Chapter 21 The neurobiology of alcohol craving and relapse DONGJU SEO AND RAJITA SINHA* Department of Psychiatry, Yale University School of Medicine, New Haven, CT, USA INTRODUCTION A major problem jeopardizing recovery from alcoholism is high alcohol craving and the chronic, relapsing nature of the illness. Many individuals with alcohol use disor- ders (AUD) report significant difficulties with craving and struggle with relapse urges (Fox et al., 2007; Breese et al., 2011). Researchers have also identified that alcohol craving and relapse are critical factors perpetu- ating the malady of chronic alcoholism (Bottlender and Soyka, 2004; Sinha et al., 2011) and thus, mechanisms underlying alcohol craving and relapse have been a cen- tral focus of alcohol research, including in neuroimaging studies. Neuronal processes underlying alcohol craving and relapse are complex due to an interplay between neuroa- daptations from chronic alcohol abuse and environmen- tal risk factors affecting the developmental course of alcoholism. After a prolonged period of alcohol abuse, neuroadaptations from repeated alcohol consumption increase allostatic load on key neural circuit of emotion and reward regulation (Breese et al., 2011; Seo and Sinha, 2011; Seo et al., 2013) and place AUD individuals in an emotionally susceptible state. In the face of emotional or alcohol-related challenges (e.g., stress and alcohol cues), vulnerable AUD individuals often lose control over alcohol craving and make poor decisions, thereby increasing relapse risk (Bechara et al., 2001; Goldstein et al., 2009; Sinha, 2012, 2013). Thus, to have a compre- hensive understanding of neural mechanisms underlying craving and relapse, relevant brain functions should be considered in the context of neuroadaptations and inter- actions with environmental risk factors. This chapter is intended to provide a neurobiologic understanding of brain structures and functions related to alcohol craving and relapse risk. It will review relevant neuroimaging studies and discuss neural mechanisms underlying craving and relapse as well as significant risk factors in the course of chronic alcoholism. The first section provides a review of the role of neuroadaptations in chronic alcoholism. In the second section, we review the basic concepts and role of alcohol craving and relapse in the course of alcoholism. In the third section, functional brain changes associated with alcohol craving and relapse will be reviewed in the context of environ- mental risk factors such as alcohol, alcohol-associated cues, and stress. In this section, the emphasis is on the functional mechanisms related to emotion regulation and decision making in the prefrontal-striatal-limbic cir- cuit and their contributions to alcohol craving and relapse. The final section concludes the review and dis- cusses future research directions. Elucidating the neural mechanisms underlying alcohol craving and relapse in the context of its risk factors will help understand com- plex vulnerability factors for alcohol-related pathology and could facilitate the development of effective treatments. ALCOHOL-RELATED NEUROADAPTATIONS One distinctive feature of chronic alcoholism is altered neurophysiologic functions and dysregulated emotional states resulting from continued alcohol use over an extensive period of time (Li and Sinha, 2008; Breese et al., 2011). Chronic alcohol abuse gradually produces neuroadaptive changes in neural circuits of emotional modulation, which makes AUD individuals vulnerable to affect dysregulation (Breese et al., 2011; Seo and Sinha, 2011; Seo et al., 2013). It is also known that repet- itive alcohol use alters dopaminergic tone, hijacking the natural reward system and leading to compulsive *Correspondence to: Rajita Sinha, Ph.D., Professor of Psychiatry, Neurobiology and Child Study, Departments of Psychiatry, Yale University School of Medicine, 2 Church Street South, Suite 209, New Haven, CT 06519, USA. Tel: +1-203-737-3398, E-mail: Rajita.sinha@yale.edu Handbook of Clinical Neurology, Vol. 125 (3rd series) Alcohol and the Nervous System E.V. Sullivan and A. Pfefferbaum, Editors © 2014 Elsevier B.V. All rights reserved