American Journal of Medical Genetics Part B (Neuropsychiatric Genetics) 132B:29–37 (2005) Relationship Between Dopaminergic Neurotransmission, Alcoholism, and Reward Deficiency Syndrome Abdalla Bowirrat 1,2 and Marlene Oscar-Berman 1,2,3,4 * 1 Department of Psychiatry, Boston University School of Medicine, Boston, Massachusetts 2 Department of Anatomy and Neurobiology, Boston University School of Medicine, Boston, Massachusetts 3 Department of Neurology, Boston University School of Medicine, Boston, Massachusetts 4 Psychology Research Service, VA Healthcare System, Boston Campus, Boston, Massachusetts In this review, we described the neural substrates underlying Reward Deficiency syndrome which, in turn, is posited to underlie alcohol dependency. Alcoholism is a complex, multifactorial disorder that results from the interplay between genetic and environmental factors. The D 2 dopamine receptor (DRD 2 ) has been associated with plea- sure, and the DRD 2 A1 allele has been referred to as a reward gene. Evidence suggests that there is a tripartite interaction involving dopamine recep- tor deficiency, a propensity to abuse alcohol, and reduced sensitivity to rewards. This interaction relies heavily on genetic characteristics of the individual, with certain ethnic groups having a greater tendency toward alcoholism than others. The DRD 2 has been one of the most widely studied in neuropsychiatric disorders in general, and in alcoholism and other addictions in particular. The dopamine D2 (DRD2) gene, and especially its allele TaqI A1 allele and its receptor, also may be involved in comorbid antisocial personality disorder symptoms, high novelty seeking, and related traits. The mesocorticolimbic dopaminer- gic pathway system plays an especially important role in mediating reinforcement by abused drugs, and it may be a common denominator for addic- tions such as alcoholism. When the mesocortico- limbic dopamine reward system dysfunctions (perhaps caused by certain genetic variants), the end result is Reward Deficiency syndrome and subsequent drug-seeking behaviors. Reward Defi- ciency syndrome refers to the breakdown of the reward cascade, and resultant aberrant conduct, due to genetic and environmental influences. Alcohol and other drugs of abuse, as well as most positive reinforcers, cause activation and neuro- nal release of brain dopamine, which can decrease negative feelings and satisfy abnormal cravings. A deficiency or absence of DRD 2 receptors then predisposes individuals to a high risk for multiple addictive, impulsive, and compulsive behaviors. Although other neurotransmitters (e.g., gluta- mate, gamma-aminobutyric acid (GABA), and serotonin) may be important in determining the rewarding and stimulating effects of ethanol, dopamine may be critical for initiating drug use and for reinstating drug use during protracted abstinence. This article contains supplementary material, which may be viewed at the American Journal of Medical Genetics website at http:// www.interscience.wiley.com/jpages/0148-7299:1/ suppmat/index.html. ß 2004 Wiley-Liss, Inc. KEY WORDS: D2 dopamine receptor gene; addiction; association; linkage disequilibrium; neurotransmit- ters; mesocorticolimbic system; reward INTRODUCTION Alcoholism is a complex, multidimensional disorder invol- ving problematic ethanol ingestion and reflected in behavior [Oscar-Berman and Hutner, 1996]. Two aspects of problematic drinking have been recognized, alcohol abuse and alcohol dependence [American Psychiatric Association, 1994]. The former emphasizes psychological or social impairments caus- ing health problems and/or difficulties with activities of daily living, in which alcohol consumption is implicated; the latter stresses a disability (manifested by craving, tolerance, and physical need) in which drinking behaviors cannot be ade- quately restrained. Alcoholism results from an interaction between genetic and environmental factors that influence the expression and course of the disorder [Merikangas, 1990; Cools and Gingras, 1998; Porjesz and Begleiter, 1998; Gorwood, 2000; Sluyter et al., 2000; Crabbe, 2002]. Among these factors are the following: Family history of alcoholism; the severity and duration of the dependency; co-morbid neurological or psychiatric conditions; and abnorm- ality in dopaminergic neurotransmission. In this review, we summarize evidence showing a tripartite interaction that involves a propensity to abuse alcohol, dopamine receptor deficiency, and reduced sensitivity to rewards. This interaction relies heavily on genetic characteristics of the dopamine receptor. Abbreviations: ADHD, attention deficit hyperactivity disorder; BNST, bed nucleus of stria terminalis; DRD2, dopamine receptor D2; DAT, dopamine transporter; FMRI, functional magnetic resonance imaging; GABA, gamma-aminobutyric acid; NAc, nucleus accumbens; NMDA, N-methyl-D-aspartic acid; PET, positron emission tomography; PTSD, post-traumatic stress disorder; RFLP, restriction fragment length polymorphism; SLEA, sub-lenticular extended amygdala; SPECT, single photon emission computed tomography; VTA, ventral tegmental area. Grant sponsor: US Department of Health and Human Services, NIAAA; Grant numbers: R37-AA07112, K05-AA00219; Grant sponsor: Medical Research Service of the US Department of Veterans Affairs. *Correspondence to: Marlene Oscar-Berman, Ph.D., Depart- ment of Anatomy and Neurobiology, Boston University School of Medicine, 715 Albany Street, L-815, Boston, MA 02118. E-mail: oscar@bu.edu Received 22 August 2003; Accepted 4 May 2004 DOI 10.1002/ajmg.b.30080 ß 2004 Wiley-Liss, Inc.