Stress, Dysregulation of Drug Reward Pathways, and the Transition to Drug Dependence

Abstract

This review provides a neuroadaptive perspective regarding the role of the hormonal and brain stress systems in drug addiction with a focus on the changes that occur during the transition from limited access to drugs to long-term compulsive use of drugs. A dramatic escalation in drug intake with extended access to drug self-administration is characterized by a dysregulation of brain reward pathways. Hormonal studies using an experimenter-administered cocaine binge model and an escalation self-administration model have revealed large increases in ACTH and corticosterone in rats during an acute binge with attenuation during the chronic binge stage and a reactivation of the hypothalamic-pituitary-adrenal axis during acute withdrawal. The activation of the hypothalamicpituitary-adrenal axis with cocaine appears to depend on feed-forward activation of the mesolimbic dopamine system. At the same time, escalation in drug intake with either extended access or dependence-induction produces an activation of the brain stress system's corticotropin-releasing factor outside of the hypothalamus in the extended amygdala, which is particularly evident during acute withdrawal. A model of the role of different levels of hormonal/brain stress activation in addiction is presented that has heuristic value for understanding individual vulnerability to drug dependence and novel treatments for the disorder.Drug addiction has been conceptualized as a chronic relapsing disorder characterized by compulsive drug-taking behavior with impairment in social and occupational functioning. From a psychiatric perspective, drug addiction has aspects of both impulse control disorders and compulsive disorders (1). Impulse control disorders are characterized by an increasing sense of tension or arousal before the commission of an impulsive act; pleasure, gratification, or relief at the time of commission of the act; and following the act, there may or may not be regret, self-reproach, or guilt (2). In contrast, compulsive disorders are characterized by anxiety and stress before the commission of a compulsive repetitive behavior and relief from the stress by performing the compulsive behavior. As an individual moves from an impulsive disorder to a compulsive disorder, there is a shift from positive reinforcement driving the motivated behavior to negative reinforcement driving the motivated behavior. Drug addiction has been conceptualized as a disorder that progresses from impulsivity to compulsivity in a collapsed cycle of addiction composed of three stages: preoccupation/anticipation, binge/intoxication, and withdrawal/negative affect (3). Different theoretical perspectives ranging from Psychoneuroendocrinology ©2003; Address correspondence and reprint requests to Dr. Koob, Committee on the Neurobiology, of Addictive Disorders, SP30-2400, the Scripps Research, Institute, 10550 North Torrey Pines Rd., La Jolla, CA 92037; gkoob@scripps.edu. All authors report no competing interests. This is publication number 16873-NP from the Scripps Research I...

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