Effects of smoking and smoking abstinence on cognition in adolescent tobacco smokers

ECLa

BntcMwaaRmsdanCco

Kt

Rmme

ddesrm1HPniteFP

F

A

R

0d

ffects of Smoking and Smoking Abstinence onognition in Adolescent Tobacco Smokers

eslie K. Jacobsen, John H. Krystal, W. Einar Mencl, Michael Westerveld, Stephen J. Frost,nd Kenneth R. Pugh

ackground: In adult animals and humans, nicotine can produce short-term cognitive enhancement and, in some cases,europrotection. Recent work in animals, however, suggests that exposure to nicotine during adolescence might be neurotoxic. We

ested for evidence of acute and chronic effects of tobacco smoking on cognition in adolescents who smoked tobacco daily and wereompared with adolescent nonsmokers.ethods: Verbal working memory, verbal learning and memory, selective, divided, sustained attention, mood, symptoms of nicotineithdrawal, and tobacco craving were examined in 41 adolescent daily smokers and 32 nonsmokers who were similar in age, gender,nd education. Analyses were controlled for general intelligence, reading achievement, parental educational attainment, baselineffective symptoms, and lifetime exposure to alcohol and cannabis.esults: In adolescent smokers, cessation of tobacco use increased tobacco craving, symptoms of nicotine withdrawal, and depressedood. Adolescent smokers were found to have impairments in accuracy of working memory performance irrespective of recency of

moking. Performance decrements were more severe with earlier age of onset of smoking. Adolescent smokers experienced furtherisruption of working memory and verbal memory during smoking cessation. As a group, male smokers initiated smoking at an earlierge than female smokers and were significantly more impaired during tests of selective and divided attention than female smokers andonsmokers.onclusions: Adolescent daily tobacco smokers experience acute impairments of verbal memory and working memory after smokingessation, along with chronic decrements in cognitive performance that are consistent with preclinical evidence that neurotoxic effects
f nicotine are more severe when exposure to nicotine occurs at earlier periods in development.
ey Words: Adolescent, tobacco, selective attention, divided at-ention, memory, working memory

ates of tobacco use among adolescents are increasingworldwide (Global Youth Tobacco Survey CollaborativeGroup 2002). Within the United States, more than 5.5

illion high school students use tobacco, with more than 4.5illion of these teenagers smoking cigarettes (Centers for Dis-

ase Control 2001b; US Census Bureau 2002).In adult humans, cessation of regular tobacco smoking pro-

uces a withdrawal syndrome, one characteristic of which isisruption of attention and memory (Pineda et al 1998; Shiffmant al 1995; Snyder et al 1989; West and Hack 1991). Tobaccomoking or administration of nicotine can reverse withdrawal-elated deficits in focused and selective attention, recognitionemory, prose recall, and working memory (Baldinger et al

995; Bates et al 1995; Foulds et al 1996; Gilbert et al 1997;oulihan et al 1996; Krebs et al 1994; Lawrence et al 2002;erkins et al 1994; Pineda et al 1998). In nonsmokers and inondeprived smokers, some studies have found that nicotinemproves finger tapping, focused, sustained, and selective atten-ion, recognition memory, and working memory, suggesting truenhancement of performance by nicotine (Ernst et al 2001;oulds et al 1996; Kumari et al 2003; Le Houezec et al 1994;erkins et al 1994; Phillips and Fox 1998; Pritchard et al 1992).

rom the Departments of Psychiatry (LKJ, JHK), Pediatrics (LKJ, KRP), Neuro-surgery (MW), and Child Study (MW), Yale University School of Medicine;and Haskins Laboratory (WEM, SJF), Yale University, New Haven, Con-necticut.

ddress reprint requests to Leslie K. Jacobsen, M.D., Yale University Schoolof Medicine, Psychiatry and Pediatrics, 100 York Street 2B, New Haven,CT 06511; E-mail: [email protected].

eceived February 27, 2004; revised June 15, 2004; revised September 28,
2004; accepted October 20, 2004.
006-3223/05/$30.00oi:10.1016/j.biopsych.2004.10.022

Other studies have found that smoking or nicotine administrationhad no effect on, or impaired the performance of, nonabstinentsmokers or nonsmokers during tests of focused attention (Land-ers et al 1992; Petrie and Dreary 1989), selective attention(Heishman et al 1993; Spilich et al 1992), sustained attention(Hasenfratz et al 1989; Keenan et al 1989), and memory (Heish-man et al 1993; Hindmarch et al 1990; Spilich et al 1992). Studiesof adult animals have shown that nicotine administration canproduce short-term enhancement of attention and memory(Hahn and Stolerman 2002; Hahn et al 2002; Levin et al 1996;Puma et al 1999; Sansone et al 1991). Furthermore, stimulation ofnicotinic acetylcholine receptors (nAChRs) on mature cells bynicotine or endogenous acetylcholine has been shown to exert aneuroprotective effect, reducing cell death resulting from cyto-toxic treatments (Kaneko et al 1997; Maggio et al 1998; Yamashitaand Nakamura 1996; Zoli et al 1999). Consistent with this,epidemiologic studies have provided evidence suggesting thatchronic exposure to tobacco smoke might protect against thedevelopment of Parkinson’s disease, the second most commonneurodegenerative disease in adult humans (Gorell et al 1999;Ross and Petrovitch 2001).

In contrast, gestational tobacco exposure has well-establishedneurotoxicity and neurodevelopmental sequelae (Fried 1995;Fried et al 2003). Recent work with a rat model of adolescentnicotine exposure has provided evidence that vulnerability to theneurotoxic effects of nicotine might extend postnatally intoadolescence (Slotkin 2002). In doses designed to model typicalhuman exposures, nicotine treatment of rats during adolescence(postnatal days 30–47) reduces cell numbers in cortex, midbrain,and hippocampus and increases markers of apoptosis in hip-pocampus in females (Trauth et al 2000b). After cessation ofnicotine exposure, elevations in high-affinity nAChR bindingpersist across brain regions in adolescent males longer than inadult and in female adolescent rodents submitted to the sametreatment regimen (Trauth et al 1999). Behavioral studies indicate
that adolescent nicotine exposure produces decrements in open
BIOL PSYCHIATRY 2005;57:56–66© 2005 Society of Biological Psychiatry

fiao

aaeotwcdsacotntJ1

M

P

psfrpocistei

T

AGCAFSWEPKWBMLC

g

dA l AnxR

L.K. Jacobsen et al BIOL PSYCHIATRY 2005;57:56–66 57

ield behavior in females, enhances passive avoidance learningn both sexes (Trauth et al 2000c), and enhances activity indolescent males to a greater extent than in adolescent femalesr in adult animals (Faraday et al 2001).

The present study examined selective, divided, and sustainedttention, working memory, and verbal learning and memory indolescent smokers and nonsmokers to test for evidence of chronicffects of tobacco smoking and acute effects of smoking cessationn cognition in this population. On the basis of preclinical evidencehat exposure to nicotine during adolescence might be neurotoxic,e anticipated that adolescent tobacco smokers would demonstrate

ognitive deficits irrespective of recency of smoking. Given theisruptive effects of nicotine withdrawal on cognition in adultmokers, we anticipated that smoking cessation would be associ-ted with further deterioration in cognitive performance in adoles-ent smokers. We further hypothesized that, consistent with previ-us observations in adolescent and adult smokers, cessation ofobacco use would be associated with increased symptoms oficotine withdrawal, depression, anxiety, and tobacco craving (Cen-ers for Disease Control 2001a; Dozois et al 1995; Hanson et al 2003;orenby et al 1996; Killen et al 2001; Rojas et al 1998; Smith et al996; Stanton et al 1996; Ward et al 2001).

ethods and Materials

articipantsForty-one adolescents who smoked tobacco daily were com-

ared with 32 adolescent nonsmokers (defined as having a lifetimemoking history of no more than two cigarettes). Demographic dataor both groups are presented in Table 1. All participants wereecruited from the community and were free of medical andsychiatric illness and substance abuse or dependence disorders,ther than nicotine dependence, as determined by structuredlinical interview (Puig-Antich et al 1980). The groups did not differn age, gender, years of education, level of anxiety at the initialcreening visit, number of stressful life events, symptoms of inatten-ion, or number of weeks of exposure to tobacco smoke constitu-nts during prenatal development (assessed by semi-structured

able 1. Demographic Data for 41 Adolescent Tobacco Smokers and 32 No

Smoker

ge (y) 17.0 � 1.1 (14–ender (% female) 65.8%igarettes/Day 11.7 � 6.7 (2–3ge at Onset of Smoking (y) 13.1 � 1.8 (9–1TND 2.6 � 1.7 (0–7creening Salivary Cotinine (ng/mL) 119 � 111 (8.7eeks of Prenatal Exposure to Tobacco Smoke 15.6 � 18.9

ducation (y) 10.1 � 1.1arent Ed (y) 13.7 � 1.9BIT Composite Score 97.8 � 8.6JR Word Attack SS 102.6 � 16.2

eck Depression Score 4.9 � 5.2ASC 33.4 � 12.7

ife Events 9.0 � 4.9onners 13.7 � 7.7

Data are presented as mean � SD (range) unless otherwise noted. Degender composition of smoker and nonsmoker groups, where df was 1.

FTND, Fagerstrom Test for Nicotine Dependence (Heatherton et al 1991);uring pregnancy with subject; KBIT, Kaufman Brief Intelligence Test (Bowchievement Word Attack subtest standard scores; MASC, Multidimensionaeport Scale (Conners 1998).

nterview of the parents regarding the mother’s smoking behavior

during her pregnancy with the subject). On average, parents ofnonsmokers had received 1.5 years more of education than hadparents of smokers. In addition, the full scale intelligence quotient(FSIQ; assessed with the Kaufman Brief Intelligence Test [Bowersand Pantle 1998]) of nonsmokers was, on average, 6.4 points higherthan that of smokers. There were trends for measures of readingachievement to be higher for nonsmokers and for measures ofsymptoms of depression at screening to be higher for smokers.

Male and female smokers did not differ in the number ofcigarettes smoked per day, pack-years, or in degree of nicotinedependence, assessed with the Fagerstrom Test for NicotineDependence (FTND [Heatherton et al 1991]; all p values � .5).The FTND is a six-item questionnaire that yields a score between0 and 10. Although there is no standard cutoff for the presence ofnicotine dependence (Moolchan et al 2002), one suggestedscoring method is as follows: 1–2 � very low dependence, 3–4 �low dependence, 5 � medium dependence, 6–7 � high depen-dence, 8–10 � very high dependence (Heatherton et al 1991).

Although no subject met criteria for a lifetime diagnosis ofsubstance abuse or dependence other than nicotine depen-dence, smokers on average had used more cannabis andalcohol than had nonsmokers [smokers: 80 � 191 lifetimeepisodes of cannabis use, 70 � 73 lifetime drinks; nonsmok-ers: 4 � 13 lifetime episodes of cannabis use, 36 � 57 lifetimedrinks; t (71) � 2.2, p � .03 and t (71) � 2.1, p � .04,respectively]. One smoker had tried cocaine on one occasion3 years before study enrollment. All other subjects deniedprevious cocaine use, and all subjects denied previous use ofopiates, amphetamines, methylenedioxymethamphetamine(ecstasy), sedatives, hallucinogens, and inhalants. Subjectswere required to stop using cannabis for at least 4 weeksbefore cognitive assessment and to stop using alcohol for atleast 48 hours before assessment. Abstinence from substanceuse before assessment was confirmed by urine toxicologyscreen.

ProcedureAfter the initial screening visit, all subjects were tested twice.

okers

Nonsmokers t/�2 p

16.6 � 1.3 (14–18) 1.08 .2862.5% .09 .77

.7) 0 � 0 5.58 �.000112.5 � 17.6 .68 .5010.1 � 1.4 .04 .9715.2 � 2.7 2.68 .009

104.2 � 8.1 3.27 .002109.3 � 16.5 1.76 .08

2.6 � 4.2 1.99 .0534.2 � 10.1 .27 .79

8.1 � 3.8 .81 .4214.0 � 8.7 .14 .89

of freedom (df) for all comparisons were 71, except for the comparison of

s of Prenatal Exposure to Tobacco Smoke, number of weeks mother smokednd Pantle 1998); WJR Word Attack SS, Woodcock-Johnson Revised Test ofiety Scale for Children (March et al 1997); Conners, Conners Adolescent Self

nsm

s

18)

0)6))–439

rees

Weekers a

Smokers were tested during ad libitum smoking and after 24

www.elsevier.com/locate/biopsych

hpdtsssowa

fjtCut

A

a(ENNiotiM1a(mpmnptmqfnot

A

ptEmtIawpnrwrpr

58 BIOL PSYCHIATRY 2005;57:56–66 L.K. Jacobsen et al

w

ours of abstinence from tobacco products. An abstinenceeriod of 24 hours was chosen because cognitive performanceecrements in adult smokers have been shown to be robust athis time point during cessation (Snyder et al 1989). Order ofmoking and abstinence assessments was randomized acrossmokers. The target interval between test sessions for bothmokers and nonsmokers was 2 weeks. To avoid the emergencef nicotine withdrawal during the smoking assessment, subjectsere permitted to smoke during a break midway through thessessment.

Subjects provided written assent or, for 18-year-olds, consentor study participation. Parental consent was obtained for sub-ects 17 years of age and younger. This study was approved byhe Yale University School of Medicine Human Investigationommittee. All procedures and assessments were conductednder the direct supervision of a child and adolescent psychia-rist (LKJ).

ssessment of Mood, Anxiety, and Nicotine WithdrawalAt the beginning of each test session, self-reported mood and

nxiety symptoms were assessed with the Profile of Mood StatesPOMS) scale (Little and Penman 1989) and the Center forpidemiologic Studies–Depression (CES-D) scale (Radloff 1977).icotine withdrawal was assessed with the Clinical Institute forarcotic Withdrawal Scale (CINA) (Peachey and Lei 1988), an

nterview-based instrument that has been reliably used to assesspiate withdrawal symptoms in opiate-dependent patients ando demonstrate involvement of the endogenous opioid systemn nicotine dependence (Krishnan-Sarin et al 1999), and theinnesota Nicotine Withdrawal Scale (Hughes and Hatsukami998), a self-report–based instrument. Tobacco craving wasssessed in smokers with the Tiffany Scale for Smoking UrgesTiffany and Drobes 1991) and the Shiffman Jarvik Scale (Shiff-an and Jarvik 1976). Subjects were permitted to choose torovide either a sample of saliva or of plasma at each visit foreasurement of nicotine and cotinine, the primary metabolite oficotine. Sixteen smokers and seven nonsmokers elected torovide plasma; all remaining subjects provided saliva. Concen-rations of nicotine and cotinine were determined by gas chro-atography (Jacob et al 1981). With this method, limits ofuantification in plasma are 1 ng/mL for nicotine and 10 ng/mLor cotinine, whereas limits of quantification in saliva are 10g/mL for both nicotine and cotinine. Expired air carbon mon-xide (CO), a product of combustion, was also measured at eachest session (Micro CO meter: Micro Direct, Auburn, Maine).

ssessment of Verbal Learning and MemoryThe Hopkins Verbal Learning Test–Revised (HVLT-R) (Sha-

iro et al 1999) is an auditory verbal memory test that begins withhree trials in which a list of 12 words is read by the examiner.ach time after the list is read, the subject is asked to recall asany words from the list as possible. The three immediate-recall

rials are followed by a delayed-recall trial 25 minutes later.mmediately after the delayed-recall trial, a recognition test isdministered in which subjects are asked to identify whichords, from a list of 24 words read aloud, were presentedreviously. Scores derived included total recall (the sum of theumber of words correctly recalled during the three immediate-ecall trials), learning (the difference between the number ofords recalled on trial 1 and the higher of trials 2 or 3), delayed

ecall (the number of words recalled after the 25 minute delay),ercent retained (the number of words recalled after the delay
elative to the number of words recalled after the higher of trials
ww.elsevier.com/locate/biopsych

2 or 3), and recognition hits (the number of true positives on therecognition task). To minimize item-related practice effects(Benedict and Zgaljardic 1998), different forms of the HVLT-Rwere administered at each of the two testing sessions. Becausethe HVLT-R was added to the battery after the study was initiated,data were available from 29 smokers and 22 nonsmokers.

Assessment of Working MemoryWorking memory was assessed with an auditory n-back task

with two levels of working memory load (1-back and 2-back)and two levels of selective attention load (binaural and dichoticstimulus presentation). In the binaural condition, the same toneand nonsense words were presented to both ears. In the dichoticcondition, different words were presented to each ear andsubjects were instructed as to which ear targets will be presented.The binaural/dichotic manipulation modulates demands on se-lective attention.

Assessment of Selective, Divided, and Sustained AttentionSustained attention was assessed with the Conners Continu-

ous Performance Test (CPT; Chen et al 1998). Selective anddivided attention were assessed with a modified version of apreviously described computerized word recognition task (Shay-witz et al 2001). Within the selective attention task, both auditoryand visual selective attention were assessed. In the auditoryselective attention condition, subjects listened to a linguisticstimulus and pressed one button if the stimulus was a real wordand another if it was not. Simultaneous with the auditorystimulus presentation, visual linguistic distracters (letter strings)were presented on the computer screen. During the visualselective attention condition, subjects viewed a letter string onthe computer screen and pressed one button if the stimulus wasa real word and another button if it was not. Simultaneous withpresentation of the visual stimulus, auditory linguistic distracterswere played through the headphones. During the divided atten-tion condition, word or nonword linguistic stimuli were pre-sented simultaneously in both auditory and visual modalities. Avisual cue was then presented to indicate which word/nonwordcombination was correct, and subjects then pressed one buttonindicating whether the seen and heard stimuli represented thecorrect combination and another button if they did not. Thus,unlike the selective attention task, the divided attention taskrequired that subjects fully process both auditory and visualstimuli before making judgments. A task in which subjects madea simple lexical decision (whether an auditory or visual stimuluswas a real word) in the absence of linguistic distracters wasincluded in this battery to assess primary auditory and visualprocessing.

To ensure that the degree to which subjects understood howto perform the tasks did not differ across test sessions, subjectsreceived training in selective, divided, and working memorytasks before the initial test session, with different stimuli lists thanthose presented during testing, until they correctly identified aminimum of 85% of targets across all conditions.

Statistical AnalysisOutcome measures for assessment of attention and working

memory included performance accuracy and speed (reaction time).Accuracy of CPT performance was assessed by computing percentof targets correctly identified (percent hits) and percent of nontar-gets incorrectly identified as targets (percent commission errors).Accuracy of working memory performance was assessed by com-
puting D= as follows: D= � [LN([pHit � (1 � pFA)]/[(1 � pHit) �

ppnippsdt

aniiwisosbfdccuecmgss

atmaew�leo

dmspas

acccictdcaota


FA])]/2 (Repp and Frost 1988), where LN is the natural logarithm,Hit is the number of targets correctly identified divided by the totalumber of targets, and pFA is the number of nontargets incorrectlydentified as targets divided by the total number of nontargets. D=rovides a measure of signal detection that takes into account therobability of correct and incorrect identifications. Accuracy ofelective and divided attention task performance was assessed byividing the number of correct responses by the total number ofrials (proportion correct).

As noted above, to control for order effects, order of smokingnd abstinence test sessions was randomized across smokers. Foronsmokers, both test sessions were coded as abstinence sessionsn the analysis. In all analyses linear mixed regression was used,mplemented in S-Plus (Insightful Corporation, Seattle, Washington)ith subject modeled as a random effect. Because group differences

n years of parental education, FSIQ, reading achievement, baselineymptoms of depression (Beck score; Beck et al 1961), and numberf lifetime alcoholic drinks and episodes of cannabis use wereignificant or nearly significant, these variables were controlled fory entering them as fixed effects in the regression models. To testor effects of group (being a smoker or nonsmoker) on theependent measures, regression models were estimated that in-luded group as a fixed effect, with no fixed effect for smokingondition. Observed significant effects of group were further eval-ated by estimating regression models that included separate fixedffects comparing performance of the smokers during the smokingondition and during the abstinence condition against the perfor-ance of the nonsmokers. These models tested whether effects ofroup stemmed from differences in performance between non-mokers, pooled across test sessions, and smokers during themoking or abstinence conditions, or during both conditions.

Effects of smoking condition on the dependent measures weressessed by estimating regression models that included group andhe group � smoking condition interaction as fixed effects. Theseodels tested the magnitude of change in the dependent measures

cross test sessions in the smokers versus the nonsmokers. Anxploratory analysis was conducted in which regression modelsere estimated that included gender, gender � group, and gendergroup � smoking condition factors as fixed effects. The verbal

earning and memory (HVLT-R) measure was excluded from thisxploratory analysis because data were available from only a subsetf subjects on this task.

Within the smokers, the relationship between degree of nicotineependence, as reflected by FTND score, and change in perfor-ance across test sessions was examined for measures showing

ignificant effects of group or smoking condition. This was accom-lished by estimating regression models that included FTND scores a fixed effect and differences between scores obtained during themoking and abstinence conditions as the dependent measure.

Previous work examining the relationship between plasmand salivary concentrations of cotinine has shown that salivaryoncentrations in youth are, on average, 20% higher than plasmaoncentrations (Jarvis et al 2003). Therefore, salivary cotinineoncentrations were multiplied by a factor of .8 before combin-ng them with measures of cotinine from plasma. Plasma nicotineoncentrations were estimated from salivary nicotine concentra-ions with a previously described power model shown to pro-uce good correlations between plasma and salivary nicotineoncentrations (Teneggi et al 2002). Expired air CO and nicotinend cotinine measures were used to confirm nonsmoking statusf nonsmokers and to confirm abstinence in smokers during theest session after 24 hours of abstinence from smoking. Expired
ir CO less than 10 ppm and an estimated plasma nicotine
concentration less than 2 ng/mL were accepted as evidence ofabstinence from tobacco use.

Results

Effects of Abstinence on Tobacco Craving, Symptoms ofNicotine Withdrawal, and Mood and Anxiety

The average duration between test sessions was 14.7 � 13.4days and did not differ between groups (p � .6). Measures ofnicotine and cotinine were nil in all nonsmokers at screening andat every test session. In smokers, abstinence significantly reducedboth cotinine [smoking: 126.7 � 84.0 ng/mL, abstinence: 57.4 �59.0 ng/mL; � � 73.6, t (72) � 8.2, p � .0001] and nicotine[smoking: 15.8 � 8.1 ng/mL, abstinence: .4 � 1.2 ng/mL; � �15.4, t (72) � 12.9, p � .0001] concentrations. Expired air COconcentrations in the smokers were also consistent with absti-nence from smoking before the abstinence test session [smoking:15.2 � 5.9 ppm, abstinence: 5.0 � 2.3 ppm; � � 10.1, t (72) �12.2, p � .0001]. Among smokers, abstinence also robustlyincreased tobacco craving as measured by the Tiffany [smoking:25.8 � 34.5, abstinence: 63.0 � 37.9; � � �37.1, t (39) � �7.0,p � .0001] and Shifman Jarvik [smoking: 4.1 � 1.7, abstinence:6.1 � 1.3; � � �2.0, t (39) � �7.6, p � .001] scales. Effects ofgender on screening and test session nicotine, cotinine, and COconcentrations, and on Shifman Jarvik scores were not significant(p values � .6). Across test sessions, Tiffany scores were higheramong female smokers than among male smokers [effect ofgender: � � 25.6, t (33) � 2.2, p � .01]. Although the differencein scores was greater during abstinence, the gender � smokingcondition interaction effect did not achieve statistical significance(smoking condition: females: 28.2 � 34.8, males: 21.4 � 34.7;abstinence condition: females: 71.8 � 36.4, males: 46.0 � 35.9).

Table 2 shows effects of group and of smoking conditionobserved for symptoms of nicotine withdrawal and depressedmood. Significant effects of smoking condition and group � gender� smoking condition interactions are plotted in Figure 1. Smokingabstinence significantly increased symptoms of nicotine withdrawalin smokers, as measured by the CINA (Figure 1A) and the MinnesotaNicotine Withdrawal Scale. Although group � gender � smokingcondition interaction effects were not significant for CINA scores,female smokers exhibited a greater increase in Minnesota NicotineWithdrawal Scale scores during abstinence than did male smokers[group � gender � smoking condition interaction: � � �5.8,t (71) � �2.3, p � .02; Figure 1B].

Smoking abstinence also increased symptoms of depression insmokers (Figure 1C). Group � gender � smoking conditioninteraction effects on depressed mood were not significant; how-ever, in the smoking condition, symptoms of anxiety, as reflected bythe POMS anxiety subscale score, were highest among male smok-ers. During abstinence, symptoms of anxiety significantly increasedin female smokers only [group � gender � smoking conditioninteraction: � � �4.5, t (71) � �2.6, p � .01; Figure 1D].

Verbal Learning and MemoryEffects of group on verbal learning and memory were not

significant (all p values � .3); however, smoking abstinence wasassociated with a significant decline in HVLT-R total recall (Table 2,Figure 2A) and trends toward a significant decline in HVLT-Rdelayed recall [smokers: smoking � 9.6 � 2.1, abstinence � 8.9 �2.1; nonsmokers: average across test sessions � 10.1 � 1.2; effect ofsmoking condition: � � .6, t (49) � 1.9, p � .06] and percent
retention [smokers: smoking � 90.0 � 11.5, abstinence � 85.4 �

1o

W

r2�(2agc

T

E

G

S

C

T t 198

FGE�


w

4.7; nonsmokers: average across test sessions � 91.4 � 6.9; effectf smoking condition interaction: � � 4.6, t (49) � 1.9, p � .06].

orking MemoryAcross test sessions, smokers performed significantly less accu-

ately than nonsmokers during the binaural 1-back (smoker’s D= �.9 � .4, nonsmoker’s D= � 3.1 � .4), dichotic 1-back (smoker’s D=

2.4 � .5, nonsmoker’s D= � 2.8 � .5), and dichotic 2-backsmoker’s D= � 1.7 � .5, nonsmoker’s D= � 2.3 � .5) tasks (Table). Examination of the contribution of performance during smokingnd abstinence conditions to these effects of group showed thatroup differences in performance were smaller during the smokingondition than during the abstinence condition, except for the

able 2. Effects of Group and Smoking Condition on Symptoms of Nicotin

ffect CINAMinnesota Nicotine

Withdrawal Scale CES-D

roup� 1.1 5.6 .8df 65 65 65t 1.8 3.6 .5p .08 .0007a .6

moking Condition� �1.8 �7.6 �2.8df 72 72 72t �3.9 �6.2 �2.8p .0002a �.0001a .007a

omment Figure 1A Figure 1B Figure 1C

CINA, Clinical Institute for Narcotic Withdrawal Scale; CES-D, Center fest-Revised; D=, a measure of accuracy of task performance (Repp and Fros

aStastically significant at p � .05.

igure 1. (A) Effect of smoking condition on symptoms of nicotine withdrawroup � gender � smoking condition interaction effect on symptoms of nffect of smoking condition on symptoms of depression, measured with the

smoking condition interaction effect on symptoms of anxiety, measured with


dichotic 2-back task, for which the effect of group was significantduring both smoking and abstinence conditions [binaural 1-back,smoking � � �.2, t (71) � �2.0, p � .05, abstinence � � �.3, t (71)� �2.5, p � .01; dichotic 1-back smoking � � �.3, t (71) � �1.9,p � .06, abstinence � � �.4, t (71) � �3.0, p � .004; dichotic2-back smoking � � �.6, t (71) � �3.6, p � .0006, abstinence � ��.5, t (71) � �3.5, p � .0009]. The effect of group on binaural2-back performance was not statistically significant; however, per-formance accuracy of smokers on this task deteriorated significantlyduring abstinence (Table 2, Figure 2B). Effects of group andsmoking condition on reaction time were not significant.

Examination of the relationship between indices of smok-ing exposure and working memory performance accuracy in

drawal, Depressed Mood, Verbal Memory, and Working Memory

HVLT-RTotal Recall

Binaural1-Back D=

Binaural2-Back D=

Dichotic1-Back D=

Dichotic2-Back D=

.1 �.3 �.3 �.4 �.643 65 65 65 65.2 �2.4 �1.9 �2.5 �3.7.9 .02a .06 .01a .0005a

1.5 .07 .2 .2 �.0249 72 72 72 722.1 .8 2.1 1.8 �.2.04a .4 .04a .07 .8

Figure 2A Figure 2B

idemiologic Studies–Depression Scale; HVLT-R, Hopkins Verbal Learning8).

easured with the Clinical Institute for Narcotic Withdrawal (CINA) Scale. (B)e withdrawal, measured with the Minnesota Nicotine Withdrawal Scale. (C)er for Epidemiologic Studies–Depression (CES-D) scale. (D) Group � gender

e With

or Ep

al, micotinCent

the Profile of Mood States.

ttt1tssat[�ad�aRFw

a�wfccaarms

S

is

Fsc


he smokers revealed a significant positive relationship be-ween age at onset of smoking and performance accuracy onhe dichotic 1-back and the dichotic 2-back tasks [dichotic-back: � � .1, t (33) � 2.1, p � .04; dichotic 2-back: � � .1,(33) � 2.4, p � .02]. Regression models that includedeparate factors for the relationship between age at onset ofmoking and performance accuracy during smoking andbstinence conditions showed that the strength of the rela-ionship was remarkably similar across smoking conditionsdichotic 1-back performance accuracy, smoking condition: �

.1, t (39)� 2.2, p � .03; dichotic 1-back performanceccuracy, abstinence condition: � � .1, t (39) � 2.0, p � .05;ichotic 2-back performance accuracy, smoking condition: �

.1, t (39) � 2.4, p � .02; dichotic 2-back performanceccuracy, abstinence condition: � � .1, t (39) � 2.5, p � .02].elationships between pack-years, cigarettes smoked per day,TND score, and working memory performance accuracyere not significant.A significant group � gender � smoking condition inter-

ction effect on binaural 2-back reaction time was observed [�103.3, t (71) � 2.5, p � .02; Figure 2C]. Here, reaction timeas relatively stable across test days for nonsmokers and for

emale smokers but slowed significantly during the abstinenceondition for male smokers. The group � gender � smokingondition interaction effect on binaural 2-back performanceccuracy was not significant (p � .6), and performanceccuracy on this task was not significantly correlated witheaction time, suggesting that males were not performingore accurately as a result of the longer reaction times (no

peed–accuracy trade-off).

elective, Divided, and Sustained AttentionEffects of group on simple auditory and visual perception

n the absence of linguistic distracters, and on selective and

igure 2. (A) Effect of smoking condition on short-term verbal memory, mmoking condition on binaural 2-back working memory performance accuondition interaction effect on binaural 2-back reaction time.

ustained attention task performance accuracy and speed

were not significant. The effect of group on divided attentiontask performance accuracy was also not significant (p �.6);however, across test sessions, smokers performed this tasksignificantly more slowly than did nonsmokers [smokers reac-tion time (RT) � 1056.7 � 305.9 msec, nonsmokers RT �944.5 � 262.5 msec; � � 144.0, t (65) � 2.1, p � .04].Examination of the contribution of performance during smok-ing and abstinence conditions to this effect showed that groupdifferences in reaction time were similar during smoking andabstinence conditions [smoking � � 147.4, t (71) � 2.1, p �.04, abstinence � � 140.6, t (71) � 2.0, p � .05].

The exploratory analysis of gender effects revealed significantgroup � gender interaction effects on accuracy of auditoryselective [� � .1, t (63) � 2.7, p � .009; Figure 3A] and divided[� � .1, t(63) � 2.3, p � .02; Figure 3B] attention task perfor-mance. Although accuracy of performance on these tasks wassimilar in female smokers and nonsmokers, male smokers per-formed significantly less accurately than did male nonsmokers.The group � gender interaction effect on visual selective atten-tion performance accuracy was nearly significant, again reflect-ing poorer performance accuracy of male smokers relative tomale nonsmokers [female smokers: .9 � .1, female nonsmokers:.9 � .1, male smokers: .8 � .1, male nonsmokers: .9 � .1; group� gender � � .1, t (63) � 2.0, p � .05]. Effects of gender on CPTperformance were not significant (p values � .2). Male andfemale smokers and male smokers and nonsmokers did not differin self-reported symptoms of inattention (Conners AdolescentSelf Report Scale [Conners 1998]; p values � .3). Similarly, maleand female smokers did not differ in estimated nicotine orcotinine concentrations at screening or at either test session anddid not differ in number of cigarettes smoked per day, pack-years, or FTND scores (p values � .5); however, age at onset ofsmoking was significantly younger for males [age at onset ofsmoking: males � 12.2 � 2.2 years, females � 13.6 � 1.4 years;

red with the Hopkins Verbal Learning Test–Revised (HVLT-R). (B) Effect ofmeasured using D= (Repp and Frost 1988). (C) Group � gender � smoking

easuracy,

t (39) � 2.4, p � .02].


RCC

nmra��TJapHs

pnFrafmrsfwdgdcs

Fad ance a


w

elationship Between Severity of Nicotine Dependence andhange in Symptoms and Cognitive Function Across Smokingonditions

The FTND score was significantly positively related to theumber of cigarettes smoked per day, cotinine concentrationseasured at screening and at the nonabstinent test session, and the

eduction in tobacco craving and symptoms of nicotine withdrawalssociated with smoking [cigarettes smoked per day: � � 1.4, t (33)3.8, p � .0007; cotinine concentration at screening: � � 24.5,t (33)3.5, p � .001; cotinine concentration at non-abstinent test session:� 29.5, t (38) � 4.4, p � .0001; abstinence Tiffany score – smokingiffany score: � � 8.4, t (33) � 3.5, p � .002; abstinence Shifmanarvik – smoking Shifman Jarvik score: � � .3, t (33) � 2.5, p � .02;bstinence CINA score – smoking CINA score: � � .6, t (33) � 2.5,� .02]. FTND score was not significantly related to the changes inVLT-R performance or binaural 2-back performance accuracy or

peed.Gender was added to the regression models to explore

ossible effects of the interaction between gender and severity oficotine dependence on cognitive function. A significant gender �TND score interaction effect on change in performance accu-acy across test sessions was observed for the auditory selectivettention task [� � �.06, t (31) � �2.7, p � .01; Figure 3C]. Foremale smokers, change in auditory selective attention perfor-ance accuracy across test sessions was small and weakly

elated to severity of nicotine dependence. In contrast, malemokers with fewer symptoms of nicotine dependence per-ormed more accurately on this task after recent smoking,hereas male smokers with more severe nicotine depen-ence performed more accurately during abstinence. A similarender � FTND score interaction effect was observed for theivided attention task, but this did not achieve statistical signifi-ance [� � �.02, t (31) � �1.9, p � .07]; here too, although male

igure 3. (A) Group � gender interaction effect on auditory selective attentttention task performance accuracy. (C) Relationship between severity ofence, and change in accuracy of auditory selective attention task perform

mokers with lower FTND scores performed more accurately


after smoking and those with higher FTND scores performedmore accurately during abstinence, change in performance ac-curacy for female smokers was not related to FTND score.

Discussion

Effects of Smoking Abstinence on Tobacco Craving,Symptoms of Nicotine Withdrawal, and Mood and Anxiety inAdolescent Smokers

Consistent with previous studies documenting cessation ef-fects in adolescent smokers (Hanson et al 2003; Killen et al 2001;Smith et al 1996), cessation of tobacco use for 24 hours wasassociated with robust increases in symptoms of nicotine with-drawal in adolescent daily tobacco smokers. In addition, symp-toms of depressed mood increased and, in females, anxietyincreased. Increased symptoms of depression during tobaccocessation has frequently been observed in adult smokers(Jorenby et al 1996; Ward et al 2001) and has been reported byadolescent smokers surveyed retrospectively regarding theirexperiences during unsuccessful quit attempts (Centers for Dis-ease Control 2001a; Stanton et al 1996). Increased anxiety duringtobacco cessation has also been reported in both adult andadolescent smokers (Dozois et al 1995; Jorenby et al 1996; Rojaset al 1998; Stanton et al 1996; Ward et al 2001), and survey datahave also suggested that cessation-related anxiety might begreater in female adolescent smokers than in male adolescentsmokers (DiFranza et al 2002).

Although male and female smokers did not differ in smokinghistory, current smoking rate, or in severity of nicotine depen-dence, female smokers reported higher levels of tobacco cravingacross test sessions and a greater increase in nicotine withdrawalsymptoms during smoking abstinence. Few studies have re-ported gender effects on prospectively assessed symptoms of

sk performance accuracy. (B) Group � gender interaction effect on dividedine dependence, measured with the Fagerstrom Test for Nicotine Depen-cross test sessions.

ion tanicot

tobacco craving and nicotine withdrawal during smoking cessa-

tgtmw1spa

abspsnsd

CA

pepnaspjtastpd(n2ntcet

oleb1dmpdttssr

CA

a


ion in adolescents. Previous work in adult smokers has sug-ested that, although prospective reports of symptoms of nico-ine withdrawal during smoking cessation do not differ betweenen and women, men tend to underreport symptoms of nicotineithdrawal during retrospective assessments (Pomerleau et al994). The present findings suggest that among adolescentmokers assessed prospectively, girls might experience moreronounced symptoms of nicotine withdrawal and withdrawalssociated increases in anxiety than boys.

Estimated plasma cotinine concentrations in smokers duringd libitum smoking were lower than those seen in adult smokersut comparable to those previously observed in adolescent dailymokers (Hanson et al 2003; Smith et al 1996). The FTND scoresredicted cotinine concentrations at screening and at the nonab-tinent session, and the magnitude of changes in symptoms oficotine withdrawal and tobacco craving across test sessions,upporting the validity of the FTND as a measure of nicotineependence in this population.

hronic Effects of Smoking and Acute Effects of Smokingbstinence on Working Memory and Verbal Memory

Irrespective of recency of tobacco use, working memoryerformance accuracy was poorer in smokers than in nonsmok-rs. Ernst et al (2001) similarly observed poorer working memoryerformance in adult smokers relative to former smokers andonsmokers that was independent of nicotine/placebo gumdministration. In the present study, age at the time of onset ofmoking was significantly positively related to working memoryerformance accuracy, indicating that the performance of sub-

ects who began to smoke at older ages was less impaired thanhat of subjects who began to smoke at younger ages. Theverage age of onset of smoking among current smokers as-essed by Ernst et al (2001) was 15.7 � 2.7 years. Thus, althoughhe possibility that observed working memory deficits wereresent before the onset of smoking cannot be excluded by theseata, the findings from the present study and that of Ernst et al2001) are consistent with preclinical data demonstrating thateurotoxic effects of nicotine extend into adolescence (Slotkin002; Trauth et al 2000b). Preclinical work has shown thateurotoxicity of nicotine is more pronounced with fetal exposurehan with adolescent onset exposure. The present findings areonsistent with the notion of a continuum of toxicity, such thatarlier exposure to nicotine is associated with greater brain insulthan is exposure occurring at later ages.

During abstinence, performance accuracy of smokers deteri-rated when they performed a task with high working memoryoad. Short-term verbal memory also became impaired in smok-rs during abstinence. These observations suggest that, as haseen observed in adult smokers (Foulds et al 1996; Roth et al992; Snyder et al 1989; West and Hack 1991), nicotine with-rawal in adolescent smokers is associated with disruption ofemory that is reversed with resumption of smoking. It isossible that heightened dysphoria experienced by smokersuring cessation might have disrupted cognition and thus con-ributed to the observed findings; however, adding CES-D scoreso the regression model as a fixed effect did not change theignificance or direction of any of the findings described above,uggesting that symptoms of depression did not play a significantole in the observed effects of nicotine withdrawal on cognition.

hronic Effects of Smoking and Acute Effects of Smokingbstinence on Sustained, Selective and Divided Attention

Across smoking conditions, smokers performed the divided
ttention task more slowly than nonsmokers. In this task, subjects
must maintain both visual and auditory linguistic tokens in workingmemory during a short delay interval (500 msec) before presenta-tion of the cue. Once the cue is presented, subjects must decidewhether the visual and auditory stimulus combination was correct.Thus, this task involves both divided attention (attending to stimulipresented to two sensory modalities) and working memory com-ponents (processing information from two sensory modalities si-multaneously). The possibility that smokers performed more slowlythan nonsmokers on this task because of deficits in divided attentioncannot be excluded by these data; however, the possibility thatslower performance of smokers during the divided attention taskstems from difficulties with the working memory component of thistask is consistent with working memory deficits observed in smok-ers during the n-back task, and thus represents a more parsimoni-ous interpretation. Absence of significant effects of group, smokingcondition, or gender on the simple auditory and visual perceptiontask indicates that observed differences in cognitive performancedid not stem from differences in primary sensory perception. Whengender was not included in the regression models, effects of groupand of smoking condition on sustained and selective attention werenot significant.

Effects of GenderAlthough female smokers experienced greater tobacco craving

across test sessions and more intense symptoms of nicotine with-drawal and anxiety during smoking cessation, male smokers per-formed less accurately than female smokers during auditory selec-tive and divided attention tasks across test sessions and experiencedgreater slowing of working memory (binaural 2-back) performanceduring smoking cessation than female smokers. Baseline ratings ofinattention were nonsignificantly lower in male smokers relative tofemales and to male nonsmokers. Consistent with this, effects ofgender on CPT performance were not significant. Male and femalesmokers did not differ in magnitude of tobacco smoke exposure orseverity of addiction; however, male smokers began smoking at asignificantly younger age than did female smokers. Thus, therelative impairments in selective and divided attention observed inmale smokers might stem from a greater neurotoxic burden sus-tained by these subjects resulting from their earlier onset of nicotineexposure. Alternatively, greater attentional impairments in malesmokers might reflect a gender-specific effect of nicotine exposureduring adolescence.

Both male and female rats treated with nicotine during adoles-cence show cortical and subcortical cell loss and persistent reduc-tions in hippocampal cholinergic tone (Slotkin 2002; Trauth et al2000a). Behavioral studies have reported deficits in open fieldbehavior in female rats pursuant to nicotine exposure duringadolescence, suggesting greater behavioral sensitivity to the neuro-toxic effects of nicotine in females of this species. Data from humansin the current study suggest that if cognitive deficits observed inadolescent smokers stem from a neurotoxic effect of nicotine, thenthe neurocircuitry subserving attention in males might be moresensitive to these neurotoxic effects than that in females.

A gender-specific relationship was observed between FTNDscores and change in accuracy of auditory selective attentionperformance across test sessions: male smokers with fewer symp-toms of nicotine dependence performed more accurately aftersmoking, whereas males with more severe nicotine dependenceperformed more accurately during abstinence. After treatment withnicotine, elevations in central nAChR binding persist for a longerperiod of time in adolescent male rodents than in adolescent femalerodents (Trauth et al 1999). If males with more severe nicotine
dependence also have greater upregulation of nAChRs in response

tdsawempntaina

L

mettipFoabdbdTtfns

iccweac(eneLpas

hwendrctns


w

o smoking than males with fewer symptoms of nicotine depen-ence, then improved cognitive performance during smoking ab-tinence could stem from having more sensitized nAChR receptorsvailable to the endogenous ligand acetylcholine during nicotineithdrawal (Leonard and Giordano 2002). Enhancement of cholin-rgic neurotransmission has been shown to improve workingemory performance by improving the selectivity of perceptualrocessing (Furey et al 2000). If nicotine induced elevations inAChRs persist for a shorter time after smoking cessation in females,hen failure to observe a similar relationship between FTND scorend change in accuracy of auditory selective attention performancen female smokers might reflect declining numbers of sensitizedAChRs in females relative to males at the time of testing (Trauth etl 1999).

imitationsThe possibility that the group differences in cognitive perfor-

ance observed in this study stem from factors unrelated to tobaccoxposure, such as differences in demographic variables or exposureo other drugs, cannot be excluded by the present data; however,he fact that effects of group and group � smoking conditionnteractions remained significant after statistically controlling forotentially confounding variables argues against this possibility.urthermore, the observed significant relationships between age atnset of smoking and cognitive performance of smokers providesdditional evidence in support of our hypothesis that nicotine mighte toxic to adolescent brain and that earlier onset of tobacco useuring adolescence will thus tend to be associated with greaterrain insult. Subjects in this study received training in selective,ivided, and working memory tasks before the initial test session.hus, performance during both test sessions reflected functioning ofhe cognitive domain probed by the task in the absence of con-ounding effects of task learning. Given this study design, however,o conclusions can be made from these data regarding effects ofmoking or of nicotine withdrawal on task learning in adolescents.

To minimize potential confounding effects of psychiatricllness, other substance abuse/dependence disorders, and psy-hotropic medications on cognitive function, adolescents withomorbid psychiatric or substance abuse/dependence disordersere excluded from the present study. Rates of smoking arelevated among persons with mental illness (Leonard et al 2001),nd the presence of psychopathology during childhood in-reases risk for initiation of tobacco smoking during adolescenceClark and Cornelius 2004). The present findings cannot bextended to this important population of teenagers. Given thaticotine might ameliorate some of the cognitive deficits experi-nced by persons with mental illness (Jacobsen et al 2004;eonard et al 2001), further work is needed to understandotential unique effects of nicotine and of nicotine withdrawal indolescent tobacco users with comorbid psychiatric and/orubstance abuse/dependence disorders.

In summary, adolescent daily tobacco smokers were found toave impairments in working memory, which were more severeith earlier age of onset of smoking, consistent with preclinicalvidence that brain insult stemming from neurotoxic effects oficotine is more severe when exposure occurs at earlier periods inevelopment. Adolescents demonstrated evidence of further dis-uption of working memory and verbal memory during smokingessation. Finally, although female smokers experienced greaterobacco craving across test sessions and more intense symptoms oficotine withdrawal and anxiety during smoking cessation, male
mokers demonstrated greater impairment of selective and divided

attention, possibly reflecting greater neurotoxic insult sustained bymales resulting from their earlier age at smoking initiation.

These findings underscore the importance of efforts aimed atpreventing smoking initiation in youth. In addition, the evidencethat adolescent smokers trying to quit might experience furthercognitive impairment associated with cessation suggests thatteenagers attempting to quit smoking might benefit from addi-tional educational support.

This research was supported by National Institutes of Healthgrants DA14655 and RR06022, and by the Department of VeteransAffairs.

We thank Jonathan Feinstein, Ph.D., for statistical consultation,Sabrina Pizzola and Michelle Rosado for assistance with datacollection, and Suchitra Krishnan-Sarin, Ph.D., for consultationregarding subject recruitment.

Baldinger B, Hasenfratz M, Battig K (1995): Comparison of the effects ofnicotine on a fixed rate and a subject-paced version of the rapidvisual information processing task. Psychopharmacology 121:396 –400.

Bates T, Mangan G, Stough C, Corballis P (1995): Smoking, processing speedand attention in a choice reaction time task. Psychopharmacology 120:209 –212.

Beck AT, Ward CH, Mendelson M, Mock J, Erbaugh J (1961): An inventory formeasuring depression. Arch Gen Psychiatry 4:561–571.

Benedict RHB, Zgaljardic DJ (1998): Practice effects during repeated admin-istrations of memory tests with and without alternate forms. J Clin ExpNeuropsychol 20:339 –352.

Bowers TL, Pantle ML (1998): Shipley institute for living scale and the Kauf-man Brief Intelligence Test as screening instruments for intelligence.Assessment 5:187–195.

Centers for Disease Control (2001a): Reasons for tobacco use and symptomsof nicotine withdrawal among adolescent and young adult tobaccousers—United States, 1993. MMWR Morb Mortal Wkly Rep 43:445– 450.

Centers for Disease Control (2001b): Youth Tobacco Surveillance—UnitedStates, 2000. MMWR Morb Mortal Wkly Rep 50:1–92.

Chen WJ, Hsiao CK, Hsiao LL, Hwu HG (1998): Performance of the ContinuousPerformance Test among community samples. Schizophr Bull 24:163–174.

Clark DB, Cornelius J (2004): Childhood psychopathology and adolescentcigarette smoking: A prospective survival analysis in children at high riskfor substance use disorders. Addict Behav 29:837– 841.

Conners CK (1998): Rating scales in attention-deficit/hyperactivity disorder:Use in assessment and treatment monitoring. J Clin Psychiatry 59(suppl7):24 –30.

DiFranza JR, Savageau JA, Rigotti NA, Fletcher K, Ockene JK, McNeill AD, et al(2002): Development of symptoms of tobacco dependence in youths: 30month follow up data from the DANDY study. Tob Control 11:228 –235.

Dozois DN, Farrow JA, Miser A (1995): Smoking patterns and cessationmotivations during adolescence. Int J Addict 30:1485–1498.

Ernst M, Heishman SJ, Spurgeon L, London ED (2001): Smoking history andnicotine effects on cognitive performance. Neuropsychopharmacology25:313–319.

Faraday MM, Elliott BM, Grunberg NE (2001): Adult vs.adolescent rats differin biobehavioral responses to chronic nicotine administration. Pharma-col Biochem Behav 70:475– 489.

Foulds J, Stapleton J, Swettenham J, Bell N, McSorley K, Russell MAH (1996):Cognitive performance effects of subcutaneous nicotine in smokers andnever-smokers. Psychopharmacology 127:31–38.

Fried PA (1995): Prenatal exposure to marihuana and tobacco during in-fancy, early and middle childhood: Effects and an attempt at synthesis.Arch Toxicol Suppl 17:233–260.

Fried PA, Watkinson B, Gray R (2003): Differential effects on cognitive func-tioning in 13- to 16-year-olds prenatally exposed to cigarettes and mar-ihuana. Neurotoxicol Teratol 25:427– 436.

Furey ML, Pietrini P, Haxby JV (2000): Cholinergic enhancement and in-creased selectivity of perceptual processing during working memory.
Science 290:2315–2319.

G

G

G

H

H

H

H

H

H

H

H

H

J

J

J

J

K

K

K

K

K

K

L

L

L

L


ilbert DG, Estes SL, Welser R (1997): Does noise stress modulate effects ofsmoking/nicotine? Mood, vigilance, and EEG responses. Psychopharma-cology 129:382–389.

lobal Youth Tobacco Survey Collaborative Group (2002): Tobacco useamong youth: A cross country comparison. Tob Control 11:252–270.

orell JM, Rybicki BA, Johnson CC, Peterson EL (1999): Smoking and Parkin-son’s disease: A dose-response relationship. Neurology 52:115–119.

ahn B, Shoaib M, Stolerman IP (2002): Nicotine-induced enhancement ofattention in the five-choice serial reaction time task: The influence of taskdemands. Psychopharmacology 162:129 –137.

ahn B, Stolerman IP (2002): Nicotine-induced attentional enhancement inrats: Effects of chronic exposure to nicotine. Neuropsychopharmacology27:712–722.

anson K, Allen S, Jensen S, Hatsukami D (2003): Treatment of adolescentsmokers with the nicotine patch. Nicotine Tob Res 5:515–526.

asenfratz M, Pfiffner D, Pellaud K, Battig K (1989): Postlunch smoking forpleasure seeking or arousal maintenance? Pharmacol Biochem Behav34:631– 639.

eatherton TF, Kozlowski LT, Frecker RC, Fagerstrom KO (1991): The Fager-strom test for nicotine dependence: A revision of the Fagerstrom Toler-ance Questionnaire. Br J Addict 86:1119 –1127.

eishman SJ, Snyder FR, Henningfield JE (1993): Performance, subject, andphysiological effects of nicotine in nonsmokers. Drug Alcohol Depend34:11–18.

indmarch I, Kerr JS, Sherwood N (1990): Effects of nicotine gum on psy-chomotor performance in smokers and nonsmokers. Psychopharmacol-ogy 100:535–541.

oulihan ME, Pritchard WS, Robinson JH (1996): Faster P300 latency aftersmoking in visual but not auditory oddball tasks. Psychopharmacology123:231–238.

ughes J, Hatsukami DK (1998): Errors in using tobacco withdrawal scale.Tob Control 7:92–93.

acob P, Wilson M, Benowitz NL (1981): Improved gas chromatographicmethod for the determination of nicotine and cotinine in biologic fluids.J Chromatogr A 222:61–70.

acobsen LK, D’Souza DC, Mencl WE, Pugh KR, Skudlarski P, Krystal JH (2004):Nicotine effects on brain function and functional connectivity in schizo-phrenia. Biol Psychiatry 55:850 – 858.

arvis MJ, Primatesta P, Erens B, Feyerabend C, Bryant A (2003): Measuringnicotine intake in population surveys: Comparability of saliva cotinineand plasma cotinine estimates. Nicotine Tob Res 5:349 –355.

orenby DE, Hatsukami DK, Smith SS, Fiore MC, Allen S, Jensen J, et al (1996):Characterization of tobacco withdrawal symptoms: Transdermal nicotinereduces hunger and weight gain. Psychopharmacology 128:130–138.

aneko S, Maeda T, Kume T, Kochiyama H, Akaike A, Shimohama S, et al(1997): Nicotine protects cultured cortical neurons against glutamate-induced cytotoxicity via �7-neuronal receptors and neuronal CNS recep-tors. Brain Res 765:135–140.

eenan RM, Hatsukami DK, Anton DJ (1989): The effects of short-termsmokeless tobacco deprivation on performance. Psychopharmacology98:126 –130.

illen JD, Ammerman S, Rojas N, Varady J, Haydel F, Robinson TN (2001): Doadolescent smokers experience withdrawal effects when deprived ofnicotine? Exp Clin Psychopharmacol 9:176 –182.

rebs SJ, Petros TV, Beckwith BE (1994): Effects of smoking on memory forprose passages. Physiol Behav 56:723–727.

rishnan-Sarin S, Rosen MI, O’Malley SS (1999): Naloxone challenge in smok-ers. Preliminary evidence of an opioid component in nicotine depen-dence. Arch Gen Psychiatry 56:663– 668.

umari V, Gray JA, ffytche DH, Mitterschiffthaler MT, Das M, Zachariah E, et al(2003): Cognitive effects of nicotine in humans: An fMRI study. Neuroim-age 19:1002–1013.

anders DM, Crews DJ, Boutcher SH, Skinner JS, Gustafsen S (1992): Theeffects of smokeless tobacco on performance and psychophysiologicalresponse. Med Sci Sports Exerc 24:895–903.

awrence NS, Ross TJ, Stein EA (2002): Cognitive mechanisms of nicotine onvisual attention. Neuron 36:539 –548.

e Houezec J, Halliday R, Benowitz NL, Callaway E, Naylor H, Herzig K (1994):A low dose of subcutaneous nicotine improved information processingin non-smokers. Psychopharmacology 114:628 – 634.

eonard S, Adler LE, Benhammou K, Berger R, Breese CR, Drebing C, et al (2001):
Smoking and mental illness. Pharmacol Biochem Behav 70:561–570.
Leonard S, Giordano L (2002): Are differential behavioral responses to smok-ing and smoking cessation in schizophrenia related to nicotinic receptorlevels? Neuropsychopharmacology 27:1082–1083.

Levin ED, Kim P, Meray R (1996): Chronic nicotine working and referencememory effects in the 16-arm radial maze: Interactions with D1 agonistand antagonist drugs. Psychopharmacology 127:25–30.

Little K, Penman E (1989): Measuring subacute mood changes using theprofile of mood states and visual analogue scales. Psychopathology1989:42– 49.

Maggio R, Riva M, Vaglini F, Fornai F, Molteni R, Armogida M, et al (1998):Nicotine prevents experimental parkinsonism in rodents and inducesstriatal increase of neurotrophic factors. J Neurochem 71:2439 –2446.

March JS, Parker JD, Sullivan K, Stallings P, Conners CK (1997): The Multidi-mensional Anxiety Scale for Children (MASC): Factor structure, reliability,and validity. J Am Acad Child Adolesc Psychiatry 36:554 –565.

Moolchan ET, Radzius A, Epstein DH, Uhl G, Gorelick DA, Cadet JL, et al(2002): The Fagerstrom Test for Nicotine Dependence and the Diagnos-tic Interview Schedule: Do they diagnose the same smokers? AddictBehav 27:101–113.

Peachey JE, Lei H (1988): Assessment of opioid dependence with naloxone.Br J Addict 83:193–201.

Perkins KA, Grobe JE, Fonte C, Goettler J, Caggiula AR, Reynolds WA, et al (1994):Chronic and acute tolerance to subjective, behavioral and cardiovasculareffects of nicotine in humans. J Pharmacol Exp Ther 270:628–638.

Petrie RX, Dreary IJ (1989): Smoking and information processing. Psychop-harmacology 99:393–396.

Phillips S, Fox P (1998): An investigation into the effects of nicotine gum onshort-term memory. Psychopharmacology 140:429 – 433.

Pineda JA, Herrera C, Kang C, Sandler A (1998): Effects of cigarette smokingand 12-h abstention on working memory during a serial-probe recogni-tion task. Psychopharmacology 139:311–321.

Pomerleau CS, Tate JC, Lumley MA, Pomerleau OF (1994): Gender differ-ences in prospectively versus retrospectively assessed smoking with-drawal symptoms. J Subst Abuse Treat 6:433– 440.

Pritchard WS, Robinson JH, Guy TD (1992): Enhancement of continuousperformance task reaction time by smoking in non-deprived smokers.Psychopharmacology 108:437– 442.

Puig-Antich J, Orvaschel H, Tabrizi MA, Chambers W (1980):The Schedule forAffective Disorders and Schizophrenia for School-Age Children-Epidemio-logic Version (Kiddie-SADS-E), 3rd ed. New York: New York State Psychiat-ric Institute and Yale University School of Medicine.

Puma C, Deschaux O, Molimard R, Bizot JC (1999): Nicotine improves mem-ory in an object recognition task in rats. Eur Neuropsychopharmacol9:323–327.

Radloff L (1977): The CES-D scale: A self report depression scale for researchin the general population. Appl Psychol Measures 1:385– 401.

Repp BH, Frost R (1988): Detectability of words and nonwords in two kinds ofnoise. J Acoust Soc Am 84:1929 –1932.

Rojas NL, Killen JD, Haydel KF, Robinson TN (1998): Nicotine dependenceamong adolescent smokers. Arch Pediatr Adolesc Med 152:151–156.

Ross GW, Petrovitch H (2001): Current evidence for neuroprotective effects ofnicotine and caffeine against Parkinson’s disease. Drugs Aging 18:797–806.

Roth N, Lutiger B, Hasenfratz M, Battig K, Knye M (1992): Smoking depriva-tion in “early” and “late” smokers and memory functions. Psychopharma-cology 106:253–260.

Sansone M, Castellano C, Battaglia M, Ammassari-Teule M (1991): Effects ofoxiracetam-nicotine combinations on active and passive avoidancelearning in mice. Pharmacol Biochem Behav 39:197–200.

Shapiro AM, Benedict RH, Schretlen D, Brandt J (1999): Construct and con-current validity of the Hopkins Verbal Learning Test-revised. Clin Neuro-psychol 13:348 –358.

Shaywitz BA, Shaywitz SE, Pugh KR, Fulbright RK, Skudlarski P, Mencl WE, etal (2001): The functional neural architecture of components of attentionin language-processing tasks. Neuroimage 13:601– 612.

Shiffman S, Paty JA, Gnys M, Kassel JD, Elash C (1995): Nicotine withdrawal inchippers and regular smokers: Subjective and cognitive effects. HealthPsychol 14:301–309.

Shiffman SM, Jarvik ME (1976): Smoking withdrawal symptoms in two weeksof abstinence. Psychopharmacology 50:35–39.

Slotkin TA (2002): Nicotine and the adolescent brain: Insights from andanimal model. Neurotoxicol Teratol 24:369 –384.

Smith TA, House RF, Croghan IT, Gauvin TR, Colligan RC, Offord KP, et al (1996):
Nicotine patch therapy in adolescent smokers. Pediatrics 98:659–667.

S

S

S

T

T

T

T


w

nyder FR, Davis FC, Henningfield JE (1989): The tobacco withdrawal syn-drome: Performance decrements assessed on a computerized test bat-tery. Drug Alcohol Depend 23:259 –266.

pilich GJ, June L, Renner J (1992): Cigarette smoking and cognitive perfor-mance. Br J Addict 87:1313–1326.

tanton WR, Lowe JB, Gillespie AM (1996): Adolescents’ experiences ofsmoking cessation. Drug Alcohol Depend 43:63–70.

eneggi V, Squassante L, Iavarone L, Milleri S, Bye A, Gomeni R (2002):Correlation and predictive performances of saliva and plasma nico-tine concentration on tobacco withdrawal-induced craving. Br J ClinPharmacol 54:407– 414.

iffany ST, Drobes DJ (1991): The development and initial validation of aquestionnaire on smoking urges. Br J Addict 86:1467–1476.

rauth JA, McCook EC, Seidler FJ, Slotkin TA (2000a): Modeling adolescentnicotine exposure: Effects on cholinergic systems in rat brain regions.Brain Res 873:18 –25.

rauth JA, Seidler FJ, McCook EC, Slotkin TA (1999): Adolescent nicotineexposure causes persistent upregulation of nicotinic cholinergic recep-
tors in rat brain regions. Brain Res 851:9 –19.

Trauth JA, Seidler FJ, Slotkin TA (2000b): An animal model of adolescentnicotine exposure: Effects on gene expression and macromolecular con-stituents in rat brain regions. Brain Res 867:29 –39.

Trauth JA, Seidler FJ, Slotkin TA (2000c): Persistent and delayed behav-ioral changes after nicotine treatment in adolescent rats. Brain Res880:167–172.

US Census Bureau (2002): U.S. Summary: 2000; Census 2000 Profile. Available at:http://www.census.gov/prod/cen2000/dpl/2khoo.pdf. Accessed Novem-ber 29, 2004.

Ward MM, Swan GE, Jack LM (2001): Self-reported abstinence effects in thefirst month after smoking cessation. Addict Behav 26:311–327.

West R, Hack S (1991): Effect of cigarettes on memory search and subjectiveratings. Pharmacol Biochem Behav 38:281–286.

Yamashita H, Nakamura S (1996): Nicotine rescues PC12 cells from deathinduced by nerve growth factor deprivation. Neuroscience letters 213:145–147.

Zoli M, Picciotto MR, Ferrari R, Cocchi D, Changeux JP (1999): Increasedneurodegeneration during ageing in mice lacking high-affinity nicotinic
receptors. EMBO J 18:1235–1244.
http://www.census.gov/prod/cen2000/dpl/2khoo.pdf

Effects of smoking and smoking abstinence on cognition in adolescent tobacco smokers

Documents

Transcript of Effects of smoking and smoking abstinence on cognition in adolescent tobacco smokers