Stress, dysregulation of drug reward pathways, and the transition to drug dependence.
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 hypothalamic-pituitary-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.
Koob
George
G
Committee on the Neurobiology of Addictive Disorders, the Scripps Research Institute, La Jolla, CA 92037, USA. gkoob@scripps.edu
Kreek
Mary Jeanne
MJ
D000818:Animals; D016739:Behavior, Addictive / Q000503:physiopathology*; D001921:Brain / Q000503:physiopathology*; D003346:Corticotropin-Releasing Hormone / Q000502:physiology; D004195:Disease Models, Animal; D004567:Electrodes, Implanted; D006854:Hydrocortisone / Q000502:physiology; D007031:Hypothalamus / Q000187:drug effects / Q000503:physiopathology; D013287:Illicit Drugs / Q000009:adverse effects / Q000494:pharmacology; D008959:Models, Neurological; D011388:Prolactin / Q000502:physiology; D051381:Rats; D012054:Reinforcement, Psychology; D012201:Reward; D012646:Self Administration; D013312:Stress, Physiological / Q000503:physiopathology*; D019966:Substance-Related Disorders / Q000209:etiology / Q000503:physiopathology*
D013287:Illicit Drugs; D011388:Prolactin; D003346:Corticotropin-Releasing Hormone; D006854:Hydrocortisone