Drug addiction is a chronic relapsing disease in which
drug administration becomes the primary stimulus that drives behavior regardless of the adverse consequence that may ensue. As
drug use becomes more compulsive, motivation for natural rewards that normally drive behavior decreases. The discontinuation of
drug use is associated with somatic signs of withdrawal, dysphoria, anxiety, and
anhedonia. These consequences of
drug use are thought to contribute to the maintenance of
drug use and to the reinstatement of compulsive
drug use that occurs during the early phase of abstinence. Even, however, after prolonged periods of abstinence, 80-90% of human addicts relapse to addiction, suggesting that repeated
drug use produces enduring changes in brain circuits that subserve incentive motivation and stimulus-response (habit) learning. A major goal of addiction research is the identification of the neural mechanisms by which drugs of abuse produce these effects. This article will review data showing that the
dynorphin/
kappa-opioid receptor (KOPr) system serves an essential function in opposing alterations in behavior and brain neurochemistry that occur as a consequence of repeated
drug use and that aberrant activity of this system may not only contribute to the dysregulation of behavior that characterizes addiction but to individual differences in vulnerability to the pharmacological actions of
cocaine and alcohol. We will provide evidence that the repeated administration of
cocaine and alcohol up-regulates the
dynorphin/KOPr system and that pharmacological treatments that target this system may prove effective in the treatment of
drug addiction.