Stress, dysregulation of drug reward pathways, and the transition to drug dependence

Am J Psychiatry. 2007 Aug;164(8):1149-59. doi: 10.1176/appi.ajp.2007.05030503.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Review

MeSH terms

  • Animals
  • Behavior, Addictive / physiopathology*
  • Brain / physiopathology*
  • Corticotropin-Releasing Hormone / physiology
  • Disease Models, Animal
  • Electrodes, Implanted
  • Hydrocortisone / physiology
  • Hypothalamus / drug effects
  • Hypothalamus / physiopathology
  • Illicit Drugs / adverse effects
  • Illicit Drugs / pharmacology
  • Models, Neurological
  • Prolactin / physiology
  • Rats
  • Reinforcement, Psychology
  • Reward*
  • Self Administration
  • Stress, Physiological / physiopathology*
  • Substance-Related Disorders / etiology
  • Substance-Related Disorders / physiopathology*


  • Illicit Drugs
  • Prolactin
  • Corticotropin-Releasing Hormone
  • Hydrocortisone