Addiction. Hales Et Al (2011) American Psychiatric Publishing Textbook of Substance Abuse...

The American Psychiatric Publishing Textbook of Substance AbuseTreatment, 4th EditionEdited by Marc Galanter, M.D., and Herbert D. Kleber, M.D.DOI: 10.1176/appi.books.9781585623440 What is this?

CONTENTS

Part 1: The Basis of Addictive DisordersChapter 1. Neurobiology of AddictionChapter 2. Genetics of AddictionChapter 3. Epidemiology of AddictionChapter 4. Cross-Cultural Aspects of Addiction

Part 2: The Nature of TreatmentChapter 5. Assessment of the PatientChapter 6. Patient Placement CriteriaChapter 7. Evolution in Addiction Treatment Concepts and Methods

Part 3: Specific Drugs of AbuseAlcoholChapter 8. Neurobiology of AlcoholChapter 9. Clinical Management of Alcohol Abuse and DependenceStimulantsChapter 10. Neurobiology of StimulantsChapter 11. Clinical Management: CocaineChapter 12. Clinical Management: MethamphetamineHallucinogens and Club DrugsChapter 13. Neurobiology of HallucinogensChapter 14. Hallucinogens and Club DrugsOther SubstancesChapter 15. Nicotine and TobaccoChapter 16. Benzodiazepines and Other Sedatives and HypnoticsChapter 17. Treatment of Anabolic-Androgenic SteroidRelated DisordersOpioidsChapter 18. Neurobiology of Opiates and OpioidsChapter 19. Detoxification of OpioidsChapter 20. Opioid Maintenance TreatmentChapter 21. Buprenorphine MaintenanceChapter 22. Antagonists of Opioids

Part 4: Treatment Modalities

1 of 2 10:01 PM

1 of 756

Chapter 23. PsychodynamicsChapter 24. Cognitive-Behavioral TherapiesChapter 25. Motivational EnhancementChapter 26. Twelve-Step Facilitation: An Adaptation for Psychiatric Practitioners and PatientsChapter 27. Contingency ManagementChapter 28. Network TherapyChapter 29. Group TherapyChapter 30. Family Therapy

Part 5: Rehabilitation SettingsChapter 31. Inpatient TreatmentChapter 32. Therapeutic CommunitiesChapter 33. Community-Based TreatmentAlcoholics Anonymous and Other 12-Step ProgramsChapter 34. Psychological Mechanisms in Alcoholics AnonymousChapter 35. The History of Alcoholics Anonymous and the Experiences of PatientsChapter 36. Outcome Research on 12-Step and Other Self-Help Programs

Part 6: Special PopulationsChapter 37. Adolescent Substance AbuseChapter 38. The Mentally Ill Substance AbuserChapter 39. Women and AddictionChapter 40. Perinatal Substance Abuse: Drug Dependence, Motherhood, and the NewbornChapter 41. HIV/AIDS and Hepatitis CChapter 42. Prescription Drug AbuseChapter 43. Substance Use Disorders Among PhysiciansChapter 44. Gay Men and LesbiansChapter 45. Minorities

Part 7: Special TopicsChapter 46. Testing to Identify Recent Drug UseChapter 47. Medical EducationChapter 48. Prevention of Substance AbuseChapter 49. Forensic Addiction Psychiatry

Copyright Amer can Psychiatr c Association. All Rights Reserved.Copyright & Legal Disclaimer Privacy Policy Terms of Use

PsychiatryOnline

2 of 2 10:01 PM

2 of 756

EditorsMarc Galanter, M.D.Professor of Psychiatry, Department of Psychiatry; Director of the Division of Alcoholism and Drug Abuse,New York University School of Medicine, New York, New YorkHerbert D. Kleber, M.D.Professor of Psychiatry and Director, Division of Substance Abuse, Columbia University, New York, NewYork

ContributorsSudie E. Back, Ph.D.Assistanct Professor, Division of Clinical Neuroscience, Medical University of South Carolina, Charleston,South CarolinaMonica Barros, M.D.Chief Resident, Department of Psychiatry, Georgetown University Hospital, Washington, DCSteven L. Batki, M.D.Department of Psychiatry, University of California, San Francisco; Director, Addiction Psychiatry ResearchProgram, San Francisco VA Medical Center, San Francisco, CaliforniaAdam Bisaga, M.D.Associate Professor of Clinical Psychiatry, Department of Psychiatry, Columbia University College ofPhysicians and Surgeons; Research Psychiatrist, New York State Psychiatric Institute, New York, New YorkJ. Wesley Boyd, M.D., Ph.D.Associate Director, Physician Health Services, Massachusetts Medical Society; Assistant Clinical Professorof Psychiatry, Harvard Medical School; Staff Psychiatrist, Cambridge Health Alliance, Cambridge,MassachusettsKathleen T. Brady, M.D., Ph.D.Professor of Psychiatry, Division of Clinical Neuroscience, Medical University of South Carolina, Charleston,South CarolinaDavid W. Brook, M.D.Professor of Psychiatry, New York University School of Medicine, New York, New YorkJudith S. Brook, Ed.D.Professor of Psychiatry, New York University School of Medicine, New York, New YorkKirk J. Brower, M.D.Associate Professor of Psychiatry, Department of Psychiatry; Executive Director, University of MichiganAddiction Treatment Services, University of Michigan, Ann Arbor, MichiganRobert Paul Cabaj, M.D.Director, San Francisco Department of Public Health Community Behavioral Health Services; AssociateClinical Professor in Psychiatry, University of California, San Francisco, San Francisco, CaliforniaKathleen M. Carroll, Ph.D.Professor of Psychiatry, Division of Substance Abuse, Yale University School of Medicine, West Haven,ConnecticutCrystal A. Caudill, M.P.H.Director, Wedco District Health Department, Cynthiana, KentuckyHarvey L. Causey III, M.D.Medical Director, Morris Village Alcohol and Drug Addiction Treatment Center, South Carolina Departmentof Mental Health; Clinical Assistant Professor of Psychiatry, Department of Neuropsychiatry, University ofSouth Carolina School of Medicine, Columbia, South Carolina

PsychiatryOnline - Info

2 of 3 10:02 PM

3 of 756

Print Close Window

George F. Koob: Chapter 1. Neurobiology of Addiction, in The American Psychiatric Publishing Textbook of Substance Abuse Treatment. Edited by Marc Galanter, Herbert D.Kleber. Copyright 2011 American Psychiatric Publishing, Inc. DOI: 10.1176/appi.books.9781585623440.344000. Printed 10/7/2011 from www.psychiatryonline.comTextbook of Substance Abuse Treatment >

Neurobiology of AddictionGeorge F. Koob, Ph.D.CONCEPTUAL FRAMEWORK, DEFINITIONS, AND ANIMAL MODELSDrug add ction, also known as substance dependence, is a chron c, relapsing disorder characterized by 1) compulsion to seek and take the drug, 2) loss of control inlimiting intake, and 3) emergence of a negative emotional state (e.g., dysphoria, anxiety, irr tabil ty) when access to the drug is prevented (defined here asdependence) (Koob and Le Moal 1997). Addiction and substance dependence, as currently defined in DSM-IV-TR (American Psychiatr c Association 2000), will be usedinterchangeably throughout this chapter and refer to a final stage of a usage process that moves from drug use to addict on. Clinically, the occas onal but limited useof a drug w th the potential for abuse or dependence is distinct from escalated drug use and the emergence of a chronic drug-dependent state. An important goal ofcurrent neurobiolog cal research is to understand the neuropharmacolog cal and neuroadaptive mechanisms within specific neurocircuits that mediate the trans tionfrom occasional, controlled drug use to the loss of behav oral control over drug seeking and drug taking that defines chronic addiction.Addict on has been conceptualized as a chronic, relapsing disorder with roots in both impulsiv ty and compulsivity and w th neurob ological mechanisms that change asan indiv dual moves from one domain to the other. Subjects w th impulse control disorders experience an increasing sense of tension or arousal before comm tting animpulsive act; pleasure, gratif cat on, or relief at the time of comm tting the act; and, finally, regret, self-reproach, or guilt following the act. In contrast, individualswith compulsive disorders experience anxiety and stress before comm tting a compulsive, repetitive behavior and then relief from the stress by performing thecompulsive behav or. In addict on, drug-taking behavior progresses from impulsivity to compulsivity in a three-stage cycle: binge/intoxication, withdrawal/negativeaffect, and preoccupation/anticipation. As individuals move from an impulsive to a compulsive disorder, the drive for the drug-taking behav or shifts from pos tive tonegative reinforcement (Figures 11 and 12). Impulsivity and compulsivity can coexist in different stages of the addict on cycle.

FIGURE 11. Diagram showing stages of impulse control disorder and compulsive disorder cycles related to the sources of reinforcement.

In impulse control disorders, an increasing tens on and arousal occurs before the impulsive act, with pleasure, gratificat on, or relief during the act. Following the actthere may or may not be regret or guilt. In compulsive disorders, there are recurrent and persistent thoughts (obsessions) that cause marked anxiety and stressfollowed by repet tive behaviors (compulsions) that are aimed at preventing or reducing distress (American Psychiatr c Association 1994). Positive reinforcement(pleasure/gratif cat on) is more closely associated with impulse control disorders. Negative reinforcement (relief of anxiety or relief of stress) is more closelyassociated with compulsive disorders.Source. Reprinted from Koob GF: "Allostatic View of Motivat on: Implications for Psychopathology," in Motivational Factors in the Etiology of Drug Abuse (NebraskaSymposium on Motivat on, Volume 50). Lincoln, NE, Univers ty of Nebraska Press, 2004. Used w th permiss on.

FIGURE 12. Diagram describing the addiction cyclepreoccupation/anticipation, binge/intoxication, and withdrawal/negative affectfrom apsychiatric perspective with the different criteria for substance dependence incorporated from DSM.

Chapter 1. Neurobiology of Addiction

1 of 8

5 of 756

Much of the recent progress in understanding the neurob ology of add ction has derived from the study of animal models of add ction that have focused on specificdrugs such as opiates, psychostimulants, and alcohol (Shippenberg and Koob 2002). Although no animal model of addiction fully emulates the human condition,animal models do permit investigation of specific elements of the process of drug add ct on. Such elements can be categorized by models of different stages of theadd ction cycle. Much of the focus in animal studies has been on the synaptic sites and transductive mechanisms in the nervous system on wh ch drugs withdependence potential act initially to produce their positive reinforcing effects (binge/intoxication stage). But components of new animal models that comprise thenegative reinforcing effects of dependence (withdrawal/negative affect stage) and the craving stage (preoccupation/ant cipat on) have been developed and arebeginning to be used to explore how the nervous system adapts to drug use (Shippenberg and Koob 2002) (Table 11). The neurobiolog cal mechanisms of addictioninvolved in various stages of the add ction cycle have a specif c focus on certain brain circuits and the molecular/neurochemical changes associated with those circu tsduring the transition from drug taking to drug add ct on and how those changes persist in the vulnerability to relapse (Koob and Le Moal 2001).Research was supported by National Institutes of Health grants AA06420 and AA08459 from the National Institute on Alcohol Abuse and Alcoholism, DA04043 andDA04398 from National Institute on Drug Abuse, and DK26741 from the National Institute of Diabetes and Digestive and Kidney Diseases. Research was alsosupported by the Pearson Center for Alcoholism and Addiction Research at The Scripps Research Institute. The author would like to thank Mike Arends for hisassistance with manuscript preparation. This is publication number 18781 from The Scripps Research Institute.NEUROBIOLOGICAL MECHANISMS OF THE BINGE/INTOXICATION STAGEIt has long been hypothesized that a key element of drug add ction is that drugs of abuse activate brain reward systems and that understanding the neurobiologicalbases for acute drug reward is v tal to understanding how these systems change during the development of add ction (Koob 2004; Koob and Le Moal 1997). Researchon the neurobiology of the pos tive reinforcing effects of drugs with addict on potential has focused principally on the origins and terminal areas of themesocorticolimbic dopamine system. Indeed, there is compelling evidence indicating the importance of this system in psychostimulant reward. However, study of thespecific circuitry associated w th drug reward has been broadened to include the many neural inputs and outputs that interact with the basal forebrain. More recently,research on specific components of the basal forebrain that have been dentified as associated with drug reward has focused on both the nucleus accumbens andamygdala (Koob and Le Moal 2001; Koob et al. 1998) (see Figure 13). As our understanding about the neural circuits involved in the reinforcing effects of drugs withdependence potential has evolved, so too has our understanding of the role of neurotransmitters/neuromodulators. Five of those systems have been dentified ashaving a role in the acute reinforcing effects: dopamine, opio d peptides, -aminobutyric ac d (GABA), serotonin, and endocannabinoids (Table 12).

FIGURE 13. Sagittal section through a representative rodent brain illustrating the pathways and receptor systems implicated in the acutereinforcing actions of drugs of abuse.

Cocaine and amphetamines activate the release of dopamine in the nucleus accumbens and amygdala via direct act ons on dopamine terminals. Opioids activateop o d receptors in the ventral tegmental area, nucleus accumbens, and amygdala via direct act ons on interneurons. Opioids facil tate the release of dopamine inthe nucleus accumbens via an act on e ther in the ventral tegmental area or the nucleus accumbens, but are also hypothesized to activate elements independent ofthe dopamine system. Alcohol activates -aminobutyr c ac dA (GABAA) receptors in the ventral tegmental area, nucleus accumbens, and amygdala via either directactions at the GABAA receptor or through indirect release of GABA. Alcohol is hypothesized to facilitate the release of opioid pept des in the ventral tegmental area,nucleus accumbens, and central nucleus of the amygdala. Alcohol facil tates the release of dopamine in the nucleus accumbens via an action either in the ventraltegmental area or the nucleus accumbens. Nicotine activates nicotinic acetylcholine receptors in the ventral tegmental area, nucleus accumbens, and amygdala,either directly or indirectly, via actions on interneurons. Nicotine may also activate op o d pept de release in the nucleus accumbens or amygdala, independent ofthe dopamine system. Cannabinoids activate cannabino d type 1 (CB1) receptors in the ventral tegmental area, nucleus accumbens, and amygdala via direct actionson interneurons. Cannabinoids facil tate the release of dopamine in the nucleus accumbens via an action either in the ventral tegmental area or the nucleusaccumbens, but are also hypothesized to activate elements independent of the dopamine system. Endogenous cannabinoids may interact with postsynapt celements in the nucleus accumbens involving dopamine and/or opioid pept de systems. The blue arrows represent the interactions within the extended amygdalasystem hypothesized to have a key role in psychostimulant reinforcement. AC = anterior commissure; AMG = amygdala; ARC = arcuate nucleus; BNST = bednucleus of the stria terminalis; Cer = cerebellum; C-P = caudate-putamen; DMT = dorsomedial thalamus; FC = frontal cortex; Hippo = hippocampus; IF = inferiorcolliculus; LC = locus coeruleus; LH = lateral hypothalamus; N Acc = nucleus accumbens; OT = olfactory tract; PAG = periaqueductal gray; RPn = reticular pontinenucleus; SC = super or colliculus; SNr = substantia nigra pars ret culata; VP = ventral pall dum; VTA = ventral tegmental area.


2 of 8

6 of 756

Source. Reprinted from Koob GF: "The Neurocircuitry of Add ct on: Implications for Treatment." Clinical Neuroscience Research 5:89101, 2005. Used withpermission.

The mesolimb c dopamine system is well established as having a cr t cal role in the activating and reinforcing effects of indirect sympathomimetics such as cocaine,methamphetamine, and nicotine. However, although all drugs of abuse acutely activate the mesolimb c dopamine system, particularly in the medial shell reg on ofthe nucleus accumbens, the role of dopamine becomes less cr t cal w th opioid drugs, alcohol, and 9-tetrahydrocannabinol ( 9-THC). Here, other neurotransm ttersystems such as op o d peptides, GABA, and endocannabinoids may play key roles e ther in series or independent of activation of the mesolimb c dopamine system.For example, a particularly sens tive site for blockade of the acute reinforcing effects of alcohol w th opioid and GABAergic antagonists appears to be the centralnucleus of the amygdala (Koob 2003). Op o d peptide antagonists also block the reinforcing effects of 9-THC, a key active ingredient in marijuana.Serotonin receptors at specif c subtypes modulate psychostimulant and alcohol reward. Moreover, endocannabinoid mechanisms have been implicated inpsychostimulant, op oid, alcohol, and cannabino d reward. For example, serotonin type 1B (5-HT1B) receptor agonists facilitate cocaine reward (Parsons et al. 1998)and decrease alcohol reward (Tomkins and O'Neill 2000). Cannabinoid type 1 (CB1) antagonists block op o d, alcohol, and cannabino d reward (Justinova et al. 2004,2005). In summary, multiple neurotransmitters are implicated in the acute reinforcing effects of drugs of abuse. Key players in the nucleus accumbens and amygdalaare dopamine, opioid peptide, and GABA systems with modulation via serotonin and endocannabinoids.NEUROBIOLOGICAL MECHANISMS OF THE WITHDRAWAL/NEGATIVE AFFECT STAGEThe neural substrates and neuropharmacological mechanisms for the negative motivational effects of drug withdrawal may involve disrupt on of the same neuralsystems implicated in the positive reinforcing effects of drugs but also involve recruitment of anti-reward systems. Measures of brain reward funct on during acuteabstinence from all major drugs w th dependence potential have revealed increases in brain reward thresholds as measured by direct brain-stimulat on reward(Epping-Jordan et al. 1998; Gardner and Vorel 1998; Markou and Koob 1991; Paterson et al. 2000; Schulteis et al. 1994, 1995). These increases in reward thresholdsmay reflect decreases in the activity of reward neurotransmitter systems in the midbrain and forebrain implicated in the positive reinforcing effects of drugs.Changes at the neurochem cal level that reflect changes in the neurotransmitter system impl cated in acute drug reward are called within-system neuroadaptations tochronic drug exposure. These neuroadaptations include decreases in dopaminerg c and serotonerg c transmiss on in the nucleus accumbens during drug withdrawal asmeasured by in vivo microdialysis (Parsons and Justice 1993; Weiss et al. 1992), increased sens tiv ty of opioid receptor transduction mechanisms in the nucleusaccumbens during opioid w thdrawal (Stinus et al. 1990), decreased GABAerg c and increased N-methyl-D-aspartate (NMDA) glutamatergic transmission duringalcohol withdrawal (Dav dson et al. 1995; Morrisett 1994; Roberts et al. 1996; Weiss et al. 1996), and differential regional changes in n cotinic receptor function(Collins et al. 1990; Dani and Heinemann 1996).It is hypothesized that decreases in reward neurotransm tters reflect a w thin-system neuroadaptation and contribute significantly to the negative motivational stateassociated w th acute drug abstinence. In a within-system neuroadaptation, "the primary cellular response element to the drug would itself adapt to neutralize thedrug's effects; persistence of the opposing effects after the drug disappears would produce the withdrawal response" (Koob and Bloom 1988, p. 720). The decreasedreward system function may persist in the form of long-term biochemical changes that contribute to the clinical syndrome of protracted abstinence and vulnerabil tyto relapse.The emot onal dysregulation associated w th the w thdrawal/negative affect stage may also involve a between system neuroadaptation, in which neurochem calsystems other than those involved in positive rewarding effects of drugs of abuse are recru ted or dysregulated by chronic activation of the reward system (Koob andBloom 1988). In addition, brain neurochem cal systems involved in stress modulation may be engaged w thin the neurocircu try of the brain stress systems in anattempt to overcome the chronic presence of the perturbing drug and to restore normal funct on desp te the drug's presence. Both the hypothalamic-pituitary-adrenalaxis and the brain stress system mediated by corticotropin-releasing factor (CRF) are dysregulated by chronic administration of all major drugs with dependence orabuse potential, resulting in the common response of elevated adrenocort cotrop c hormone, corticosterone, and amygdala CRF during acute withdrawal (Delfs et al.2000; Koob et al. 1994; Merlo-Pich et al. 1995; Olive et al. 2002; Rasmussen et al. 2000; Rivier et al. 1984). Acute withdrawal from drugs may also increase therelease of norepinephrine in the bed nucleus of the stria terminalis (BNST) and decrease levels of neuropept de Y (NPY) in the central and medial nuclei of theamygdala (Roy and Pandey 2002).During the development of dependence, these results suggest not only a change in the function of neurotransmitters associated with the acute reinforcing effects ofdrugs (dopamine, opioid peptides, serotonin, GABA, and endocannabino ds) but also recru tment of the brain stress system (CRF and norepinephrine) anddysregulat on of the NPY brain anti-stress system (Koob and Le Moal 2001) (Table 13). Moreover, activat on of the brain stress systems may not only contribute tothe negative motivational state associated w th acute abstinence but may also contribute to the vulnerability to stressors observed during protracted abstinence inhumans.The neuroanatomical ent ty termed the extended amygdala (Heimer and Alhe d 1991) may represent a common anatom cal substrate for acute drug reward and acommon neuroanatom cal substrate for the negative effects on reward function produced by stress that help drive compulsive drug administrat on. The extendedamygdala is composed of the BNST, the central nucleus of the amygdala, and a transition zone in the medial subreg on of the nucleus accumbens (shell of the nucleusaccumbens). Each of these regions has cytoarchitectural and circuitry similarities (Heimer and Alheid 1991). The extended amygdala receives numerous afferentsfrom limbic structures such as the basolateral amygdala and hippocampus and sends efferents to the medial part of the ventral pallidum and a large project on to thelateral hypothalamus. Thus, the specific brain areas that link class cal limb c (emot onal) structures with the extrapyram dal motor system are further defined (Alhe det al. 1995).The concept of an anti-reward system has been recently formulated to accommodate the signif cant changes in brain emot onal systems associated with thedevelopment of dependence (Koob and Le Moal 2005). The anti-reward concept is based on the hypothesis that there are brain systems in place to limit reward (Kooband Bloom 1988), an opponent-process concept that forms a general feature of biological systems. The concept of an anti-reward system is derived from thehypothesis that between-system neuroadaptations result from activat on of the reward system at the neurocircu try level. A between-system neuroadaptat on is acircu try change in which circuit B (anti-reward circuit) is activated by circuit A (reward circuit). This concept has ts origins in the theoretical pharmacology thatpredates opponent-process theory (Martin 1967). Thus, the activation of brain stress systems such as CRF, norepinephrine, and dynorphin w th concom tantdysregulat on of the NPY system may represent the recruitment of an anti-reward system in the extended amygdala that produces the motivational components ofdrug withdrawal and provides a baseline hedon c shift that facilitates craving mechanisms (Koob and Le Moal 2005).NEUROBIOLOGICAL MECHANISMS OF THE PREOCCUPATION/ANTICIPATION STAGEThe preoccupation/ant cipat on stage of the add ct on cycle has long been hypothesized to be a key element of relapse in humans, and t contributes to the definit onof addict on as a chron c, relapsing disorder. Although often linked to the construct of craving, craving per se has been difficult to measure in human clinical studies(Tiffany et al. 2000) and often does not correlate with relapse. Nevertheless, the stage of the add ct on cycle when the individual reinstates drug-seeking behaviorafter abstinence remains a challenge for researchers who focus on neurobiological mechanisms and med cat on development for treatment.Animal models of craving can be divided into two domains: craving type 1 involves drug seeking induced by stimuli paired w th drug taking; craving type 2 featuresdrug seeking induced by an acute stressor or a state of stress (Table 14). Craving type 1 animal models emphasize the use of drug-primed reinstatement andcue-induced reinstatement. Craving type 2 animal models are characterized by stress-induced reinstatement in animals that have acquired drug self-administrat onand then have been subjected to extinction of responding for the drug.Most evidence from animal studies suggests that drug-induced reinstatement is localized to the medial prefrontal cortex/nucleus accumbens/ventral pall dum circuitmediated by the neurotransmitter glutamate (McFarland and Kalivas 2001). In contrast, neuropharmacological and neurobiological studies using animal models forcue-induced reinstatement include the basolateral amygdala as a crit cal substrate, with a possible feed-forward mechanism through the prefrontal cortex systeminvolved in drug-induced reinstatement (Ever tt and Wolf 2002; Weiss et al. 2001). Neurotransmitter systems involved in drug-induced reinstatement arecharacterized by a glutamatergic project on from the frontal cortex to the nucleus accumbens that is modulated by dopamine activ ty in the frontal cortex.Cue-induced reinstatement involves dopamine modulation in the basolateral amygdala and a glutamatergic project on to the nucleus accumbens from both thebasolateral amygdala and ventral sub culum (Everitt and Wolf 2002; Vorel et al. 2001). In contrast, stress-induced reinstatement of drug-related responding in animal


3 of 8

7 of 756

models appears to depend on the activat on of both CRF and norepinephrine in elements of the extended amygdala (central nucleus of the amygdala and BNST)(Shaham et al. 2003; Shalev et al. 2002). Protracted abstinence, largely described in alcohol dependence models, appears to involve overactive glutamaterg c andCRF systems (De Witte et al. 2005; Valdez et al. 2002).OVERALL NEUROCIRCUITRY OF ADDICTIONIn summary, three neurob olog cal circuits have been dentified that have heuristic value for the study of the neurobiological changes associated with the developmentand persistence of drug dependence (Figure 14). The acute reinforcing effects of drugs of abuse that make up the binge/intox cat on stage most likely involve actionswith an emphasis on the extended amygdala reward system and inputs from the ventral tegmental area and arcuate nucleus of the hypothalamus. In contrast, thesymptoms of acute w thdrawal that are important in add ct on, such as negative affect and increased anxiety associated with the w thdrawal/negative affect stage,most likely include decreases in function of the extended amygdala reward system but also a recruitment of brain stress neurocircuitry. The craving stage, orpreoccupat on/anticipation stage, features key afferent projections to the extended amygdala and nucleus accumbens, specifically the prefrontal cortex (fordrug-induced reinstatement) and the basolateral amygdala (for cue-induced reinstatement). Compulsive drug-seeking behavior is thought to be driven by ventralstriatalventral pallidalthalamic-cortical loops.

FIGURE 14. Key common neurocircuitry elements in drug-seeking behavior of addiction.

Three major circu ts that underlie addict on can be distilled from the literature. A drug reinforcement circuit (reward and stress) is composed of the extendedamygdala, including the central nucleus of the amygdala, the bed nucleus of the stria terminalis, and the transition zone in the shell of the nucleus accumbens.Multiple modulator neurotransmitters are hypothesized, including dopamine and opioid peptides for reward; and cort cotropin-releasing factor and norepinephrinefor stress. The extended amygdala is hypothesized to mediate integration of rewarding stimuli or stimuli with positive incentive salience and aversive stimuli orstimuli with negative aversive salience. During acute intox cat on, valence is weighted on processing rewarding stimuli, and, during the development of dependence,aversive stimuli come to dominate function. A drug- and cue-induced reinstatement (craving) neurocircuit is composed of the prefrontal (anter or cingulate,prelimb c, orb tofrontal) cortex and basolateral amygdala, w th a primary role hypothesized for the basolateral amygdala in cue-induced craving and a primary rolefor the medial prefrontal cortex in drug-induced craving, based on animal studies. Human imaging studies have shown an important role for the orbitofrontal cortexin craving (see text). A drug-seeking circu t (compulsive) circuit is composed of the nucleus accumbens, ventral pallidum, thalamus, and orbitofrontal cortex. Thenucleus accumbens has long been hypothesized to have a role in translating motivation to action and forms an interface between the reward funct ons of theextended amygdala and the motor functions of the ventral striatalventral pallidalthalam c-cort cal loops. The striatal-pallidal-thalamic loops reciprocally movefrom prefrontal cortex to orb tofrontal cortex to motor cortexultimately leading to drug-seeking behavior. Note that, for the sake of simplic ty, other structuresare not included, such as the hippocampus (which presumably mediates context-specific learning, including that associated with drug act ons). Also note thatdopamine and norepinephrine both have w despread innervat on of cort cal reg ons and may modulate function relevant to drug add ction in those structures. CRF =cort cotropin-releasing factor; DA = dopamine; -END = -endorphin; ENK = emkephalin; NE = norepinephrine; VTA = ventral tegmental area.Source. Reprinted from Koob GF, Le Moal M: Neurobiology of Addiction. London, Academic Press, 2005. Used with permiss on.

MOLECULAR AND CELLULAR MECHANISMS IN THE BRAIN CIRCUITS ASSOCIATED WITH ADDICTIONDetermining which genetic and environmental factors produce the vulnerability to add ction has become one of the most exciting pursuits in the study of theneurobiology of addiction. One hypothesis is that molecular changes at the gene or gene transcript on level will provide the key to understanding such vulnerabil ty.The search at the molecular level has led to an examinat on of how repeated perturbation of intracellular signal transduction pathways leads to changes in nuclearfunction and altered rates of transcript on of particular target genes. Altered expression of such genes would lead to altered activ ty of the neurons where suchchanges occur and, ultimately, to changes in the function of neural circuits in which those neurons operate.Two transcription factors in particular have been impl cated in the plast city associated with add ction: cyclic adenosine monophosphate (cAMP) response element-binding protein (CREB), and FosB. CREB regulates the transcript on of genes that contain a cAMP response element site within the regulatory reg ons and can befound ubiqu tously in genes expressed in the central nervous system such as those that encode neuropeptides, synthetic enzymes for neurotransmitters, signalingproteins, and other transcript on factors. CREB can be phosphorylated by protein kinase A and by protein kinases regulated by growth factors, putting it at a point ofconvergence for several intracellular messenger pathways that can regulate the expression of genes.Much work in the add ction field has shown that activation of CREB in the nucleus accumbens is a consequence of chron c exposure to opiates, cocaine, and alcohol,and deactivation of CREB in the central nucleus of the amygdala w th alcohol and nicotine. The activat on of CREB is linked to the activat on of the dysphoria-inducing op o d receptor that binds the opioid peptide dynorphin. Up-regulat on of the cAMP pathway and CREB in the nucleus accumbens is thus believed to represent amechanism of motivat onal tolerance and dependence. More specifically, these molecular adaptat ons may decrease an individual's sens tiv ty to the rewarding effectsof subsequent drug exposures (tolerance) and impair the reward pathway (dependence) so that after removal of the drug the individual is left in an amotivational,dysphoric, or depressed-like state (Nestler 2004).In contrast, decreased CREB phosphorylat on has been observed in the central nucleus of the amygdala during alcohol w thdrawal and has been linked to decreasedNPY function and, consequently, the increased anxiety-like responses associated w th acute alcohol withdrawal (Pandey 2004). Increased CREB in the nucleus


4 of 8

8 of 756

accumbens and decreased CREB in the central nucleus of the amygdala are not necessarily mutually exclusive. Furthermore, these effects point to transductionmechanisms that could produce neurochemical changes in the neurocircu ts outlined above as being important for breaks w th reward homeostasis in addict on.The molecular changes associated w th long-term changes in brain function as a result of chron c exposure to drugs of abuse have also been linked to changes intranscript on factors, which can change gene expression and produce long-term changes in protein expression and, as a result, neuronal function. Although acuteadministration of drugs of abuse can cause a rap d (hours) activation of members of the Fos family, such as c-fos, FosB, Fra-1, and Fra-2, in the nucleus accumbens,other transcript on factors, isoforms of FosB, accumulate over longer per ods of time (days) with repeated drug administration (Nestler 2004). Animals w thactivated FosB have exaggerated sensitivity to the rewarding effects of drugs of abuse. Therefore, FosB may be a sustained molecular trigger that helps to initiateand maintain a state of addict on. How changes in FosB that can last for days can also translate into vulnerability to relapse remains a challenge for future work(Nestler 2004).Genetic and molecular-genetic animal models have prov ded a molecular basis to support the neuropharmacolog cal substrates dentified in neurocircuitry studies.Alcohol-preferring rats have been bred that show particularly high levels of voluntary consumpt on of alcohol, increased anxiety-like responses, and numerousneuropharmacological phenotypes, such as decreased dopaminergic activity and decreased NPY activity (McBr de et al. 1990; Murphy et al. 2002). In an alcohol-preferring and -nonpreferring cross, a quantitative trait locus was dentified on chromosome 4, a reg on on which the gene for NPY has been mapped. In the inbredpreferring- and nonpreferring-quant tative trait loci analyses, loci on chromosomes 3, 4, and 8 have been dentified that correspond to loci near the genes for thedopamine D2 and serotonin 5-HT1B receptors (Carr et al. 1998).Advances in molecular biology have given researchers the ability to systemat cally inactivate genes that control the express on of proteins that make up receptors orneurotransmitters/neuromodulators in the central nervous system using the gene knockout approach. "Knockout" m ce have a gene inactivated by homologousrecombinat on. A knockout mouse deficient in both alleles of a gene is homozygous for the deletion and is termed a null mutation (/). A mouse that is deficient inonly one of the two alleles for the gene is termed a heterozygote (+/). Transgen c knockin m ce have an extra gene introduced into their germline. An addit onalcopy of a normal gene is inserted into the genome of the mouse to examine the overexpress on effects of the product of that gene. Alternatively, a new gene, notnormally found in the mouse, can be added, such as a gene associated w th a specif c pathology in humans. Wild-type controls are animals bred through the samebreeding strategies involving mice that receive the transgene injected into the fertilized egg (transgenics) or a targeted gene construct injected into the genome viaembryonic stem cells (knockout) but lacking the mutation on either allele of the gene in question. Although such an approach does not guarantee that these genes arethe vulnerable ones in the human population, the genes do prov de viable candidates for exploring the genet c basis of endophenotypes associated with add ct on(Koob et al. 2001).Notable positive results with gene knockout studies in mice have focused on knockout of the opioid receptor, wh ch eliminates opioid, nicotine, and cannabinoidreward and alcohol drinking in m ce (Contet et al. 2004). Op o d (morphine) reinforcement as measured by cond t oned place preference or self-administrat on isabsent in knockout mice, and there is no development of somat c signs of dependence to morphine in these mice. Indeed, to date, all morphine effects tested,including analgesia, hyperlocomotion, respiratory depress on, and inhib tion of gastrointestinal transit, are abolished in knockout m ce (Gaveriaux-Ruff and Kieffer2002).Selective delet on of the genes for express on of different dopamine receptor subtypes and the dopamine transporter has revealed significant effects to challengeswith psychomotor stimulants. D1 receptor knockout m ce show no response to D1 agonists or antagonists and show a blunted response to the locomotor-activatingeffects of cocaine and amphetamine. When compared with wild-type m ce, D1 knockout mice are also impaired in their acquis tion of intravenous cocaineself-administration (Caine et al. 2007). D2 knockout m ce have severe motor def cits and blunted psychostimulant responses to psychostimulants and opiates, but theeffects on psychostimulant reward are less consistent. Dopamine transporter knockout mice are dramatically hyperactive but also show a blunted response topsychostimulants. Although developmental factors must be taken into account for the compensatory effect of deleting any one or a combination of genes, t is clearthat D1 and D2 receptors and the dopamine transporter play important roles in the actions of psychomotor stimulants (Caine et al. 2002, 2007).BRAIN IMAGING CIRCUITS INVOLVED IN HUMAN ADDICTIONBrain imaging studies using magnet c resonance imaging techn ques or positron emission tomography w th ligands for measuring oxygen utilizat on or glucosemetabolism are providing dramatic insights into the neurocircu try changes in the human brain associated w th the development of, maintenance of, and vulnerabilityto addiction. Overall, these imaging results show a striking resemblance to the neurocircu try identified in studies in animals. During acute intox cation with alcohol,n cotine, or cocaine, there is an activat on of the orbitofrontal cortex, prefrontal cortex, anter or cingulate, extended amygdala, and ventral striatum. This activationis often accompanied by an increase in availability of the neurotransm tter dopamine. During acute and chronic withdrawal there is a reversal of these changesaccompanied by decreases in metabol c activ ty, particularly in the orbitofrontal cortex, prefrontal cortex, and anter or cingulate, and decreases in basal dopamineactivity as measured by decreased D2 receptors in the ventral striatum and prefrontal cortex. Cue-induced reinstatement appears to involve a reactivation of thesecircu ts, much like that of acute intox cat on (Bonson et al. 2002; Bre ter et al. 2001; Childress et al. 1999). Craving or cues associated w th cocaine and nicotineproduce activat on of the prefrontal cortex and anterior cingulate gyrus (Lee et al. 2005; Risinger et al. 2005). Imaging studies also show evidence that cuesassociated w th cocaine craving increase dopamine release in the striatum as well as op o d peptides in the anterior cingulate and frontal cortex (Gorel ck et al. 2005;Volkow et al. 2006; Wong et al. 2006). Craving in alcoholic individuals appears to be correlated with higher opio d peptide activity in the striatum but lowerdopaminerg c activ ty (Heinz et al. 2004, 2005). Thus, imaging studies to date reveal baseline decreases in orbitofrontal function and dopamine function duringdependence, but a reactivat on of the dopamine and reward system function during acute craving episodes consistent w th the early formulat on of different neuralsubstrates for craving type 1 and type 2 (see above).CONCLUSIONMuch progress in neurob ology has provided a useful neurocircu try framework w th which to dentify the neurobiolog cal and neuroadaptive mechanisms involved inthe development of drug add ction. The brain reward system implicated in the development of addict on is composed of key elements of the basal forebrain, w th thenucleus accumbens and central nucleus of the amygdala playing part cularly important roles.Neuropharmacolog cal studies in animal models of add ct on have provided evidence that ind cates the activat on of specif c neurochemical mechanisms in specificbrain reward neurochemical systems in the basal forebrain (dopamine, opioid peptides, GABA, serotonin, and endocannabinoids) during the binge/intoxication stage.During the withdrawal/negative affect stage, there is a dysregulat on of the same brain reward neurochem cal systems in the basal forebrain. There is alsorecruitment of brain stress systems (CRF and norepinephrine) and dysregulat on of brain anti-stress systems (NPY) that contribute to the negative motivational stateassociated w th drug abstinence. During the preoccupation/ant cipation stage, neurob ological circuits that engage the frontal cortex glutamatergic project ons to thenucleus accumbens are crit cal for drug-induced reinstatement, whereas basolateral amygdala and ventral subiculum glutamatergic project ons to the nucleusaccumbens are involved in cue-induced reinstatement. Stress-induced reinstatement appears to be mediated by changes in the anti-reward systems of the extendedamygdala. The changes in craving and anti-reward (stress) systems are hypothesized to remain outs de of a homeostat c state. As such, these changes convey thevulnerabil ty for development of dependence and relapse in add ction. To date, genetic studies in animals suggest roles for the genes encoding the neurochemicalelements involved in the brain reward (dopamine, op o d peptide) and stress (NPY) systems in the vulnerability to addiction. Molecular studies have dentifiedtransduction and transcription factors that may mediate the dependence-induced reward dysregulation (CREB) and chron c-vulnerability changes ( FosB) inneurocircuitry associated with the development and maintenance of addiction. Human imaging studies reveal similar neurocircu ts involved in acute intoxication,chronic drug dependence, and vulnerabil ty to relapse.Although no exact imaging results necessarily predict addiction, two salient changes in established and unrecovered substance-dependent individuals that cut acrossdifferent drugs are decreases in orb tofrontal/prefrontal cortex funct on and in brain D2 receptors. No molecular markers are suff ciently specific to predictvulnerabil ty to addict on, but changes in certain intermediate early genes with chron c drug exposure in animal models show promise of long-term changes in specificbrain regions that may be common to all drugs of abuse. The continually evolving knowledge base of biolog cal and neurob ological aspects of substance use disordersprovides a heurist c framework to better develop the diagnoses, prevention, and treatment of substance abuse disorders.KEY POINTS The brain reward system impl cated in the development of addict on comprises key elements of the basal forebrain such as the ventral striatum, the extended


5 of 8

9 of 756

amygdala, and ts connections. Neuropharmacolog cal studies in animal models of addict on have provided evidence to indicate that there are decreases of specif c neurochemical mechanisms inspecif c brain reward neurochemical systems in the ventral striatum and amygdala (dopamine, op o d peptides, -aminobutyric ac d, and endocannabinoids; lightside of addiction). Recruitment of brain stress systems (cort cotropin-releasing factor and norepinephrine; dark side of addiction) and dysregulation of brain anti-stress systems(neuropept de Y) provide the negative motivat onal state associated with drug abstinence. Changes in the reward and stress systems are hypothesized to maintain hedonic stabil ty in an allostatic state (altered reward set point), as opposed to ahomeostatic state and, as such, convey the vulnerability for the development of dependence and relapse in add ction. Similar neurochem cal systems have been implicated in animal models of relapse, with dopamine and opioid peptide systems (and glutamate) being impl cated indrug- and cue-induced relapse, possibly more in prefrontal cortical and basolateral amygdala projections to the ventral striatum and extended amygdala than in thereward system tself. The brain stress systems in the extended amygdala are directly implicated in stress-induced relapse. Genet c studies to date in animals using knockouts of specif c genes suggest roles for the genes encoding the neurochemical elements involved in the brain reward(dopamine, op o d pept de) and stress (neuropept de Y) systems in the vulnerability to add ction.REFERENCESAlhe d GF, De Olmos JS, Beltramino CA: Amygdala and extended amygdala, in The Rat Nervous System. Edited by Paxinos G. San Diego, CA, Academ c Press, 1995,pp 495578Amer can Psychiatric Association: Diagnostic and Statistical Manual of Mental Disorders, 4th Edition. Washington, DC, Amer can Psychiatric Associat on, 1994Amer can Psychiatric Association: Diagnostic and Statistical Manual of Mental Disorders, 4th Edition, Text Revision. Washington, DC, Amer can Psychiatric Associat on,2000Bonson KR, Grant SJ, Contoreggi CS, et al: Neural systems and cue-induced cocaine craving. Neuropsychopharmacology 26:376386, 2002 [PubMed]Breiter HC, Aharon I, Kahneman D, et al: Functional imaging of neural responses to expectancy and experience of monetary gains and losses. Neuron 30:619639,2001 [PubMed]Caine SB, Negus SS, Mello NK, et al: Role of dopamine D2-like receptors in cocaine self-administrat on: studies w th D2 receptor mutant mice and novel D2 receptorantagonists. J Neurosci 22:29772988, 2002 [PubMed]Caine SB, Thomsen M, Gabriel KI, et al: Lack of self-administrat on of cocaine in dopamine D1 receptor knock-out mice. J Neurosci 27:1314013150, 2007 [PubMed]Carr LG, Foroud T, B ce P, et al: A quantitative tra t locus for alcohol consumption in selectively bred rat lines. Alcohol Clin Exp Res 22:884887, 1998 [PubMed]Childress AR, Mozley PD, McElgin W, et al: Limbic activation during cue-induced cocaine craving. Am J Psychiatry 156:1118, 1999 [Full Text] [PubMed]Collins AC, Bhat RV, Pauly JR, et al: Modulation of n cotine receptors by chronic exposure to nicotinic agonists and antagonists, in The B ology of Nicotine Dependence(Ciba Foundation Symposium, Vol 152). Ed ted by Bock G, Marsh J. New York, Wiley, 1990, pp 87105Contet C, Kieffer BL, Befort K: Mu opioid receptor: a gateway to drug add ct on. Curr Opin Neurob ol 14:370378, 2004 [PubMed]Dani JA, Heinemann S: Molecular and cellular aspects of nicotine abuse. Neuron 16:905908, 1996 [PubMed]Dav dson M, Shanley B, Wilce P: Increased NMDA-induced excitability during ethanol w thdrawal: a behav oural and histological study. Brain Res 674:9196, 1995[PubMed]Delfs JM, Zhu Y, Druhan JP, et al: Noradrenaline in the ventral forebrain is crit cal for opiate withdrawal-induced aversion. Nature 403:430434, 2000 [PubMed]De W tte P, Littleton J, Parot P, et al: Neuroprotective and abstinence-promoting effects of acamprosate: elucidating the mechanism of act on. CNS Drugs19:517537, 2005Epping-Jordan MP, Watkins SS, Koob GF, et al: Dramatic decreases in brain reward function during nicotine w thdrawal. Nature 393:7679, 1998 [PubMed]Everitt BJ, Wolf ME: Psychomotor stimulant addiction: a neural systems perspective. J Neurosci 22:33123320, 2002; erratum in J Neurosci 22:1a, 2002Gardner EL, Vorel SR: Cannabinoid transmiss on and reward-related events. Neurob ol Dis 5:502533, 1998 [PubMed]Gaveriaux-Ruff C, Kieffer BL: Opioid receptor genes inactivated in mice: the highlights. Neuropeptides 36:6271, 2002 [PubMed]Gorel ck DA, Kim YK, Bencherif B, et al: Imaging brain mu-op o d receptors in abstinent cocaine users: time course and relation to cocaine craving. B ol Psychiatry57:15731582, 2005 [PubMed]Heimer L, Alheid G: Piecing together the puzzle of basal forebrain anatomy, in The Basal Forebrain: Anatomy to Function (Advances in Experimental Medicine andBiology, Vol 295). Edited by Napier TC, Kalivas PW, Hanin I. New York, Plenum, 1991, pp 142Heinz A, Siessmeier T, Wrase J, et al: Correlation between dopamine D(2) receptors in the ventral striatum and central processing of alcohol cues and craving. Am JPsychiatry 161:17831789, 2004; erratum in Am J Psychiatry 161:2344, 2004Heinz A, Reimold M, Wrase J, et al: Correlat on of stable elevat ons in striatal mu-opioid receptor availability in detoxified alcoholic patients with alcohol craving: apositron emission tomography study using carbon 11-labeled carfentanil. Arch Gen Psychiatry 62:5764, 2005; erratum in Arch Gen Psychiatry 62:983, 2005Justinova Z, Tanda G, Munzar P, et al: The op o d antagonist naltrexone reduces the reinforcing effects of delta 9 tetrahydrocannabinol (THC) in squirrel monkeys.Psychopharmacology (Berl) 173:186194, 2004 [PubMed]Justinova Z, Solinas M, Tanda G, et al: The endogenous cannabino d anandam de and ts synthet c analog R(+)-methanandamide are intravenously self-administeredby squirrel monkeys. J Neurosci 25:56455650, 2005 [PubMed]Koob GF: Alcoholism: allostasis and beyond. Alcohol Clin Exp Res 27:232243, 2003 [PubMed]Koob GF: Allostatic view of motivation: impl cat ons for psychopathology, in Motivat onal Factors in the Et ology of Drug Abuse (Nebraska Symposium on Motivat on,Vol 50). Lincoln, University of Nebraska Press, 2004, pp 118Koob GF: The neurocircuitry of addiction: impl cat ons for treatment. Clin Neurosci Res 5:89101, 2005Koob GF, Bloom FE: Cellular and molecular mechanisms of drug dependence. Science 242:715723, 1988 [PubMed]Koob GF, Le Moal M: Drug abuse: hedonic homeostatic dysregulat on. Science 278:5258, 1997 [PubMed]Koob GF, Le Moal M: Drug add ction, dysregulation of reward, and allostasis. Neuropsychopharmacology 24:97129, 2001 [PubMed]Koob GF, Le Moal M: Plasticity of reward neurocircuitry and the 'dark side' of drug addict on. Nat Neurosci 8:14421444, 2005 [PubMed]Koob GF, Le Moal M: Neurobiology of Addiction. London, Academic Press, 2006Koob GF, Heinrichs SC, Menzaghi F, et al: Corticotropin releasing factor, stress and behavior. Seminars in the Neurosciences 6:221229, 1994Koob GF, Sanna PP, Bloom FE: Neuroscience of addict on. Neuron 21:467476, 1998 [PubMed]


6 of 8

10 of 756

Koob GF, Bartfai T, Roberts AJ: The use of molecular genet c approaches in the neuropharmacology of corticotropin-releasing factor. Int J Comp Psychol 14:90110,2001Lee JH, Lim Y, Wiederhold BK, et al: A funct onal magnetic resonance imaging (FMRI) study of cue-induced smoking craving in virtual environments. ApplPsychophysiol B ofeedback 30:195204, 2005 [PubMed]Markou A, Koob GF: Post-cocaine anhedonia: an animal model of cocaine withdrawal. Neuropsychopharmacology 4:1726, 1991 [PubMed]Martin WR: Op o d antagonists. Pharmacol Rev 19:463521, 1967 [PubMed]McBride WJ, Murphy JM, Lumeng L, et al: Serotonin, dopamine and GABA involvement in alcohol drinking of selectively bred rats. Alcohol 7:199205, 1990 [PubMed]McFarland K, Kalivas PW: The circu try mediating cocaine-induced reinstatement of drug-seeking behav or. J Neurosci 21:86558663, 2001 [PubMed]Merlo-Pich E, Lorang M, Yeganeh M, et al: Increase of extracellular cort cotropin-releasing factor-like immunoreactiv ty levels in the amygdala of awake rats duringrestraint stress and ethanol w thdrawal as measured by microdialysis. J Neurosci 15:54395447, 1995 [PubMed]Morrisett RA: Potentiation of N-methyl-D-aspartate receptor-dependent afterdischarges in rat dentate gyrus following in vitro ethanol withdrawal. Neurosci Lett167:175178, 1994 [PubMed]Murphy JM, Stewart RB, Bell RL, et al: Phenotypic and genotypic characterizat on of the Indiana University rat lines selectively bred for high and low alcoholpreference. Behav Genet 32:363388, 2002 [PubMed]Nestler EJ: Historical review: molecular and cellular mechanisms of opiate and cocaine add ction. Trends Pharmacol Sci 25:210218, 2004 [PubMed]Olive MF, Koenig HN, Nannini MA, et al: Elevated extracellular CRF levels in the bed nucleus of the stria terminalis during ethanol withdrawal and reduction bysubsequent ethanol intake. Pharmacol B ochem Behav 72:213220, 2002 [PubMed]Pandey SC: The gene transcription factor cyclic AMP-responsive element binding protein: role in pos tive and negative affective states of alcohol add ction. PharmacolTher 104:4758, 2004 [PubMed]Parsons LH, Justice JB Jr: Perfusate serotonin increases extracellular dopamine in the nucleus accumbens as measured by in vivo microdialysis. Brain Res606:195199, 1993 [PubMed]Parsons LH, Weiss F, Koob GF: Serotonin-1B receptor stimulation enhances cocaine reinforcement. J Neurosci 18:1007810089, 1998 [PubMed]Paterson NE, Myers C, Markou A: Effects of repeated withdrawal from continuous amphetamine administrat on on brain reward function in rats. Psychopharmacology(Berl) 152:440446, 2000 [PubMed]Rasmussen DD, Boldt BM, Bryant CA, et al: Chronic daily ethanol and w thdrawal, 1: long-term changes in the hypothalamo-pitu tary-adrenal axis. Alcohol Clin ExpRes 24:18361849, 2000 [PubMed]Risinger RC, Salmeron BJ, Ross TJ, et al: Neural correlates of high and craving during cocaine self-administration using BOLD fMRI. Neuroimage 26:10971108, 2005[PubMed]Rivier C, Bruhn T, Vale W: Effect of ethanol on the hypothalam c-pitu tary-adrenal axis in the rat: role of cort cotropin-releasing factor (CRF). J Pharmacol Exp Ther229:127131, 1984 [PubMed]Roberts AJ, Cole M, Koob GF: Intra-amygdala muscimol decreases operant ethanol self-administrat on in dependent rats. Alcohol Clin Exp Res 20:12891298, 1996[PubMed]Roy A, Pandey SC: The decreased cellular expression of neuropeptide Y protein in rat brain structures during ethanol withdrawal after chronic ethanol exposure.Alcohol Clin Exp Res 26:796803, 2002 [PubMed]Schulteis G, Markou A, Gold LH, et al: Relative sensitivity to naloxone of multiple ind ces of opiate withdrawal: a quantitative dose-response analysis. J PharmacolExp Ther 271:13911398, 1994 [PubMed]Schulteis G, Markou A, Cole M, et al: Decreased brain reward produced by ethanol withdrawal. Proc Natl Acad Sci U S A 92:58805884, 1995 [PubMed]Shaham Y, Shalev U, Lu L, et al: The reinstatement model of drug relapse: history, methodology and major findings. Psychopharmacology (Berl) 168:320, 2003[PubMed]Shalev U, Grimm JW, Shaham Y: Neurobiology of relapse to heroin and cocaine seeking: a review. Pharmacol Rev 54:142, 2002 [PubMed]Shippenberg TS, Koob GF: Recent advances in animal models of drug add ct on and alcoholism, in Neuropsychopharmacology: The Fifth Generation of Progress.Edited by Davis KL, Charney D, Coyle JT, et al. Philadelphia, PA, Lippincott Williams & Wilkins, 2002, pp 13811397Stinus L, Le Moal M, Koob GF: Nucleus accumbens and amygdala are possible substrates for the aversive stimulus effects of opiate withdrawal. Neuroscience37:767773, 1990 [PubMed]Tiffany ST, Carter BL, Singleton EG: Challenges in the manipulat on, assessment and interpretation of craving relevant variables. Add ction 95 (suppl 2):S177S187,2000Tomkins DM, O'Neill MF: Effect of 5-HT(1B) receptor ligands on self-administration of ethanol in an operant procedure in rats. Pharmacol B ochem Behav 66:129136,2000 [PubMed]United Nat ons International Drug Control Programme and World Health Organization: Informal Expert Group Meeting on the Craving Mechanism, Vienna, January2830, 1992 (report no. V92-54439T). Geneva, World Health Organization, 1992Valdez GR, Roberts AJ, Chan K, et al: Increased ethanol self-administrat on and anxiety-like behavior during acute withdrawal and protracted abstinence: regulationby corticotropin-releasing factor. Alcohol Clin Exp Res 26:14941501, 2002 [PubMed]Volkow ND, Wang GJ, Telang F, et al: Cocaine cues and dopamine in dorsal striatum: mechanism of craving in cocaine addict on. J Neurosci 26:65836588, 2006[PubMed]Vorel SR, Liu X, Hayes RJ, et al: Relapse to cocaine-seeking after hippocampal theta burst stimulat on. Science 292:11751178, 2001 [PubMed]Weiss F, Markou A, Lorang MT, et al: Basal extracellular dopamine levels in the nucleus accumbens are decreased during cocaine withdrawal after unlimited-accessself-administration. Brain Res 593:314318, 1992 [PubMed]Weiss F, Parsons LH, Schulteis G, et al: Ethanol self-administrat on restores withdrawal-associated deficiencies in accumbal dopamine and 5-hydroxytryptaminerelease in dependent rats. J Neurosci 16:34743485, 1996 [PubMed]Weiss F, Ciccocioppo R, Parsons LH, et al: Compulsive drug-seeking behavior and relapse: neuroadaptation, stress, and cond t oning factors, in The Biological Basis ofCocaine Add ction (Annals of the New York Academy of Sciences Vol 937). Ed ted by Quinones-Jenab. New York, New York Academy of Sciences, 2001, pp 126Wong DF, Kuwabara H, Schretlen DJ, et al: Increased occupancy of dopamine receptors in human striatum during cue-elic ted cocaine craving [erratum in:Neuropsychopharmacology 2006; 32:256]. Neuropsychopharmacology 31:27162727, 2006 [PubMed]SUGGESTED READING


7 of 8

11 of 756

Koob GF: Allostatic view of motivation: impl cat ons for psychopathology, in Motivat onal Factors in the Et ology of Drug Abuse (Nebraska Symposium on Motivat on,Vol 50). Ed ted by Bevins RA, Bardo MT. Lincoln, Univers ty of Nebraska Press, 2004, pp 118Koob GF, Le Moal M: Drug add ction, dysregulation of reward, and allostasis. Neuropsychopharmacology 24:97129, 2001Koob GF, Le Moal M: Plasticity of reward neurocircuitry and the "dark s de" of drug addict on. Nat Neurosci 8:14421444, 2005Koob GF, Le Moal M: Neurobiology of Addiction. London, Academic Press, 2006

Copyright 2011 American Psychiatric Association. All Rights Reserved.


8 of 8

12 of 756

Print Close Window

Joel Gelernter, Henry R. Kranzler: Chapter 2. Genetics of Addiction, in The American Psychiatric PublishingTextbook of Substance Abuse Treatment. Edited by Marc Galanter, Herbert D. Kleber. Copyright 2011American Psychiatric Publishing, Inc. DOI: 10.1176/appi.books.9781585623440.344402. Printed 10/7/2011from www.psychiatryonline.comTextbook of Substance Abuse Treatment >

Genetics of AddictionJoel Gelernter, M.D.Henry R. Kranzler, M.D.GENETICS OF ADDICTION: INTRODUCTIONLike other important psychiatric traits, substance dependence (SD) is genetically influenced, and thisgenetic influence is complex. This means that the genetic influence plays out in something other than aMendelian mode (i.e., dominant, recessive, or X-linked), and, practically speaking, this means there aremany genes involvednone of which ever fully determines that a person will be affected. Moreover, aswith other complex traits, SD risk is influenced by both genetic and environmental factors. But in thecase of SD risk there is a special twist: there is a necessary component of gene-by-environmentinteraction. A person cannot become substance dependent without exposure to the substance,regardless of genetic constitution. This places a trait like cocaine dependence (you cannot be cocainedependent if you do not have access to cocaine) in contrast to a trait like schizophrenia, in which, as faras we know, special environmental exposure is not required for the condition to develop.Although this is of obvious inherent interest to geneticists, we also need to ask, what are the clinicalimplications of the genetic contribution to SD? This is important for several reasons. First, it can help usto appreciate that, if different individuals experience different levels of risk, the nature of some part ofthis risk is purely biological. Second, once specific genetic factorsalleles at particular genetic loci, orgenesare identified, our understanding of the biology of the addiction process is increasedsubstantially. Knowledge of new mechanisms can reasonably be expected to lead to the identification ofnovel pharmacological targets and new treatments. Finally, as we learn more about the genetic factorsinfluencing risk, course, and biological treatment of SD, we become better able to elucidate theenvironmental contributors to risk, as well as the nature of the interactive effects of genes andenvironment in determining risk.In this chapter, we review the progress made in identifying genes and alleles that influence risk for SD.Because genetic epidemiological studies have provided clear evidence of the genetic influence on SD, wefirst briefly discuss the evidence from such studies, examining the genetic contribution to major forms ofSD. We also discuss results from genetic linkage analyses in which the entire genome was searched inorder to identify regions of chromosomes that contain susceptibility genes. We then explore some of theevidence supporting the relationship of specific candidate genes to phenotype. In addition, we reviewcurrent methodological advances that carry the prospect of accelerating the already rapid pace of geneidentification in the next few years. Recent years have already seen remarkable developments in ourunderstanding of the genetic influence on risk of several kinds of SD. A series of consistent andreplicated findings have emerged that are already providing new insight into the biological mechanismsof these disorders.This work was supported in part by National Institute on Drug Abuse grants R01 DA12849, R01DA12690, and K24 DA15105; National Institute on Alcohol Abuse and Alcoholism grants R01 AA11330and K24 AA13736; and funds from the U.S. Department of Veterans Affairs (the VA Medical ResearchProgram, and the VA Connecticut-Massachusetts Mental Illness Research, Education and Clinical Center).IMPORTANCE OF GENES FOR DRUG DEPENDENCE RISKFour types of SD are among the greatest public health problems in the United States: alcohol

Chapter 2. Genetics of Addiction

1 of 14 9:22 PM

13 of 756

dependence (AD); cocaine dependence (CD); opioid dependence (OD); and nicotine, or tobacco,dependence (ND). All of these disorders cut across geography, race, ethnicity, and socioeconomic statusand adversely affect the individual and those around him or her, as well as society at large. Thesedisorders are of varying importance internationally; since alcohol and tobacco are the most consistentlyavailable substances, AD and ND are the most consistent problems worldwide.Family studies may show the range of related phenotypes and may indicate that disorders are familial,but they cannot demonstrate the heritability of a disorder per se. Support for the importance of geneticfactors in risk for a disorder usually comes from twin and adoption studies.Heritability of Alcohol DependenceFamilial, and specifically genetic, factors are important for the development of AD, as established bytwin, family, and adoption studies. The largest twin studies have yielded heritability estimates in therange of 50%60%, indicating that half or more of the risk for AD is genetic (e.g., Kendler et al. 1992,1997; Prescott and Kendler 1999). Kendler et al. (1997) considered the intersection between theSwedish Twin Registry, which logged almost all twins born in Sweden from 1902 to 1949 (about 9,000male pairs), and temperance board registrations in that country from 1929 to 1974 (about 2,500 twinpairs). Subjects came to the attention of temperance boards mostly through physicians and lawenforcement agencies because of alcoholism or crimes related to alcohol consumption. Temperanceboard registration served as a proxy measure for the diagnosis of AD. Because multiple cohorts of twinswere assessed in this study, it was possible to consider not only the heritability of AD per se but also thestability of the heritability over time in a sample drawn from the general population. These authorsfound that, although the prevalence of AD was similar overall in monozygotic (MZ) and dizygotic (DZ)twins, the concordance rate was significantly higher among the former. Moreover, in this sample,heritability was stable over time, suggesting that the environmental contributions to the risk for ADwere consistent as well (in magnitude, if not in their exact nature) and that major social and historicalchanges did not affect environmentally determined AD risk. Thus, in this study, the diagnostic constructsused for AD, for which genetic liability can be estimated, appeared to be valid and meaningful in termsof consequences and outcomes for individuals.Heritability of Drug DependenceTsuang et al. (1996) analyzed data from the Vietnam Era Twin Registry, which includes more than 3,000male twin pairs. In the analysis, abuse of a particular substance was defined as at least weekly use ofthe drug in question. This study yielded detailed and comprehensive information regarding theheritability of abuse of a variety of substances. Significant pairwise concordance rates showed a familialbasis for all of the drugs considered. A significant pairwise difference in concordance rates between MZand DZ twins was seen for abuse of or dependence on marijuana, stimulants, cocaine, and all drugscombined. For OD, the additive genetic heritability was 0.43. Despite the large number of twin pairs,there were relatively few with OD; MZ concordance for this disorder was 13.3% and DZ concordance2.9% (based on about 30 pairs of each type of twin). For stimulant abuse, the estimated heritability was0.44, with MZ concordance being 14.1% (21/149) and DZ concordance 5.3% (6/113). A significantdifference among proportions was evident. Using the same twin registry, Tsuang et al. (1998) alsoexamined genetic risk for the co-occurrence of different forms of substance abuse. They determined thatgenetic factors exist that are both specific to certain individual drugs of abuse, including stimulants, andgeneral to multiple forms of abuse or dependence.Kendler and Prescott (1998) published twin study data showing unexpectedly high heritability for cocaineuse disorders. In a sample of female twins, heritabilities for cocaine abuse and dependence wereestimated at 0.79 and 0.65, respectively. A similar estimate for CD was obtained in a sample of maletwins, for whom the heritability was 0.79 (Kendler et al. 2000a). The twin samples used in these studieswere large. However, because the samples were drawn from the general population, in which theprevalence of the disorders is low, the number of twin pairs from which heritabilities were estimatedwas considerably smaller. Nonetheless, to date, these findings provide the best and most specific


2 of 14 9:22 PM

14 of 756

evidence of heritability and are the most specific in addressing the genetic liability for cocaine abuse anddependence.Many behaviors related to ND have been shown to be heritable. For example, research based on theVietnam Era Twin Registry estimated that the heritability of ND was >60% (True et al. 1999). Theheritability of AD was estimated as 0.55 in the same sample, with the genetic correlation between NDand AD shown to be 0.68. Madden et al. (2000) also found the genetic risk for these disorders to becorrelated. Heritability of regular tobacco use was estimated to be >60%, based on comparison of alarge sample of Swedish twin pairs who were reared either together or apart (Kendler et al. 2000b). Forthis investigation, the phenotype was defined by the subject's response that he or she smoked or usedsnuff regularly. In a large Finnish twin study, the heritability for the age at which smoking was initiatedwas 0.59 for males and 0.36 for females, for the amount smoked it was 0.54 in males and 0.61 infemales, and for smoking cessation it was 0.58 in males and 0.50 in females (Broms et al. 2006).A meta-analysis of twin studies for phenotypes related to ND showed that smoking initiation heritabilitycould be estimated at 0.37 for males and 0.55 for females, while smoking persistence heritability wasestimated to be 0.59 for males and 0.46 for females (Li et al. 2004).SummaryAlcohol and drug dependence are both familial and genetically influenced. A suitable model for thesedisorders is one in which there are both general and specific risk factorsthat is, some genetic loci actgenerally to influence risk for dependence on any substance, and others appear to influence risk forspecific kinds of SD. Establishing the genetic bases for these disorders through twin and adoption studiesprovides a clear rationale for efforts to identify the specific genes that underlie risk for theirdevelopment.GENOMEWIDE LINKAGE AND ASSOCIATION STUDIESBecause we do not fully understand the biology of SD, the genes that are involved are not known apriori. There are now two general methods that can be used to identify risk genes without a prioriknowledge of risk mechanisms. These methods both query the entire genome and use statistical (ratherthan biological) methods of inference. Genomewide linkage studies are the traditional approach toidentifying risk loci. These are family-based studies that require the investigation of markers that mapthroughout the entire genome, allowing the identification of chromosomal regions where markers arecoinherited with the phenotype of interest. Genomewide linkage scans have been completed for AD, CD,OD, ND, and for related traits. Genomewide association studies feature a newer methodology in whichvery closely spaced markersat least 100,000 and sometimes more than 1,000,000are studied in aneffort to discover those that vary in frequency in cases compared to controls. The goal of this type ofstudy is to genotype enough markers such that there is at least one marker within linkagedisequilibriumdistance of any point in the genome. There has been one genomewide association studyaddressing a specific SD diagnosis, ND, with individual genotyping of subjects.Successful genomewide linkage studies give the chromosomal locations of risk loci but generally do notidentify specific genes. In contrast, successful genomewide association studies can implicate specificgenes and alleles.Linkage StudiesStudies of alcohol dependenceGenome scan linkage mapping projects have identified promising chromosomal locations for ADsusceptibility loci, which in some cases have led to discovery of disease-influencing loci. Linkage studiesof AD by investigators in the Collaborative Studies on Genetics of Alcoholism (COGA) (Foroud et al.2000; Reich et al. 1998) and in the intramural program of the National Institute on Alcohol Abuse andAlcoholism (Long et al. 1998) have yielded promising logarithm of odds scores (lod scores; a measure ofthe likelihood that loci mapping to the region are linked to the disorder under study) for several


3 of 14 9:22 PM

15 of 756

chromosomal locations influencing risk of AD. Both groups reported that loci influencing risk for AD mapclose to an alcohol dehydrogenase (ADH) gene cluster on the long arm of chromosome 4. Several otherlinkage peaks, even ones that did not meet standard criteria for genomewide significance, have led tothe identification of likely disease-influencing loci for AD. Analyses of the COGA data set using thetransmission disequilibrium test and related family-based methods have revealed several additionalareas of interest (Camp and Bansal 1999; Page et al. 1999; Nielsen and Zaykin 1999; Sun et al. 1999).Wilhelmsen et al. (2003) reported a genomewide linkage study for a low level of response to alcohol,which, like a family history of AD, has been identified as a risk factor for the subsequent development ofAD (Schuckit et al. 2006). Although this study considered only 139 sibling pairs, several suggestivelinkages were identified. Ehlers et al. (2004) conducted a linkage analysis in a sample of 243 MissionIndians in the southwest United States. Although there were no lod scores suggestive of linkage for thediagnosis of AD, several lod scores in excess of 2.0 (i.e., suggestive of linkage) were identified for thephenotypes of severity of alcohol consumption (chromosomes 4 and 12) and for alcohol withdrawal(chromosomes 6, 15, and 16). A recent large study focused on a set of 474 small families recruited inIreland (Prescott et al. 2006) and reported strongest results (up to a multipoint lod score of 4.59) onchromosome 4.Studies of drug dependenceThere have been numerous genomewide linkage scans for ND and related traits (e.g., Beirut et al.2004; Gelernter et al. 2004; Li et al. 2006; Straub et al. 1999), one for CD (Gelernter et al. 2005), andtwo for OD (Gelernter et al. 2006a; Glatt et al. 2006). Uhl (2004) noted convergence among many ofthese and other linkage studies that considered substance dependence traits on a set of chromosomalregions of interest.Studies of nicotine dependence and related traitsIn their 2004 review, Li and colleagues noted that putative linkages in numerous genomewide linkagescans for cigarette smoking and related phenotypes had been identified on at least 12 chromosomes.Since then, additional linkage studies have been reported (Bierut et al. 2004; Ehlers and Wilhelmsen2006; Gelernter et al. 2004; Li et al. 2006; Swan et al. 2006; Vink et al. 2004; Wang et al. 2004). Manystudies have used patient samples recruited for an index trait other than ND. We reported genomewidesignificant linkage of score on the Fagerstrm Test for Nicotine Dependence, which measures theseverity of tobacco dependence, to chromosome 5 markers in African American subjects (Gelernter etal. 2007).Study of cocaine dependenceGelernter et al. (2005) conducted a genomewide linkage scan in a sample of small nuclear familiesascertained through two siblings affected with CD. The sample included 528 full- and 155 half-siblingpairs, of whom 45.5% were European American and 54.5% were African American. The phenotypes ofCD diagnosis, cocaine-induced paranoia, and six cocaine-related subtypes that were derived usingcluster analytical methods were examined. For the diagnosis of CD, the authors found evidencesuggestive of linkage on chromosome 10 in the full sample, and at different locations on chromosome 3in the European American families. The cluster-derived subtypes yielded the strongest results, includinga lod score of 4.66 on chromosome 12 (in European Americans only) for membership in the clustercharacterized as "heavy usecocaine predominant" and a lod score of 3.35 for membership in the clustercharacterized as "moderate cocaine and opioid abuse" on chromosome 18. A genomewide significant lodscore of 3.65 on chromosome 9 was obtained for African American families for the trait of cocaine-induced paranoia, which is reported by a substantial proportion of heavy users of cocaine.Studies of opioid dependenceUsing a sample overlapping with the one studied in the CD linkage study, Gelernter et al. (2006a)conducted a genomewide linkage scan in a sample of small nuclear families (393 families, including 250


4 of 14 9:22 PM

16 of 756

full-sibling pairs and 46 half-sibling pairs) ascertained through two siblings affected with OD. Weexamined linkage of the DSM-IV diagnosis of OD, and, analogous to the CD study, the two cluster-defined phenotypes represented by at least 250 families: a "heavy opioid users" cluster and a "nonopioidusers" cluster. Further exploratory analyses were completed for three other cluster-defined phenotypes.As with the CD linkage study, the strongest statistical results were obtained for the cluster-definedtraits: for the heavy opioid users we observed a lod score of 3.06, among European American andAfrican American subjects combined, on chromosome 17 (empirical pointwise P = 0.0002); and for thenonopioid users, we obtained a lod score of 3.46 (empirical pointwise P = 0.00002) elsewhere onchromosome 17, among European American subjects only.Glatt et al. (2006) reported the initial results from a genomewide linkage scan of heroin dependence in asample of Han Chinese subjects from Yunnan Province (which is near the "Golden Triangle," a regionknown for opium poppy production in the past century). This study included information from 194independent affected sibling pairs (ASPs). The result from this study that showed greatest statisticalsignificance for possible linkage was a region on chromosome 17q (P = 0.009, uncorrected); this wasnot the same region of chromosome 17 as that identified as linked by Gelernter et al. (2006a).Association StudiesStudies using pooling strategies exclusivelyDeoxyribonucleic acid (DNA) pooling provides a relatively economical way to complete a genomewideassociation analysis, but with serious compromises made that affect accuracy, the ability to identifyspecific genotype/phenotype correlations, and haplotype reconstruction. This approach has been usedseveral times to address SD phenotypes (Johnson et al. 2006; Liu et al. 2005, 2006). These studies haveproduced results of interest, and have identified novel candidates for future study, but require futurestudies with individual genotyping, for validation.Study of nicotine dependenceThe only genomewide association study for a specific SD trait published to date that involved genotypingsubjects individually focused on ND (Bierut et al. 2007). A two-stage design was implemented: first,pooled DNA was used to screen 2.4 million single nucleotide polymorphisms (SNPs); second, >30,000SNPs, selected on the basis of the first stage, were screened individually in 1,050 cases and 879controls. Numerous genes were identified as possibly associated with ND, including both novel genes(e.g., neurexin 1, NRXN1, and vacuolar protein sorting 13 homolog A, VPS13A) and genes that werepreviously considered candidates based on known physiology (e.g., cholinergic receptor, nicotinic, beta3, CHRNB3). This work is of great interest and has the potential to identify new biological pathwaysimportant for addiction, but replication is extremely important. In the presence of a very high level ofmultiple testing, it would be expected that many of the results from this study (as for all studies of thisdesign) are actually false positives.CANDIDATE GENE STUDIESThe following review summarizes some of the notable candidate gene studies in SD. Many of the genesdiscussed below are associated with both AD and drug dependence (DD).Alcohol Dependence Candidate Gene StudiesAlcohol-metabolizing enzymesInfluence of genetic polymorphism at some loci encoding the acetaldehyde dehydrogenases and ADHson risk of AD in some populations is well established. The mechanism for these effects is very clear.Ethanol is metabolized to acetaldehyde by ADHs, with the most important loci for AD research beingADH1B (previously known as ADH2) and ADH1C (previously known as ADH3). Acetaldehyde ismetabolized primarily by acetaldehyde dehydrogenases, the relevant locus for which is ALDH2.Acetaldehyde, a toxic intermediate in the metabolic pathway, produces a "flushing reaction"


5 of 14 9:22 PM

17 of 756

characterized by a set of uncomfortable symptoms including flushing, lightheadedness, palpitations, andnausea. Thus, deviation from the normal metabolism of ethanol that results in increased exposure toacetaldehyde, such as that produced by the medication disulfiram or that which occurs due to geneticvariation, produces an aversive effect of ethanol consumption, which might decrease the behavior andthereby the risk of AD (Goedde et al. 1979). A genetic variant that greatly reduces or eliminatesacetaldehyde dehydrogenase function, thereby decreasing the elimination of acetaldehyde (which occursmostly in Asian populations), has long been known to be protective against AD; ADH variants thatincrease function, yielding elevated acetaldehyde concentrations, may also be protective (e.g., seeHasin et al. 2002; Konishi et al. 2003; Thomasson et al. 1991).As noted earlier in this chapter, several genomewide linkage scans have implicated a region ofchromosome 4q that contains an ADH gene cluster, which has prompted more intensive investigation ofthe ADHs. ADH4 (Edenberg et al. 2006; Luo et al. 2005a, 2005b, 2006a) is one of several disease-influencing loci in this cluster. In adults, the subunit encoded by ADH4 mainly contributes to ADHactivity in the liver (Edenberg et al. 1999; Li and Bosron 1987; Li et al. 1977). Edenberg et al. (1999)demonstrated that a variant that could affect subunit regulation, the 75A allele, has promoter activitythat is more than twice that of the 75C allele. Despite the important role of ADH4 in alcoholmetabolism, it has, until recently, been largely overlooked in relation to AD. Luo et al. (2005a), (2005b)reported strong associations of ADH4 markers to AD using a variety of methods.Variants in the ADH gene and in ALDH2 are associated with AD (Luo et al. 2006b). Sixteen markerswithin the ADH gene cluster were genotyped, with four markers within ALDH2 and 38 unlinked ancestry-informative markers in a case-control sample. All markers were found to be in Hardy-Weinbergequilibrium (HWE) in controls, but some markers showed Hardy-Weinberg disequilibrium (HWD) inspecific cases. Genotypes of many markers were associated with AD. Diplotype trend regressionanalysis showed that ADH5 genotypes, and diplotypes of ADH1A, ADH1B, ADH7, and ALDH2, wereassociated with AD in European Americans, African Americans, or, in some cases, both. In this study,fine mapping of the risk-influencing alleles showed them to coincide with some well-known functionalvariants.Edenberg et al. (2006) similarly genotyped SNPs across the ADH gene cluster on chromosome 4q in aset of families with high risk for alcoholism from COGA. They found the most consistent evidence ofassociation with AD for ADH4, extending into the 3' untranslated region of that gene bordering on ADH5.Haplotype analysis consisting of tag SNPs covering the entire ADH4 gene together with both upstreamand downstream regions of the gene also showed significant evidence for association. Theseinvestigators also obtained suggestive evidence of association with AD for ADH1A and ADH1B.GABRA2Work reported by the COGA group (Porjesz et al. 2002) demonstrated, first, linkage ofelectroencephalogram beta frequencies (considered to be an AD-related endophenotype) tochromosome 4p; then, linkage disequilibrium to a -aminobutyric acid (GABA)A receptor gene cluster inthis same chromosomal region, in a sample ascertained through extended pedigrees with multiple ADindividuals. Fine mapping showed strongest association to GABRA2, one of four GABAA genes in thisregion (Edenberg et al. 2004). Several groups of investigators, using case-control samples, havereplicated this major finding, with evidence of association of AD to a haplotype at GABRA2 in multiplepopulations (Covault et al. 2004; Fehr et al. 2006; Lappalainen et al. 2005). Enoch et al. (2006) alsofound an association of GABRA2 in Plains Indians and Finnish Caucasians. As in prior studies, theseinvestigators identified two common haplotypes, which differed markedly in frequency in the populationsbeing studied. Using harm avoidance, a dimensional measure of anxiety, they found haplotype linkageto alcoholism with high and low dimensional anxiety, and to harm avoidance itself, in both populations.They interpreted the results as suggesting that, within the 3' portion of GABRA2, there is a functionallocus (or loci) that differs by population and alters risk for alcoholism via the mediating action ofanxiety. Although the AD association has been replicable, no specific causative variant has been


6 of 14 9:22 PM

18 of 756

reported, and we must consider the possibility that the origin of the association signal is in a gene orregulatory region adjacent to GABRA2 rather than in GABRA2 itself. Further, Pierucci-Lagha et al. (2005)found an association of GABRA2 with subjective response to alcohol in healthy subjects. Two other genesencoding GABAA receptor subunits, GABRA1 and GABRAG3, have also been shown to be associated withAD, although the evidence supporting these loci is presently substantially weaker than that for GABRA2(Dick et al. 2004, 2006).CHRM2Two reports have provided moderately strong support for muscarinic acetylcholine receptor M2 (geneticlocus CHRM2) as an AD risk locus (Luo et al. 2005b; Wang et al. 2004). As for the ADH cluster andGABRA2,CHRM2 maps into a chromosomal region that had been identified as putatively linked to ADlinkage (Reich et al. 1998). Several CHRM2 SNPs were reported to be significantly associated to AD;different CHRM2 SNPs were associated with major depression. Luo et al. (2005c) found evidence ofassociation of markers at this locus with the same two phenotypes. It is therefore reasonable to askexactly what phenotypes are influenced by polymorphic variation at the locus of interest. Is thisvariation related to diagnosis per se, or is it some intermediate phenotype, or both? Luo et al. (2007)have shown that CHRM2 variation is related to personality measures, and this suggests one possiblemechanism for effects on diagnosis traits.Opioid receptor genesThe opioid receptor has been implicated in the pathogenesis of dependence on many abusablesubstances. At first, studies examining association of the opioid receptor gene (genetic locus OPRM1)with SD focused on the A118G polymorphism, which encodes an Asn40Asp amino acid substitution andhas been shown to be functional. Arias et al. (2006) used meta-analysis to examine the association ofAsn40Asp with SD in 22 published articles describing 28 distinct samples and over 8,000 subjects. Thesestudies considered OD and AD, predominantly. Nearly equal numbers of studies showed significantlyhigher frequency of the Asp40 allele among SD cases than among controls. Overall, there was nosignificant association between Asn40Asp and SD (odds ratio = 1.01; 95% confidence interval =0.861.19), nor was there substantial evidence of a moderator effect (e.g., AD vs. OD).In a more comprehensive study of the locus, Zhang et al. (2006) examined 13 SNPs spanning theOPRM1 coding region among 382 European Americans affected with AD and/or DD and 338 healthycontrols. Two haplotype blocks were identified. Genotype distributions for all SNPs were consistent withHWE expectations in controls, but in cases, SNPs mapping to both Block I and Block II showed deviationfrom HWE; this can be an indicator of association with phenotype. Significant differences were foundbetween cases and controls in allele and/or genotype frequencies for SNPs mapping in both blocks.Frequency distributions of haplotypes differed significantly for cases and controls (P

Dopa decarboxylase is an enzyme of major importance for dopamine synthesis; it also plays a role inserotonin biosynthesis. Ma et al. (2005) studied DDC, the gene encoding this protein, in ND, based bothon its physiology and its map location in an ND linkage peak they identified. They showed associationbetween long-range DDC haplotypes and three correlated quantitative traits of smoking behavior usingfamily-based association tests (FBATs) in families, each ascertained through an affected sibling pair forND. Yu et al. (2006) replicated and extended these results, and reported an association of alleles andhaplotypes at DDC with the DSM-IV diagnosis of ND or Fagerstrm Test for Nicotine Dependence score.They genotyped 18 SNPs spanning a region including DDC and the genes immediately flanking it, in theaffected sibling pair sample recruited for opioid or cocaine dependence (i.e., the linkage sampledescribed above). Evidence of association was observed with several SNPs for both traits. The mostsignificant result was obtained for the relationship of Fagerstrm Test for Nicotine Dependence score toan SNP that maps to the same intron as an important DDC splice site. These findings were consistentwith those of Ma et al. (2005), and served to localize the causative variants to the 3' end of the codingregion.DRD2/ANKK1/TTC12The possible association of variants that map at or near the DRD2 locus with drug or alcohol dependencehas provoked a long-running controversy. Although there are many articles published on the

Addiction. Hales Et Al (2011) American Psychiatric Publishing Textbook of Substance Abuse...

Documents

Transcript of Addiction. Hales Et Al (2011) American Psychiatric Publishing Textbook of Substance Abuse...