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KHROYAN 147 BASIC MECHANISMS OF NICOTINE ADDICTION 148 ANIMAL MODELS OF NICOTINE ADDICTION 149 Self-Administration 149 The Place-Conditioning Paradigm 151 Preclinical Genetic Models: Insights into Individual Differences in Nicotine-Induced Behavior 152 Relevance of Preclinical Studies to Understanding Tobacco Dependence 152 SOCIAL AND PSYCHOLOGICAL RISK FACTORS FOR INITIATION AND MAINTENANCE OF TOBACCO USE 153 Gender and Ethnic Differences 153 Cognitive Effects of Smoking 153 Psychiatric Comorbidity and Tobacco Dependence 153 ENVIRONMENTAL RISK FACTORS FOR INITIATION 154 Tobacco Advertising and Promotions 154 Effects of Pricing and Tobacco Control Policies 154 Youth Access to Tobacco 155 PREVENTION AND TREATMENT OF TOBACCO DEPENDENCE 155 Cessation Methods 155 EVIDENCE FOR GENETIC INFLUENCE ON TOBACCO USE IN HUMANS 157 Deﬁnition of Phenotypes 158 Evidence for a Genetic Basis to a Variety of Smoking-Related Phenotypes 158 Tobacco Dependence: A Construct in Need of Reﬁnement 159 The Potential Importance of Gene-Behavior-Environment Interactions in Tobacco Dependence 160 PUBLIC HEALTH IMPERATIVE FOR COLLABORATIVE, TRANSDISCIPLINARY RESEARCH 160 Ethical Considerations 161 SUMMARY 161 REFERENCES 162 Tobacco dependence is determined by psychosocial, envi- ronmental, and biological factors. Individual differences in exposure to various environmental risk factors in”uence sus- ceptibility to become addicted to nicotine initially just as do differences in a multitude of biological and physiological characteristics. Moreover, the extent to which the various risk factors interact with each other within and across these broad sources of individual variation provide additional sources of in”uence that can determine an individual•s likelihood of becoming addicted to nicotine once exposed. Smoking be- havior can be viewed as a sequence of speci“c components that vary across the life-cycle. Thus, just as biological and en- vironmental factors can exert main and interactive effects to determine susceptibility, so too can they in”uence the likeli- hood of maintaining tobacco dependence once it is estab- lished, response to treatment for tobacco dependence, and the likelihood of relapse following treatment. This chapter re- views state-of-the-art “ndings and poses questions in need of further investigation. Tobacco smoke, inhaled either directly or as second-hand smoke, contains more than 4,000 different compounds, many of which are proven carcinogens (Roberts, 1988). There is substantial evidence suggesting that nicotine plays a pivotal role in mediating the addictive nature of tobacco in humans U.S. Department of Health and Human Services ([USDHHS], 1988). Nicotine is readily absorbed across the respiratory tract epithelium, buccal mucosa (cheek), and skin. Systemic bioavailability through the gastrointestinal tract is limited because of “rst-pass liver metabolism. After inhalation, nicotine reaches the brain in approximately 10 to 19 seconds (Benowitz, Porchet, Sheiner, & Jacob, 1988), re- sulting in rapid onset of behaviorally reinforcing effects on the nervous system, including pleasure, relief of anxiety, im- proved task performance, improved memory, mood modula- tion, and skeletal muscle relaxation (Benowitz, 1999). These Preparation of this chapter was supported in part by grants from the Tobacco-Related Disease Research Program, University of California (7PT2000), the National Cancer Institute (CA71358), and the National Institute on Drug Abuse (DA11170). The authors wish to thank Ms. Kymberli Hemberger for her assistance with the preparation of this manuscript. 148 Tobacco Dependence positive effects, mediated by alterations in neurotrans- mitter levels, give way to negative, withdrawal effects in the absence of nicotine among dependent tobacco users. Withdrawal symptoms include anger/irritability, anxiety, dif“culty concentrating, drowsiness, fatigue, hunger/weight gain, impatience, and restlessness (Hughes, Gust, Skoog, Keenan, & Fenwick, 1991). These symptoms tend to manifest in the “rst 24 hours, peak in the “rst 1 to 2 weeks, and gener- ally resolve within 30 days after quitting. Although many pa- tients report cravings for cigarettes many months or years after quitting. An estimated 47.2 million Americans smoke (Centers for Disease Control and Prevention, 2000); 70% want to quit completely (Centers for Disease Control and Prevention, 1994); and each year, approximately 17 million adult smok- ers in the United States make a serious attempt to quit. Despite decades of research into improving methods for at- taining cessation, smoking quit rates remain low„annually , only an estimated 2.5% are able to quit permanently (Centers for Disease Control and Prevention, 1993). Economically, the burden of smoking is enormous, costing the United States an estimated $72 billion annually in lost productivity and med- ical care (Horgan, Marsden, & Larson, 1993). Figure 7.1, a summary of numerous studies (Chassin, Presson, Sherman, & Edwards, 1990; Choi, Pierce, Gilpin, Farkas, & Berry, 1997; Flay, 1999; Gilpin, Lee, Evans, & Pierce, 1994; Gritz et al., 1998; Jessor & Jessor, 1977; Johnston, O•Malley, & Bachman, 1991, 1995; Kendler, 1999), illustrates the development of tobacco dependence. Tobacco dependence consists of several identi“able phases when viewed from a developmental perspective. Following initial exposure to tobacco, an individual will experiment with it and, assuming that the consequences of ex- perimentation have provided more positive than negative con- sequences, that individual will acquire regular tobacco use as a feature of his or her behavioral repertoire. To the extent that tobacco use itself acquires an instrumental component (e.g., helping the individual to cope with stress, manage weight, reg- ulate affect), it will be maintained and, depending on the per- son and environmental conditions, perhaps even strengthen over time (increase in cigarettes smoked per day, for exam- ple). There is the possibility that tobacco use will lessen (smoking fewer cigarettes or •lighterŽcigarettes) and perhaps extinguish altogether. For many people desiring to quit, how- ever, there begins a process of cessation-reacquisition-relapse that commonly is repeated many times. BASIC MECHANISMS OF NICOTINE ADDICTION The diverse effects of nicotine on brain function are mediated by activating nicotinic acetylcholine receptors (nACHRs). The nACHRs are formed by the combination of “ve and/or subunits. Thus far, 11 subunits have been identi“ed in dif- ferent neuronal populations, those being 2 to 9 and 2 to 4. In the brain, nACHRs can be divided into two subfami- lies: homoligomeric receptors that are composed of identical subunits ( 7, 8, or 9 subunits); and heteromeric receptors that are composed of varying combinations of 2, 3, 4, and 6 with either 2 or 4 and in some cases also with 5or 3 subunits (Clementi, Fornasari, & Gotti, 2000; Paterson & Nordberg, 2000). The nACHRs are found on the cell body Exposure Experimentation Acquisition Maintenance Extinction Cessation Reacquisition Relapse Cycling Depression ADHD Anti-social personality Neuroticism Gender Metabolism Brain reward system Brain opioid system Brain serotonergic system Stress End-organ changes Receptor function and density Heightened concentration Mood alterations Withdrawal sxs Weight loss Boredom Dysphoria Demand for vigilance Demand for thinness Parental smoking Peer influences Advertising Preexisting Conditions Environmental Conditions Secondary Conditions Figure 7.1 A working model of genetic and environmental factors in the developmental span of smoking. Animal Models of Nicotine Addiction 149 region and axons of many important neurotransmitter systems; stimulation of these receptors can in”uence the re- lease of other neurotransmitters such as dopamine, norepi- nephrine, acetylcholine, GABA, and glutamate, leading to behavioral changes associated with arousal, mood, and cognition function (for review, see Clementi et al., 2000; Paterson & Nordberg, 2000). Similar to other drugs of abuse, nicotine is hypothesized to produce its reinforcing effects by activating the mesocorticol- imbic dopamine system (for reviews, see Di Chiara, 2000; Stolerman & Shoaib, 1991; Watkins, Koob, & Markou, 2000). This pathway originates in the ventral tegmental area (VTA) and projects to the nucleus accumbens (NAc) and other corti- cal target areas. Nicotine depolarizes dopaminergic neurons in the VTA in vitro, and stimulates the release of dopamine in the NAc in vivo (Calabresi, Lacey, & North, 1989; Imperato, Mulas, & Di Chiara, 1986). In humans, functional magnetic resonance imaging reveals that an acute nicotine injection re- sults in an increase in neuronal activity in limbic and cortical brain regions such as the amygdala, NAc, cingulate, and frontal cortical lobes (Stein et al., 1998). This increase is ac- companied by increases in behavioral measures of feelings such as •rush,Ž •high,Žand drug liking (Stein et al., 1998). In animals, intravenous (i.v.) nicotine self-administration in the rat produces regional brain activation in the NAc, medial prefrontal cortex, and medial caudate area, as assessed by c-Fos and Fos-related protein expression (Pagliusi, Tessari, DeVevey, Chiamulera, & Pich, 1996; Pich et al., 1997). Variability in the metabolism of nicotine across indi- viduals might contribute to nicotine•s addictive potential. For example, •slowŽ metabolizers of nicotine may be more sub- ject to the aversive properties of nicotine because of the higher levels of untransformed nicotine per unit time and, consequently, may use less tobacco. Conversely, •fastŽ me- tabolizers of nicotine may be less subject to nicotine toxicity because of lower levels of nicotine and, consequently, need to use more tobacco per unit time to maintain suf“cient levels of nicotine. It has been suggested that the nicotine metabolism pathway may be altered via genetic polymorphisms (Idle, 1990). Studies have examined genetic variation of enzymes involved in the metabolism of nicotine, however, the out- comes are not conclusive and warrant further investigation. Understanding of individual differences in nicotine metabo- lism and their relationship to susceptibility for becoming and/or remaining a regular tobacco user is in the early stages. Increased information is needed on the full array of genes in- volved in the various metabolic processes, the extent of indi- vidual variation in the genetic substrate, along with a better appreciation of how these differences in”uence susceptibility to become addicted to nicotine. ANIMAL MODELS OF NICOTINE ADDICTION Animal models examining the reinforcing effects of nicotine have been used to assess the various contributing factors of tobacco dependence as observed in the human population. The extent to which animal models can be used to interpret the underlying nature of dependence in humans depends mainly on the validity of the model. Animal models have been evaluated based on predictive, face, and construct valid- ity (Willner, 1991). Predictive validity of an animal model is de“ned as •performance in the test predicts performance in the condition being modeled.Ž For example, valid animal models of drug reward can differentiate between drugs that are abused by humans and those that are not and can therefore be used to evaluate whether a novel drug possesses abuse li- ability as well as to detect potential candidate medications for prevention of drug addiction. Face validity is an indication of whether the •behavioral and pharmacological qualitiesŽ of an animal model are similar in nature to those seen in the human condition. Construct validity is assessed by determining whether there is a •sound theoretical rationaleŽ between the animal model and the human condition being modeled (Willner, 1991). Table 7.1 addresses the questions that assess the validity of each animal model discussed next as related to nicotine addiction. Several animal models have been used to examine the reinforcing effects of nicotine. In the following paragraphs, we discuss methodology, “ndings directly related to nico- tine addiction, and validity (see Table 7.1) of two frequently used animal models, the self-administration and the place- conditioning paradigms. Self-Administration The self-administration (SA) paradigm provides a measure of the reinforcing effects of drugs. The animal learns the re- lationship of its behavior such as pressing a lever or a nose- poke and a reinforcer such as an i.v. injection of a drug. If the relationship between the animal•s behavior and the re- sponse is reinforcing, the probability of the animal continu- ing the behavior is increased. It has taken 10 to 15 years of research with animals to map out the conditions that will support reliable SA of nicotine. Nicotine SA has been demon- strated in nonhuman primates (Goldberg, Spealman, & Gold- berg, 1981), rats (Corrigall & Coen, 1989; Donny, Caggiula, Knopf, & Brown, 1995), and mice (Picciotto et al., 1998; Stolerman, Naylor, Elmer, & Goldberg, 1999). The role of the mesocorticolimbic dopamine system in mediating nico- tine SA has also been examined. For example, lesions of dopaminergic neurons in the NAc, and administration of TABLE 7.1 Validity of Animal Models as Related to Human Tobacco Dependence Predictive Validity Face Validity Construct Validity Animal model Self-administration (SA) Place-conditioning (PC) •Does the animal model provide a valid measure of the reinforcing effects of nicotine?Ž Moderate-High: Animals will self-administer nicotine, however, under limited experimental conditions. Moderate-High: Nicotine can produce PC, however, nicotine PC has been dif“cult to establish. •Does the animal model have phenomenological similarities with human smoking behavior?Ž High: Animals have control over nicotine delivery. SA paradigm provides a measure of compulsive nicotine-taking behavior. The intravenous route of SA is used, providing a route allowing rapid absorption. Moderate: Unlike human nicotine consumption, nicotine delivery is passive with the PC animal model. But: Intravenous route of administration can be used (rapid absorption). Animals receive repeated injections of nicotine over many days. Animals •seekŽ nicotine similar to humans. The environment paired with nicotine produces a conditioned response (similar to humans). •Is the theoretical premise underlying the animal model similar to that for tobacco dependence in humans?Ž and •Is there evidence for the role of dopamine in modulating the effects of nicotine?Ž High: SA provides a good measure of reinforcement since primary reinforcers (such as food and water) are also self-administered. Studies have examined the importance of the dopamine system in mediating nicotine SA. Moderate-High: PC paradigm provides a valid measure of both nicotine-induced reward and aversion (at higher doses). PC is a valid model of incentive motivation. Neurochemical evidence is sparse. Only one reported study of the importance of dopamine in acquisition of nicotine PC. 150 Animal Models of Nicotine Addiction 151 antagonists systemically and directly into the VTA produces dose-related decreases in nicotine SA (Corrigall & Coen, 1991; Corrigall, Coen, & Adamson, 1994; Corrigall, Franklin, Coen, & Clarke, 1992). Further evidence for pos- sible long-term adaptations in the mesocorticolimbic system stems from research examining activation of immediate early genes such as the transcription factor c-Fos induced in neu- rons following various environmental and pharmacological manipulations. Nicotine SA increases c-Fos-related antigens expressed in the NAc as well as other regions similar to that seen with cocaine SA (Pagliusi et al., 1996; Pich et al., 1997). Thus, nicotine self-administration can result from an action of nicotine on nACHRs that activate the mesocorticolimbic dopamine system. The SA paradigm has high predictive validity since com- pounds that are deemed addictive in humans will also support SA. For example, similar to other drugs of abuse such as cocaine and morphine, animals will self-administer nicotine (see above). The SAparadigm also possesses a high degree of face validity. First, similar to human drug intake, animals are given control over the drug administration and they perform a required schedule of responses to obtain the drug. Second, because the current smoking epidemic involves routes of ad- ministration that allow rapid distribution to brain tissue, the i.v. route often used in animal SA studies is a route that closely mimics human drug intake. The degree of construct validity associated with the SA paradigm is high. In humans, nicotine becomes addictive in nature partially because it pro- duces reinforcing interoceptive stimuli or positive subjective effects. Similarly, a drug is said to maintain SA behavior in animals because it acts as a positive reinforcer. Thus, the addictive nature of smoking in humans is assumed to be the same as that measured by the SA paradigm. With regard to construct validity, the SA paradigm also provides evidence for the role of dopamine in mediating the reinforcing effects of nicotine. The various aspects of validity of the SA model as a measure for nicotine addiction are summarized in Table 7.1. The Place-Conditioning Paradigm The place-conditioning (PC) paradigm has also been used to measure the rewarding as well as the aversive properties of drugs of abuse. The PC paradigm measures the incentive motivational properties of stimuli that become associated with drug effects through classical conditioning. The drug is administered in a distinct environment. After several pair- ings, the environment becomes associated with the effects of the drug, thereby acquiring incentive-motivational proper- ties. Thus, the environment provides cues eliciting either approach (i.e., conditioned place preference, CPP) or avoid- ance (i.e., conditioned place aversion, CPA) behaviors de- pending on whether rewarding or aversive properties of the drug have been conditioned, respectively. Nicotine-induced PC has been examined in rodents; how- ever, similar to nicotine SA, nicotine-induced PC has been dif“cult to establish (Clarke & Fibiger, 1987). Nicotine- induced CPP and CPA have been shown in a variety of strains of rats and mice (Acquas, Carboni, Leone, & Di Chiara, 1989; Calcagnetti & Schechter, 1994; Fudala, Teoh, & Iwamoto, 1985; Martin & Itzhak, 2000; Schechter, Meehan, & Schechter, 1995). The role of dopamine in mediating nicotine- induced CPP has not been extensively studied. In one pub- lished study, a dopamine receptor antagonist, SCH23390, prevents acquisition of nicotine-induced CPP (Acquas et al., 1989). Further studies are needed to clarify the role of dopamine in mediating the rewarding/aversive effects of nicotine as measured by the PC paradigm. The PC paradigm is considered to have a high degree of predictive validity since drugs that are addictive in humans also produce CPP in animals. On the other hand, the PC par- adigm is thought to possess a low degree of face validity relative to the SA paradigm in regard to the method of drug delivery. In the PC paradigm, nicotine delivery is passive and does not depend on the animal•s behavior, whereas with the SA paradigm the animal actively self-administers nicotine. However, the PC paradigm possesses a certain level of face validity since the environment that is paired with effects of nicotine acquires the status of a conditioned stimulus. Thus, when the animal is given access to both compartments, and the resulting effect is a CPP, the environment is said to have elicited a conditioned response. Conditioned responses also play an important role in human smoking behavior. Previous research has shown that drug-associated environments as well as paraphernalia associated with drug taking (the condi- tioned stimuli) can evoke both physiological and psycholog- ical drug-related responses (Ehrman, Robbins, Childress, & O•Brien, 1992). This parallel seen with human smoking behavior and the PC paradigm provides evidence for some degree of face validity with this animal model. The PC para- digm possesses a high degree of construct validity since it measures drug-induced reinforcement or incentive motiva- tion. These theoretical constructs play a fundamental role in addiction theory (T. Robinson & Berridge, 1993). Similar to the SA paradigm, “ndings using the PC paradigm also support the dopamine hypothesis of addiction. Evidence sup- porting the latter is sparse in regard to nicotine-induced PC since only one published experiment has examined the ef- fects of a dopamine antagonist (see Acquas et al., 1989). However, previous research has thoroughly examined the 152 Tobacco Dependence effects of dopamine in mediating CPP induced by other drugs of abuse such as cocaine, amphetamine, and morphine (Hoffman, 1989; Schechter & Calcagnetti, 1993). Various aspects of validity as related to the PC paradigm are sum- marized in Table 7.1. Preclinical Genetic Models: Insights into Individual Differences in Nicotine-Induced Behavior Animal studies using inbred strains have indicated that there are potential strain differences providing some insight as to why there are individual differences in the development of nicotine addiction in humans. Indeed, when inbred strains of mice are provided with a choice of nicotine or vehicle solu- tions, the strains differ dramatically in their self-selection of nicotine (Crawley et al., 1997; Meliska, Bartke, McGlacken, & Jensen, 1995; S. Robinson, Marks, & Collins, 1996). Across the different strains, the higher the preference for the nicotine solution, the lower the sensitivity to nicotine-induced seizures (S. Robinson et al., 1996). Thus, the negative toxic actions of nicotine limit nicotine consumption in mice. There are also differences in SAof nicotine by inbred strains of mice, where nicotine can serve as a positive reinforcer in c75BL/6 mice but not in DBA/2 mice (Stolerman et al., 1999). Genetically altered mice with certain targeted gene muta- tions are also becoming important tools in studying the molecular nature of nicotine addiction (Mohammed, 2000; Picciotto et al., 1998). These •knock outŽ mice are mutant mice lacking genetic information encoding speci“c nACHR subunits. Because the 2 subunit is widely expressed in the central nervous system and is found in the mesocorticolimbic dopamine system, the reinforcing effects of nicotine have been examined in 2-knockout mice (Picciotto et al., 1998). Picciotto et al. (1998) report that nicotine-induced dopamine release in the ventral striatum is only observed in wild-type mice and not in 2-knockout mice. Furthermore, mesen- cephalic dopamine neurons are no longer responsive in 2-knockout mice. Similar to their wild-type counterparts, 2-knockout mice learned to self-administer cocaine. How- ever, when nicotine was substituted for cocaine, nicotine SA was attenuated in the 2-knockout mice relative to wild- types. These “ndings suggest that the 2 receptor subtype plays a crucial role in the reinforcing effects of nicotine. Studies using mutant mice provide some insight as to indi- vidual differences in tobacco smoking. For example, differ- ent expression of nACHR subtypes (i.e., by knocking out various nACHR subunits in animals) can partially account for differences in nicotine effects. Although genetic knockout mice are a powerful tool, research using this technique has not yet reached its full potential. Thus far, the gene of interest is knocked out prior to birth, possibly resulting in compensatory changes in the developing central nervous system of the animal. For a “ner assessment of the role of various nACHR subtypes, mutant mice that undergo gene- speci“c mutations in certain brain regions at a precise time in their adult life are needed. Eventually, this line of research will provide identi“cation of molecular sites that modulate nicotine addiction facilitating medication development for the treatment of tobacco dependence in human smokers. Relevance of Preclinical Studies to Understanding Tobacco Dependence Animal models, such as the SA and PC paradigms (discussed previously), provide a unique contribution toward our under- standing of tobacco dependence in humans. These models allow the examination of the reinforcing effects of nicotine that are highly relevant to tobacco dependence in humans, and that cannot be easily studied in human subjects mainly for ethical reasons. In animals, potential behavioral effects of pharmacological agents can be more fully characterized. Furthermore, these animal models allow the investigation of the basic underlying neurochemical mechanisms that are rel- evant to nicotine addiction. Animal models also can be used to study environmental factors in initiation and maintenance of nicotine addiction. Smokers report that environmental factors such as stress in- duce smoking behavior and that smoking helps to alleviate stress (McKennell, 1970; USDHHS, 1988). Preclinical stud- ies have shown that environmental stressors can increase cor- ticosterone levels and in turn can alter behavioral responses to administration of drugs of abuse. For example, prenatal stress (Deminiere et al., 1992), isolation (Alexander, Coambs, & Hadaway, 1978; Schenk, Lacelle, Gorman, & Amit, 1987), foot-shocks (Goeders & Guerin, 1994), and exposure to social defeat stress (Miczek & Mutschler, 1996) can activate as well as facilitate SA of psychomotor stimulants and opioids. In addition, exposure to intermittent foot-shock can reinstate heroin (Shaham & Stewart, 1995), cocaine (Ahmed & Koob, 1997; Erb, Shaham, & Stewart, 1996), alcohol (Lê et al., 1998), and nicotine (Buczek, Lê, Stewart, & Shaham, 1999) drug-seeking behavior following extinction and an extended period of abstinence. However, the role of environmental stressors in eliciting nicotine reinforcement using animal models has not been characterized thoroughly. These ex- periments will lead to the development of animal models of gene-environment interactions in nicotine addiction. Future experiments will provide us with clues as to whether the inter- actions can be demonstrated, the magnitude of their effect, and the conditions under which the interactions vary in strength. Social and Psychological Risk Factors for Initiation and Maintenance of Tobacco Use 153 Next, we present an overview of several of the psycholog- ical and social and environmental factors known or suspected to enhance the likelihood of initiation and/or maintenance of regular tobacco use in humans. SOCIAL AND PSYCHOLOGICAL RISK FACTORS FOR INITIATION AND MAINTENANCE OF TOBACCO USE Gender and Ethnic Differences It has been estimated that every day approximately 5,500 youth experiment with cigarettes for the “rst time and nearly 3,000 young people transition to daily smoking (Gilpin, Choi, Berry, & Pierce, 1999). The factors involved in the initiation of smoking are numerous, and indeed, there are several important studies involving careful longitudinal as- sessment of environmental, social, and contextual smoking initiation among adolescents (Chassin, Presson, Pitts, & Sherman, 2000; Colder et al., 2001; Duncan, Tildesley, Duncan, & Hops, 1995). Giovino (1999) provides a thorough review of the current state of knowledge of the epidemiology of tobacco use and concludes that male and female adolescents are equally as likely to smoke cigarettes with approximately 20% of per- sons aged 12 to 17 years in the United States having smoked within the past 30 days. The prevalence of smoking varies as a function of ethnicity. Among male high school seniors, 41% of American Indian/Alaska Natives, 33% of Whites, 29% of Hispanics, 21% for Asian Americans/Paci“c Islanders, and 12% of African Americans are current smokers. Among female high school seniors, corresponding prevalence estimates of cur- rent smoking for each of the ethnic groups mentioned earlier are 39%, 33%, 19%, 14%, and 9%, respectively. The ethnic differ- ences that exist in smoking prevalence have attracted recent at- tention. Great interest exists, for example, in understanding the apparent susceptibility among White adolescents to social in- ”uences to smoke, while African American youth appear to be comparatively resistant to these in”uences to smoke. Mermel- stein (1999), in a review of the literature, concludes that the source of these ethnic differences in smoking may generate from the differential role that parental and family factors or youth ability to cope with negative affect play across the vari- ous ethnicities. Cognitive Effects of Smoking Individual differences in cognitive assets and liabilities may also play a role in susceptibility to tobacco dependence. There is substantial evidence to suggest that nicotine plays a role in attention, learning, and memory. In humans, a wide variety of studies have reported the positive effects of nicotine on cognitive function (Heishman, 1999; Levin & Rezvani, 2000). However, in most of these studies, certain methodological issues cloud the conclusions that can be drawn. For example, the majority of the earlier studies ex- amined cognitive effects in cigarette smokers. Nicotine administration can produce a marked improvement in vigi- lance, rapid information processing, and short-term verbal recall and reduces time to name a color on the Stroop test (Hatsukami, Fletcher, Morgan, Keenan, & Amble, 1989; Warburton, 1992; Warburton & Wesnes, 1984). Some stud- ies have not found this positive effect on memory. In a nicotine-dependent population, it is dif“cult to determine whether enhancement in cognitive function is due to relief of attentional de“cits mediated by nicotine withdrawal. If smokers are deprived of nicotine, cognition is impaired and these de“cits can be reversed once the individual is re- exposed to nicotine (Hatsukami et al., 1989; Parrott & Roberts, 1991; Snyder & Henning“eld, 1989). To try to rule out the effects of nicotine on withdrawal versus cognitive performance, experiments have examined the effects of nicotine on attention in normal nonsmoking adults. For ex- ample, in a computerized test of attention, nicotine can sig- ni“cantly reduce errors in normal nonsmoking adults (Levin et al., 1998). However, even though examination of the ef- fects of nicotine in nonsmoking adults provides a reasonable baseline, it is still dif“cult to compare these “ndings directly to those seen in smokers since smokers may differ from nonsmokers on a variety of different factors including ge- netic, environmental, and psychological factors (Gilbert, 1995). Psychiatric Comorbidity and Tobacco Dependence Attention-de“cit hyperactivity disorder (ADHD) is charac- terized by an increase in inactivity, an inability to retain attention for any length in time, and increased impulsivity.