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Treating Smoking Dependence in Depressed Alcoholics

Nassima Ait-Daoud, M.D.; Wendy J. Lynch, Ph.D.; J. Kim Penberthy, Ph.D.; Alison B. Breland, Ph.D.; Gabrielle R. Marzani-Nissen, M.D.; and Bankole A. Johnson, D.Sc., M.D., Ph.D.

Alcoholism and dependence share many neurobiological underpinnings; the presence of one can cause a person to crave the other. Depressive illness can complicate comorbid and by exacerbating the negative affect encountered during attempts to abstain from one or both . Given the morbidity and mortality associated with cigarette smoking, it is imperative to identify treatments to promote smoking cessation and address comorbid psychiatric conditions contemporaneously. Pharmacotherapeutic options demonstrating varying degrees of efficacy and promise in preclinical and clinical studies include nicotine replacement therapy (NRT), selective inhibitors (SSRIs), , , tricyclic , and bupropion plus NRT. has shown potential for promoting smoking cessation in alcoholics, although its safety in depressed patients has not been fully explored. The efficacy of for treating nicotine dependence is generally enhanced by the inclusion of behavioral interventions such as cognitive behavioral therapy. When group cohesion and social support are stressed, success rates increase among depressed smokers undergoing smoking cessation treatment. Additional treatment strategies targeting dually dependent individuals with comorbid psychiatric disorders, including special populations such as women and adolescents, await further investigation. KEY WORDS: Alcohol and ; alcoholism; cigarette smoking; nicotine dependence; emotional and psychiatric depression; comorbidity; agents for alcohol and other drug (AOD) concurrent mental disorders; cessation of AOD use (AODU); smoking cessation treatment; serotonin receptors; serotonin reuptake inhibitors; pharmacotherapy; bupropion; varenicline; topiramate; tricyclic ; nicotine replacement therapy; psychotherapy; cognitive behavioral therapy

igarette smoking is the leading consequences of comorbid1 substance NASSIMA AIT-DAOUD, M.D., is an cause of preventable morbidity abuse and can complicate the course of assistant professor; WENDY J. LYNCH, and mortality in the United psychiatric disorders. C PH.D., is an assistant professor; J. KIM States (McGinnis and Foege 1993). People who are dependent on either PENBERTHY, PH.D., is an assistant Fifty to 90 percent of people with men- alcohol or nicotine often are at increased professor; ALISON B. BRELAND, PH.D., risk for the other comorbid disorder. tal illness or also are nicotine was an assistant professor; GABRIELLE R. Smokers have two to three times greater dependent (Williams and Ziedonis MARZANI-NISSEN, M.D., is an assistant risk for than non- 2004). Compared with the general professor; and BANKOLE A. JOHNSON, smokers (Breslau 1995), and about population, alcohol-dependent or other D.SC., M.D., PH.D., is an alumni 80 percent of alcoholics also are depen- mentally ill smokers have increased professor and chairman, all in the dent on nicotine (Hughes 1996). physical health consequences and Department of Psychiatry and Indeed, recent research has suggested a mortality rates (Williams and Ziedonis Neurobehavioral Sciences, University neurobiological link between nicotine 2004). Further, co-occurrence of sub- of Virginia, Charlottesville, Virginia. stance abuse and depression is associ­ and alcohol dependence. For instance, alcohol and nicotine share a common ated with greater impairment and ALISON B. BRELAND, PH.D., currently is neurobiological substrate involving the worse treatment outcomes than either an adjunct instructor in the Department disorder alone (Brown et al. 2000). 1For a definition of this and other technical terms used in of Psychology, Virginia Commonwealth Therefore, smoking exacerbates the this article, please see the glossary, p. 220. University, Richmond, Virginia.

Vol. 29, No. 3, 2006 213 cortico-mesolimbic system, response to the discomfort associated would be expected to be more difficult which is critical for expressing the posi­ with the urge to drink or to enhance to treat. This article will review some of tive reinforcing effects of these drugs their mood (Rohsenow et al. 1997). the treatments available to help patients (Hemby et al. 1997; Wise 1996). Some practitioners might be reluc­ with comorbid alcohol and nicotine Preclinical studies also show that neu­ tant to treat nicotine dependence in dependence and depression, discuss the rochemical interactions between alco­ mental health settings if they think that limitations of these treatments, and hol and nicotine can augment the rein­ it would depress mood and increase introduce some of the new treatment forcing effects of the combination anxiety among patients trying to over­ approaches that might lessen the chal­ (Soderpalm et al. 2000) and that the come other or mental illness. lenge of treating this population. presence of one drug can trigger drug- Nevertheless, despite the belief that seeking behavior for the other (Lê et al. smoking cessation can trigger alcohol 2003). relapse among people dependent on Basic Research Tobacco and alcohol seem to trigger both drugs, contemporary studies show similar central responses; that smoking cessation treatment does An understanding of the neurochemi­ therefore, both substances often are not cause abstinent alcoholics to relapse cal mechanisms underlying the addic­ used as self- for comorbid (Hughes and Callas 2003). Indeed, treat­ tive properties of alcohol and nicotine affective disorder (Abrams et al. 1992; ment that promotes smoking cessation is critical for the development of Hertling et al. 2005; Pomerleau and among smokers within an alcohol- potential pharmacotherapies. As with Pomerleau 1987). Thus, Currie and dependent population might decrease other drugs of abuse, the reinforcing colleagues (2001) have suggested that the likelihood of relapse to drinking. effects of both alcohol and nicotine people with a combined history of The clinical approach toward treat­ appear to be mediated, at least in part, alcohol dependence and major depres­ ing people with comorbid nicotine and by projections in the sion are at high risk of using smoking alcohol dependence becomes more cortico-mesolimbic system (Johnson as a means of mood enhancement. complicated among patients who also 2004; Koob 2003; Samson and Harris Craving for alcohol or nicotine is posi­ have a depressive illness. Such individu­ 1992). Alcohol, both directly and indi­ tively correlated with depression and als might smoke or drink to relieve rectly, can increase excitatory cellular anxiety, and alcohol-dependent patients negative affective mood states such as activation of dopaminergic cell bodies often experience the urge to smoke in depression and anxiety and therefore in the ventral tegmental area (VTA). This, in turn, leads to the facilitation of dopamine release in the nucleus accum­ bens (Brodie et al. 1999; Johnson 2005; Ortiz et al. 1995). The primary Locus coeruleus action by which alcohol increases dopamine in the nucleus accumbens appears to be via its effects on gamma­ aminobutyric acid (GABA) in the VTA (for a review, see Johnson 2004). Recent evidence, however, demonstrates that alcohol also can exert its reinforc­ ing and dopamine-enhancing effects through activation of nicotinic acetyl­ receptors. In laboratory rats, chronic treatment with nicotine increases the reinforcing and dopamine- enhancing effects of alcohol, and these effects are blocked by the nicotinic antagonist (for a review, see Larsson and Engel 2004). Nucleus Raphe These results suggest that nicotinic accumbens nuclei receptors in the VTA Ventral Pons might serve as a common substrate for tegmental alcohol–nicotine interactions. area Serotonin appears to play a critical role in mediating the reinforcing effects of alcohol and nicotine, and it has been Parts of the brain involved in alcohol/nicotine dependence and psychiatric disorders. implicated in the pathophysiology of various neuropsychiatric disorders,

214 Alcohol Research & Health Smoking Dependence and Depressed Alcoholics

including depression. Both alcohol and of SSRIs in treating alcohol dependence history of depression was comparable nicotine stimulate the system. has depended on clinical subtype. to the effect observed among smokers Long-term use of alcohol and nicotine Among patients who develop problem with no history of depression or alco­ can, however, produce a hypo-seroton­ drinking early in life, have a strong holism (Hayford et al. 1999). However, ergic state that might trigger or worsen family history of alcoholism, and fre­ because smokers with current depression a depression. For instance, both chronic quently exhibit impulsive behaviors and alcoholism (i.e., within the past alcohol and nicotine administrations (i.e., early-onset or type B alcoholics), year) were excluded from the study, dose-dependently reduce the synthesis SSRIs worsen drinking outcomes these findings might be of limited sig­ of hydroxylase (the rate- (Kranzler et al. 1996). In contrast, nificance. Unfortunately, bupropion limiting enzyme for serotonin synthesis) SSRIs improve drinking outcomes has not been found to be effective for in the , as evidenced by a among patients who develop problem treating alcohol dependence. diminution in the amount of serotonin- drinking later in life and do not have a Bupropion is the only TCA that has and –positive cells family history of alcoholism or a personal been approved by the FDA as a treat­ identified by immunochemistry (Jang et history of impulsivity (i.e., late-onset or ment for smoking dependence. Never­ al. 2002). It is reasonable, therefore, to type A alcoholics) (Pettinati et al. 2000). theless, other nonapproved TCAs have propose that the pathogenesis of alcohol- Indeed, Johnson (2000) has proposed been investigated for smoking cessation and nicotine-induced mood disorders that the variation in expression of the and are considered to be second-line might involve alcohol- and nicotine- molecular mechanism within the sero­ treatments. , a TCA that induced suppression of serotonin synthe­ tonin system might explain this differ­ has both dopaminergic and sis. Taken together, these data suggest ential response. Notwithstanding these enhancing effects, has shown efficacy in that of serotonin and findings, SSRI treatment appears to treating nicotine dependence indepen­ cortico-mesolimbic dopamine, particu­ benefit alcohol-dependent patients dently of depression history and can larly via manipulation of the nicotinic with severe depression and suicidal reduce smoking cessation–related nega­ , might reduce the ideation (Cornelius et al. 1997) but tive affect, which can be a trigger for reinforcing effects of both alcohol and not to aid those with more moderate relapse (Hall et al. 1998). Results from nicotine. Thus, pharmacological agents depressive symptoms and comorbid two separate research studies showed that reduce the reinforcing effects of alco­ alcohol dependence (Pettinati et al. that TCAs such as (Mason hol and nicotine by modulating these 2001). Further, even among depressed et al. 1996) and (McGrath systems might have patients who are co-dependent on et al. 1996) also reduced depressive potential therapeutic value for treating nicotine and alcohol, SSRI treatment symptoms among alcoholics with comor­ nicotine and alcohol dependence and alleviates the depressive mood but has bid depression. Although desipramine comorbid depression in humans. little impact on the substance abuse– also demonstrated an effect to reduce related outcomes (Torrens et al. 2005). drinking, this occurred at doses higher Patients with a dual diagnosis (i.e., of than that approved by the FDA, and Pharmacotherapeutic depression and ) there was increased risk of toxicity Approaches therefore need concomitant treatment (Mason et al. 1996). TCAs can, how­ of both disorders. ever, produce several unpleasant Nicotine replacement therapy (NRT) Bupropion is the only antidepres­ adverse effects that limit their utility in combination with psychotherapy or sant that has been approved by the as antismoking agents. These include behavioral therapy is an effective treat­ Food and Drug Administration (FDA) reducing the pleasurable effects of ment for nicotine dependence. Some for treating nicotine dependence. smoking related to its consumption by research data also suggest that NRT Bupropion is a inducing drowsiness, making smoking might be beneficial in improving mood (TCA) that inhibits noradrenergic and more hazardous by increasing the among abstinent depressed smokers dopamine uptake and, at high concen­ potential for cardiotoxicity, and increas­ (Cummings and Hyland 2005). Because trations, inhibits the firing of noradren­ ing the difficulty of smoking cessation the emergence of depressive symptoms ergic neurons in the locus coeruleus by inducing weight gain. A recent sys­ during smoking cessation treatment is (Ascher et al. 1995). Preclinical studies tematic meta-analytic review concluded associated with failed quit attempts and also show that bupropion might act as that antidepressant medication only increased probability of returning to a noncompetitive nicotinic receptor exerts a modest beneficial treatment smoking (Anda et al. 1990), alleviating antagonist (Slemmer et al. 2000), effect among patients with combined such negative affective mood states is an thereby reducing the reinforcing effects substance use and depressive disorders. important pharmacotherapeutic goal. of nicotine. Slow-release bupropion It is not a stand-alone treatment; con­ Although treating smokers with aids smoking cessation among smokers current therapy aimed at directly treat­ concurrent major depressive disorder with a history of major depression or ing the addiction also is indicated requires the administration of antide­ alcoholism. Slow-release bupropion’s (Nunes and Levin 2004). pressants such as selective serotonin dose-dependent effect on smoking ces­ The FDA recently approved a sec­ reuptake inhibitors (SSRIs), the utility sation observed among smokers with a ond medication, varenicline, as an aid

Vol. 29, No. 3, 2006 215 to smoking cessation. Varenicline is reductions in smoking were positively ria or anxious mood. Second, depressed a selective α4 β2 partial nicotinic associated with drinking decreases for smokers with or without alcohol receptor that, in the presence of the topiramate group but not for the dependence might have less self-efficacy nicotine, acts as a relative antagonist and group. These results suggest and, therefore, more difficulty becom­ diminishes nicotine’s reinforcing effects. that topiramate might have specific ing abstinent than their nondepressed In two recent trials, varenicline admin­ antismoking effects. Topiramate did counterparts. istration resulted in quit rates signifi­ not alter mood. Study participants who These models of self-medication cantly higher than those achieved among received topiramate, compared with and learned helplessness have received placebo recipients (Nides et al. 2006; those who received the placebo, experi­ empirical support in research with Oncken et al. 2006). Indeed, the results enced a significant weight reduction nicotine- and alcohol-dependent popu­ of one of these studies suggest that (i.e., 20 [44 percent] topiramate recipi­ lations. For example, smokers who varenicline might be more clinically ents experienced weight loss compared identify the prevention of negative effective than bupropion (Nides et al. with 9 [18 percent] placebo recipients; affect as their primary reason for smok­ 2006). For a review, see Johnson (2006). p = 0.008) (Johnson et al. 2005). Taken ing are more likely to fail in quit attempts. Combining NRT with non-NRT together, these results demonstrate to­ When smokers become depressed, the pharmacotherapeutic treatments appears piramate’s potential as a safe and promis­ course and prognosis of smoking cessa­ promising for patients with comorbid ing medication for treating alcohol- tion become intertwined with the depression and nicotine dependence. dependent smokers. Topiramate’s abil­ pathophysiology of depression. For For instance, combining the nicotine ity to induce weight loss might counter instance, smokers with a history of patch with bupropion increases absti­ a treatment barrier reported by some in major depressive disorder are more nence rates up to 58 percent, compared smoking cessation treatment—weight likely to experience depressed mood with bupropion alone (49 percent), gain (Jeffery et al. 2000). A double- during nicotine withdrawal (Breslau et patch alone (36 percent), or placebo blind, placebo-controlled clinical trial al. 1991) and are at greater risk for (23 percent) (Johnston et al. 1999). testing topiramate for the treatment of developing recurrent episodes of major Other studies have reported similar anger and depressive symptoms among depression than are nonsmokers trends. For example, bupropion plus mildly to moderately depressed women (Glassman et al. 2001). Depressed the transdermal nicotine patch increased in Germany showed efficacy in primary smokers also are more likely than non- 6-month, self-reported abstinence rates outcome measures, which included sig­ depressed smokers to report deficits in up to 34 percent, compared with bupro­ nificant reductions on the Hamilton coping resources, to adhere to the com­ pion alone (28 percent) and patch Depression Rating Scale, the State- ponents of smoking cessation treat­ alone (15 percent) (Gold et al. 2002). Trait Anger Expression Inventory, the ment, and to use cigarettes for amelio­ In another study, bupropion combined Test of Attention, and the SF-36 Health rating negative affect (Kinnunen et al. with the nicotine patch resulted in Survey (Nickel et al. 2005). Nevertheless, 1996). Thus, psychosocial interven­ higher 12-month abstinence rates (36 the type of alcohol-dependent smoker tions for depressed smokers with or percent) compared with nicotine patch who responds best to topiramate needs without alcohol use disorders might be alone (16 percent), bupropion alone to be elucidated more clearly, and more effective if they were focused on (30 percent), or placebo (16 percent) research is needed to determine the treating depressive symptoms simulta­ (Jorenby et al. 1999). safety of topiramate in treating comor­ neously with the smoking cessation Topiramate is an anticonvulsant drug, bid alcohol- and nicotine-dependent treatment. This would enable such with several mechanisms of action, that patients with current or a past history individuals to learn healthy coping diminishes cortico-mesolimbic dopamine of depressive illness. strategies, including affect regulation by facilitating GABAergic activity and stress management. while inhibiting activity Indeed, in one of the few studies of (for a review, see Johnson 2004). Johnson Psychotherapeutic its kind, Patten and colleagues (2002) and colleagues (2003) have shown that Intervention examined the effect of depressive symp­ up to 300 mg/day of topiramate, com­ toms on smoking abstinence and treat­ pared with placebo, significantly increases Two psychological theories have been ment adherence among smokers with a abstinence from alcohol among alco­ proposed as being related to the rela­ past history of alcohol dependence. hol-dependent patients receiving only tionships among depression, alco­ They found that smokers with a his­ brief behavioral compliance enhance­ holism, and smoking behavior. First, tory of alcohol dependence who also ment treatment. In a subset of partici­ drug use (including that of nicotine reported high levels of depressive symp­ pants from the same trial, topiramate and alcohol) might be motivated by a toms were more likely to be abstinent recipients compared with placebo person’s expectation of the outcome, from smoking at the end of treatment recipients were significantly more likely such as a decrease in negative affect and at follow-up than those with low to become abstinent from smoking and tension. If such a person is also depression scores. The authors con­ (odds ratio = 4.46; 95 percent CI depressed, there might be an even cluded that similar to research in the 1.08–18.39; p = 0.04). Interestingly, greater motivation to alleviate dyspho­ nonalcoholic literature (Zelman et al.

216 Alcohol Research & Health Smoking Dependence and Depressed Alcoholics

1992), smokers who demonstrate a modalities of psychotherapy adminis­ depressed smokers with or without vulnerability to negative affect—and tration. For instance, Ginsberg and col­ alcohol dependence. who might use drugs to regulate mood— leagues (1997) have reported that benefit more from a mood manage­ group CBT was an effective and impor­ ment–specific therapy to address their tant part of a multicomponent (CBT Gender- and Age-Specific depression in addition to smoking plus nicotine gum) smoking cessation Issues Associated With cessation treatment. program for women with and without Treatment Outcome Nevertheless, the necessity of incor­ a history of depression. In that study, porating mood management skills standard smoking cessation group Rates of smoking are much higher training for smokers with a history of CBT included learning strategies for among people who have alcohol prob­ depression has not been established. For smoking cessation, goal setting for lems and a history of depressive ill­ instance, Hall and colleagues (1994, nicotine fading, increased social sup­ nesses than among people without 1998) found that mood management port, problem-solving skills training, those disorders (Currie et al. 2001). skills training for smokers with a his­ and, finally, weaning off gum after Depression also is associated with ear­ tory of major depressive disorder was quitting nicotine. This type of CBT, lier relapse in treated teens with alcohol most effective when there was more which emphasizes group cohesion and use disorder (Cornelius et al. 2004) as frequent therapist contact time than in social support, helped to maintain well as in adult alcoholics (Greenfield the control group. However, no signifi­ adherence, thereby promoting effective et al. 1998). Among smokers, females cant effect of mood management was treatment and smoking cessation tend to have a worse problem abstain­ observed when both the target and regardless of whether there was a his­ ing from nicotine than their male control groups received equal therapist tory of depression. One caveat to this counterparts (Perkins et al. 1999). time (Hall et al. 1996). Mood manage­ study is that the authors did not evalu­ There are, at least, two possible expla­ ment did not attenuate postcessation ate the impact of the treatment on nations for this gender difference. First, increases in depression among smokers depressive symptoms. among smokers, women are more con­ with a past history of depression. Alcohol dependence complicates the cerned than men about weight gain Other types of psychotherapy might pathophysiology, course, and treatment following smoking cessation. Second, be more effective than mood manage­ outcome of depressed smokers. Patten because women are more prone to ment in treating people with comorbid and colleagues (2002) found that affective disorder, they tend to have nicotine dependence and depression. smokers with a history of alcohol greater negative affect associated with Brown and colleagues (2001) found dependence, who also reported high smoking cessation. Nevertheless, research that heavy smokers with a history of levels of depressive symptoms, were in this area is still developing, and little major depressive disorder had better more likely to be abstinent from smok­ is known about the gender- and age- outcomes when cognitive behavioral ing at the end of treatment and at fol­ specific issues associated with treatment therapy (CBT) for depression was low-up than those with low depression outcome among depressed smokers incorporated into a standard smoking scores. Thus, Zelman and colleagues who also are alcohol dependent. cessation treatment. Although CBT for (1992) have proposed that smokers depression did not decrease depressive who are vulnerable to negative affect— symptoms prior to or after smoking and who use drugs to regulate mood— Conclusions cessation, it did prevent the expected might benefit more from a mood man­ rise in such symptoms following smok­ agement–specific therapy to address People with concurrent mental disor­ ing cessation. In a recent review of their depression in addition to smoking ders, such as major depression and alco­ combination treatment for nicotine cessation treatment. hol and nicotine dependence, are dependence, Ingersoll and Cohen In summary, incorporating a behav­ increasingly prevalent in clinical prac­ (2005) reported that treatments com­ ioral intervention with pharmacother­ tice and generally have poor response bining a behavioral component with a apy for smoking cessation increases the to treatments, which can be costly. first-line pharmacotherapeutic agent success rate, perhaps because of an Nevertheless, there is growing evidence enhanced smoking cessation rates more improved adherence to treatment. that contemporaneous treatment for than either alone. They concluded that CBT that emphasizes group cohesion depressive disorder and smoking cessa­ some forms of psychosocial treatment, and social support appears to be benefi­ tion is preferable to treatment of either “such as those based on principles of cial in maintaining treatment adher­ condition alone, even in the presence effective brief therapies, and using tech­ ence among depressed smokers within of alcohol dependence. In such cases, niques of CBT, can enhance the gains smoking cessation treatment and helps combining different pharmacological achieved with first-line pharmacothera­ to prevent the expected rise in depres­ agents in conjunction with CBT or pies for smoking cessation in general sive symptoms upon quitting. The other psychotherapies appears to be populations of smokers.” added benefit of teaching mood man­ the preferred mode of treatment. New Depressed women appear to be par­ agement skills has, however, not been medications such as topiramate that ticularly responsive to certain types and established in the treatment of could treat both alcohol and nicotine

Vol. 29, No. 3, 2006 217 dependence might simplify the use of pressant activity. Journal of Clinical Psychiatry nence rates for depressive-history smokers. Journal combination therapies if there is a con­ 56:395–401, 1995. PMID: 7665537 of Consulting and Clinical Psychology 62:141–146, 1994. PMID: 8034816 comitant depressive illness. The devel­ BRESLAU, N. Psychiatric comorbidity of smoking opment of more specific pharmacologi­ and nicotine dependence. Behavior HALL, S.M.; MUNOZ, R.F.; REUS, V.I.; ET AL. cal strategies targeting the populations 25:95–101, 1995. PMID: 7733862 Mood management and nicotine gum in smoking most likely to respond—or working at treatment: A therapeutic contact and placebo-con­ BRESLAU, N.; KILBEY, M.; AND ANDRESKI, P. trolled study. Journal of Consulting and Clinical different phases of the disorder(s)—is Nicotine dependence, major depression, and anxi­ Psychology 64:1003–1009, 1996. PMID: 8916629 in its infancy. Among the various psy­ ety in young adults. Archives of General Psychiatry chotherapies, CBT that emphasizes 48:1069–1074, 1991. PMID: 1845224 HALL, S.M.; REUS, V.I.; MUNOZ, R.F.; ET AL. Nortriptyline and cognitive-behavioral therapy in BRODIE, M.S.; PESOLD, C.; AND APPEL, S.B. group cohesion and social support the treatment of cigarette smoking. Archives of Ethanol directly excites dopaminergic ventral appears to be particularly useful for General Psychiatry 55:683–690, 1998. PMID: tegmental area reward neurons. Alcoholism: Clinical 9707377 treating depressed smokers with or with­ and Experimental Research 23:1848–1852, 1999. out alcohol dependence. The necessity PMID: 10591603 HAYFORD, K.E.; PATTEN, C.A.; RUMMANS, T.A.; of teaching mood management skills ET AL. Efficacy of bupropion for smoking cessation BROWN, R.A.; KAHLER, C.W.; NIAURA, R.; ET AL. in smokers with a former history of major depres­ among people with nicotine and alco­ Cognitive-behavioral treatment for depression in sion or alcoholism. British Journal of Psychiatry hol dependence who are also depressed smoking cessation. Journal of Consulting and Clinical 174:173–178, 1999. PMID: 10211174 has not been established. New knowl­ Psychology 69:471–480, 2001. PMID: 11495176 edge is needed to develop treatments HEMBY, S.E.; JOHNSON, B.A.; AND DWORKIN, S.I. BROWN, S.; INSKIP, H.; AND BARRACLOUGH, B. Neurobiological basis of drug reinforcement. In: that might benefit special populations, Causes of the excess mortality of schizophrenia. Johnson, B.A.; and Roache, J.D., eds. including women and teenagers. ■ British Journal of Psychiatry 177:212–217, 2000. Drug Addiction PMID: 11040880 and Its Treatment: Nexus of Neuroscience and Behavior. Philadelphia: Lippincott-Raven, 1997, pp. 137–169. CORNELIUS, J.R.; MAISTO, S.A.; MARTIN, C.S.; ET HERTLING, I.; RAMSKOGLER, K.; DVORAK, A.; ET Acknowledgements AL. Major depression associated with earlier alcohol relapse in treated teens with AUD. Addictive AL. Craving and other characteristics of the comor­ Behaviors 29:1035–1038, 2004. PMID: 15219354 bidity of alcohol and nicotine dependence. European Nassima Ait-Daoud is supported through Psychiatry 20:442–450, 2005. PMID: 16095883 National Institute on Alcohol Abuse and CORNELIUS, J.R.; SALLOUM, I.M.; EHLER, J.G.; ET UGHES AL. in depressed alcoholics: A double- H , J.R. Treating smokers with current or Alcoholism (NIAAA) Grant K23 AA past alcohol dependence. American Journal of 00329– 01, and Bankole A. Johnson is blind, placebo-controlled trial. Archives of General 54:700–705, 1997. PMID: 9283504 Health Behavior 20:286–290, 1996. supported through NIAAA Grants Psychiatry CUMMINGS, K.M.; AND HYLAND, A. Impact of HUGHES, J.R.; AND CALLAS, P.W. Past alcohol AA10522–10 and AA12964–01 and problems do not predict worse smoking cessation National Institute on Drug Abuse nicotine replacement therapy on smoking behavior. Annual Review of Public Health 26:583–599, 2005. outcomes. Drug and Alcohol Dependence 71:269– Grant DA017296–01A1. PMID: 15760302 273, 2003. The authors thank the staff at the INGERSOLL, K.S.; AND COHEN, J. Combination University of Virginia Center for CURRIE, S.R.; HODGINS, D.C.; EL-GUEBALY, N.; AND CAMPBELL, W. Influence of depression and treatment for nicotine dependence: State of the Addiction Research and Education gender on smoking expectancies and temptations in science. Substance Use and Misuse 40:1923–1943, and Robert H. Cormier, Jr., for his alcoholics in early recovery. Journal of Substance 2043–2048, 2005. PMID: 16282086 Abuse 13:443–458, 2001. PMID: 11775075 assistance with manuscript preparation. JANG, M.H.; SHIN, M.C.; LEE, T.H.; ET AL. GINSBERG, J.P.; KLESGES, R.C.; JOHNSON, K.C.; ET Alcohol and nicotine administration inhibits sero­ AL. 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Vol. 29, No. 3, 2006 219 GLOSSARY Adrenergic: Relating to neurons that are activated by, characteristic convey information to adjacent or distant neurons. Neuro­ of, or secreting or substances with similar activity. modulators indirectly affect the excitation or inhibition of Affect disorder/Affective disorder: Mental disorders controlling neurons by changing the way in which neurons react to neu­ mood. rotransmitters. Antagonist: An agent that blocks or reverses the actions or : A nerve cell. effects of another agent (e.g., a drug that blocks the effects Neurotransmitter: A chemical messenger released by an excited of a neurotransmitter). or stimulated neuron. A neurotransmitter binds to a receptor Brief behavioral compliance enhancement treatment: on an adjacent neuron, usually triggering a series of chemical Psychosocial adherence enhancement program that empha­ and electrical changes in the second cell. sizes the importance of medication compliance in changing Nicotinic acetylcholine receptors: Receptors that recognize an alcoholic’s drinking behavior. and bind with both nicotine and the neurotransmitter Cardiotoxicity: A condition where there is damage to the heart acetylcholine. muscle or its function. Nicotinic : A compound that blocks Central opioid : Molecules in the brain that modify the nicotine receptors. actions of other . By altering the electrical Noradrenergic: Stimulated by or releasing the neurotransmitter properties of their target neurons, thereby making these neu­ . rons more difficult to excite, opioid peptides can influence Nucleus accumbens (see graphic): A brain structure affected the release of various neurotransmitters. As a result of this by many drugs of abuse and implicated in the rewarding modulation, opioid peptides can—among other functions— properties of addictive drugs. induce pain relief and as well as affect certain behav­ Pathogenesis: The mechanism by which certain etiological iors, including alcohol consumption. factors cause disease. Comorbidity: In general, comorbidity refers to the co-occur­ Pons (see graphic): A broad mass of nerve fibers that forms the rence or overlap of two or more psychiatric disorders. central portion of the brainstem. The pons participates in Cortico-mesolimbic dopamine system: A circuit in the brain control of respiration and coordination of muscular activity. through which dopamine is transmitted. Preclinical studies: Studies used to test experimental drugs in Dopamine: An excitatory neurotransmitter that plays a role in the test tube or in animals; the testing that occurs before tri­ the reward system in the brain and possibly in the reinforc­ als in humans may be carried out. ing properties of alcohol. Raphe nuclei (see graphic): A moderate-sized group of nuclei Dopaminergic: Relating to neurons or nerve fibers that release (clusters of neurons) found in the brainstem that releases dopamine. serotonin to the rest of the brain. Dopaminergic projections: Means by which dopamine is trans­ Rate-limiting enzyme: The slowest step in the creation of a mitted between cells. molecule, and often the most important, because it requires Dysphoria: Generally characterized as a feeling of emotional additional energy and is highly regulated. The rate-limiting and/or mental discomfort, restlessness, malaise, and depression. enzyme can have the biggest effect on the final product, so if something is wrong with it, the effect of this malfunction Excitatory: Increasing the capacity of a nerve cell to respond will translate down the chain to the end product. to stimuli. Receptor: A usually found on the surface of a neuron or GABAergic: Relating to neurons or nerve fibers that release other cell that recognizes and binds to neurotransmitters or gamma-aminobutyric acid (GABA). other chemical messengers. Gamma-aminobutyric acid (GABA): An inhibitory neurotrans­ Selective α4 β2 partial nicotinic receptor agonist: An inhibitor mitter the actions of which are influenced by alcohol; may of dopaminergic activation produced by smoking that simul­ play a role in alcohol withdrawal. taneously provides relief from the craving and withdrawal. Glutamatergic: Relating to neurons or nerve fibers that release Selective serotonin : A class of antidepressants the neurotransmitter glutamate. used in the treatment of depression, anxiety disorders, and Hypo-serotonergic state: Lacking serotonin. some personality disorders. Locus coeruleus (see graphic): A pair of identical nuclei Serotonergic: Relating to the neurotransmitter serotonin. (clusters of neurons) in the pons from which all brain connec­ Serotonin: A neurotransmitter involved in many functions, tions using norepinephrine arise. including mood, appetite, and sensory perception. A lack of Neurobiological substrate: Substance in the brain upon which serotonin in the brain is thought to be a cause of depression. enzymes act to influence emotional states and disorders. Ventral tegmental area (see graphic): The midbrain region Neuromodulation: The action of neuromodulators, substances containing dopamine cell bodies that project to various parts similar to neurotransmitters that are released by neurons and of the forebrain, including the nucleus accumbens.

220 Alcohol Research & Health