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Drug addiction is a chronic relapsing disorder, and a significant amount of research has been devoted to understand the factors that contribute to the development, loss of control, and persistence of compulsive addictive behaviors. In this review, we provide an overview of various theories of addiction to drugs of abuse and the neurobiology involved in elements of the addiction cycle. Specific focus is devoted to the role of the mesolimbic pathway in acute drug reinforcement and occasional drug use, the role of the mesocortical pathway and associated areas (e.g., the dorsal striatum) in escalation/dependence, and the contribution of these pathways and associated circuits to conditioned responses, drug craving, and loss of behavioral control that may underlie drug relapse. By enhancing the understanding of the neurobiological factors that mediate drug addiction, continued preclinical and clinical research will aid in the development of novel therapeutic interventions that can serve as effective long-term treatment strategies for drug-dependent individuals., (Copyright © 2021 Cold Spring Harbor Laboratory Press; all rights reserved.)

Drug addiction is a chronic relapsing disorder for which research has been dedicated to understand the various factors that contribute to development, loss of control, and persistence of compulsive addictive behaviors. In this review, we provide a broad overview of various theories of addiction, drugs of abuse, and the neurobiology involved across the addiction cycle. Specific focus is devoted to the role of the mesolimbic pathway in acute drug reinforcement and occasional drug use, the mesocortical pathway and associated areas (e.g., the dorsal striatum) in escalation/dependence, and the involvement of these pathways and associated circuits in mediating conditioned responses, drug craving, and loss of behavioral control thought to underlie withdrawal and relapse. With a better understanding of the neurobiological factors that underlie drug addiction, continued preclinical and clinical research will aid in the development of novel therapeutic interventions that can serve as effective long-term treatment strategies for drug-dependent individuals.