vated by nicotine in adolescents and adults. Whereas

the hypothalamic paraventricular nucleus regulates

peripheral stress response (Herman & Cullinan,

1997), the thalamic paraventricular nucleus projects

to the medial prefrontal cortex (Bubster & Deutsch,

1998; Moga, Weis, & Moore, 1995) and regulates

attention and emotion (Cardinal, Parkinson, Hall, &

Everitt, 2002; Chirstakou, Ribbins, & Everitt, 2004).

Thus, nicotine has significant, age-dependent effects

on neural circuitry that is critical to the regulation of

attention and emotion.

We also have shown that early exposure to

environmental stressors may lead to alterations in

central stress responses which, in turn, may influence

subsequent tobacco use. Neonatal handling (i.e.,

mild early environment stress) of rats significantly

reduces stress-induced corticosterone levels and

anxiety in male adolescents, but not in females

(Park, Hoang, Belluzzi, & Leslie, 2003).

Furthermore, nicotine was shown to reduce anxiety

only in males that were not handled at birth and that

showed a high degree of fearfulness when placed in a

novel environment (Park, Belluzzi, Han, Cao, &

Leslie, 2007). Thus, these studies powerfully demon-

strate that the effects of nicotine on emotional

response are dependent on the baseline state of

anxiety and stress responsiveness, and that these may

be influenced by environmental conditions.

Other tobacco constituents

Although nicotine is the major psychoactive ingre-

dient of tobacco smoke, other tobacco constituents

such as acetaldehyde (Belluzzi et al., 2005; Park,

Belluzzi, Han, Cao, & Leslie, 2007) and monoamine

S530 SMOKING TO SELF-MEDICATE ATTENTIONAL AND EMOTIONAL DYSFUNCTIONS

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oxidase inhibitors (MAOIs; Berlin, Said, Spreux-

Varoquaux, Launay et al., 1995; Berlin, Said,

Spreux-Varoquaux, Olivares et al., 1995; Fowler,

Volkow, Wang, Pappas, Logan, MacGregor et al.,

1996; Fowler, Volkow, Wang, Pappas, Logan, Shea

et al., 1996) also may play an important role in

facilitating and potentiating the rewarding actions of

nicotine. MAOIs have been used for the treatment of

ADHD (Akhonzadeh, Tavakolian, Davari-Ashtiani,

Arabgol, & Amini, 2003; Rubinstein, Malone,

Roberts, & Logan, 2006) and depression

(Amsterdam & Chopra, 2001; Robinson, 2002) and

act synergistically with nicotine to enhance its

reinforcing effects (Villegier, Lotfipour, McQuown,

Belluzzi, & Leslie, 2007; Villegier et al., 2006).

However, in contrast to acetaldehyde (Belluzzi et

al., 2005; Park et al., 2007), there are no age

differences in this synergistic interaction. Both

adolescent and adult rats treated with MAOIs

respond with increased and robust self-administra-

tion of nicotine. Taken together, these findings

indicate that the use of nicotine alone to study the

addictive and reinforcing effects of tobacco on

attention and affect regulation may be too restrictive.

Furthermore, other components of tobacco smoke,

such as MAOIs that are known to have antidepres-

sant effects, may contribute to the self-medicating

effects of smoking.

Summary

Animal studies support and complement findings

from studies of human adolescents and adults.

Findings have shown that adolescence represents

a critical period for an increased biological

sensitivity to the addictive effects of tobacco.

Nicotine, the major psychoactive ingredient in

tobacco, regulates neural circuits via specific

nicotinic receptors in the brain that are associated

with the regulation of attention and affect. Other

tobacco constituents, such as acetaldehyde and

MAOIs, facilitate the rewarding actions of nicotine

and may contribute to the self-medicating effects of

nicotine. Early exposure to environmental stressors

may influence central nervous system responses,

which may predispose individuals to subsequent

tobacco use and addiction. More research is needed

on how early environment, along with age, sex, and

tobacco constituents, may influence responses to

nicotine in individuals with attentional and emo-

tional dysfunctions.

Conclusion: Translation of findings for tailored

smoking prevention and cessation strategies

The UCI TTURC’s contribution to the understand-

ing of the relationship between smoking and

attentional and emotional dysfunctions is unique in

that it presents converging evidence from various

disciplines and integrates basic neuroscience, human

behavioral research, human brain imaging, and

public policy. Researchers in marketing, education,

and social ecology also participated in the process of

developing unifying theoretical constructs and the-

ories. Such theoretical constructs served as a basis to

explore the varying responses to tobacco across

developmental stages and to identify characteristics

that put people at risk for smoking. Within this

framework, we examined the linkage between smok-

ing, attention, and affect with an emphasis on

integrating human findings from behavioral studies

and those from brain imaging and animal studies.

The findings on dispositional risk factors (i.e.,

ADHD, hostility, depression, aggression), age, and

gender in the human behavioral and brain imaging

studies along with animal models suggest that

attentional and emotional dysfunctions elevate the

risk for smoking initiation and uptake in adolescents.

This increased risk for smoking initiation and

subsequent nicotine addiction in individuals with

attentional and emotional dysfunctions may be

mediated in part by genetic polymorphisms.

Genetic variations in the dopamine pathway asso-

ciated with nicotine abuse and addiction (e.g.,

Audrain-McGovern, Lerman, Wileyto, Rodriguez,

& Shields, 2004) also may coregulate the expression

of attentional dysfunction (e.g., Waldman et al.,

1998). In addition, interactions have been found

between smoking, emotional dysfunctions, and

serotonin transporter genes (Hu et al., 2000;

Lerman et al., 2000). Research has shown that the

serotonin transporter short allele is associated with

reduced prefrontal cortex activation during emo-

tional challenge, which may result in decreased

inhibitory regulation of the amygdala (Heinz et al.,

2005; Pezawas et al., 2005). People with such

genotypes and corticolimbic dysfunctions may ben-

efit the most from tailored smoking prevention and

cessation strategies that aim to improve attention

and affect regulation.

The notion that some people may use smoking as a

stimulant drug, whereas others may use smoking to

regulate their affect, has important implications for

smoking cessation strategies, suggesting the need to

tailor interventions to subgroups for whom smoking

serves different functions and may be maintained by

different reinforcing mechanisms. Tailored interven-

tions may need to be adjusted depending on where the

individual is on the smoking trajectory. Early affect

management interventions with adolescents who have

emotional dysfunctions may prevent smoking uptake.

However, adolescents with both emotional dysfunc-

tions and high rates of smoking (i.e., 10 cigarettes/day

or more) may need to learn strategies for overcoming

NICOTINE & TOBACCO RESEARCH S531

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nicotine withdrawal symptoms such as inability to

concentrate and elevated levels of negative affect. For

such individuals, affective regulation training plus

nicotine replacement may be the most potent smoking

cessation strategy. Similarly, adolescents with atten-

tional dysfunctions may need pharmacotherapy such

as stimulant medication to prevent or delay smoking

initiation and nicotine replacement therapy when

tobacco dependent.

Although the negative health consequences from

smoking are indisputable, the effects of nicotine and

other tobacco constituents may delay and alter the

onset and course of some diseases. In fact, the self-

medication hypothesis has found its strongest sup-

port in nicotine therapies that aim to treat cognitive

and affective impairments such as those character-

istic of Alzheimer’s disease (Newhouse, Potter,

Kelton, & Corwin, 2001; Sahakian, Jones, Levy,

Gray, & Warburton, 1989; White & Levin, 1999;

Wilson et al., 1995), Parkinson’s disease (Kelton,

Kahn, Conrath, & Newhouse, 2000), ADHD (Levin

et al., 2001; Potter & Newhouse, 2004), depression

(Haro & Drucker-Colin, 2004a, 2004b), and anxiety

(Salin-Pascual & Basanez-Villa, 2003). However,

findings documenting beneficial effects of nicotine

are not always replicated, and more research needs to

be done on well-defined patient groups with close

monitoring of clinical symptoms and characteriza-

tion of side effects and potential drug interactions.

The potential benefits of nicotine have to be weighed

against its addictive and health-threatening proper-

ties. An important consideration to emerge from the

UCI TTURC research is the interaction of nicotine

with other tobacco constituents such as acetaldehyde

and MAOIs (Belluzzi et al., 2005; Park et al., 2007;

Villegier et al., 2006). Animal studies show that the

effects of nicotine are modulated by other compo-

nents of tobacco smoke. Further research is needed

to characterize these interactions and their under-

lying mechanisms. Such studies may lead to the

development of novel therapeutic strategies for the

treatment of tobacco addiction.

Acknowledgments

This research was supported by the U.S. Public Health Services

(DA13332, DA018752, DA19138, DA21267, CA80301) and the

California Tobacco-Related Disease Research Program (14RT-0147

and 10RT-0255). The authors thank the members of the UCI TTURC

and the dedicated staff and students whose contributions made this

work possible.

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