Dynorphin and the pathophysiology of drug addiction

Abstract

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.

Fig.1

Simplified schematic representation of the basal ganglia-thalamo-cortical neuronal circuitry illustrating neurotransmitter interactions between limbic and sensory-motor regions of the brain. Abbreviations: AMG – amygdala, DSTR dorsal striatum, GPe – external globus pallidus, NAc – nucleus accumbens, PFC – prefrontal cortex, SN substantia nigra, STN – subthalamic nucleus, THAL – thalamus, VTA – ventral tegmental area. Black symbols represent excitatory glutamatergic pathways. Dark shaded symbols represent dopaminergic pathways. Light shaded symbols represent GABAergic pathways. Small trapezoids represent localization of KOPr.