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.

Tissue plasminogen activator modulates the cellular and behavioral response to cocaine

“…Overexpression of CREB with resulting increases in ppDyn gene expression in the NAc has been shown to decrease the rewarding effects of cocaine (29). Further, both Dyn and KOP-r Ϫ/Ϫ mice display enhanced behavioral sensitization (4). Hence, the lack of behavioral sensitization and reward in tPAϪ/Ϫ mice could also be due to an increased basal level of dynorphin.…”

“…The mesolimbic DAergic system is thought to be the primary target for cocaine-induced molecular and behavioral adaptations in the brain (1). In addition, the dynorphin (Dyn)/ kappa opioid receptor (KOP-r) system, which is highly expressed in the nucleus accumbens (NAc), has been implicated in regulating the behavioral effects of cocaine by playing a homeostatic role that opposes alterations in brain function and behavior that result from cocaine exposure (3)(4)(5). Further, acute pretreatment with KOP-r agonists is effective in decreasing mesoaccumbal DA neurotransmission and cocaine reward (3,4).…”

Stress-induced reinstatement of cocaine seeking is mediated by the kappa opioid system

“…The dynorphin/kappa opioid system has been postulated to counteract the stimulating and rewarding properties produced by drugs of abuse (Carlezon et al 2005), and this system has been found to be critical in the development and relapse to drug seeking (for review, see Shippenberg et al 2007). Briefly, increased activation of the nucleus accumbens results in a cAMP-response-element-binding-protein-mediated increase in dynorphin release that acts on inhibitory kappa receptors on the terminals and cell body of dopaminergic ventral tegmental area neurons.…”

Upregulation of Gene Expression in Reward-Modulatory Striatal Opioid Systems by Sleep Loss

“…Another important consideration is that striatal ENK and DYN were upregulated in concert. DYN signaling is associated with aversive or depression-like effects in animal studies (Nestler and Carlezon, 2006), and striatal DYN levels are elevated in post-mortem brains of suicide victims and in animal models of stress and drug withdrawal (Horner et al, 2009;Hurd et al, 1997;Shippenberg et al, 2007;Shirayama et al, 2004). Hence, coordinated upregulation of ENK and DYN could produce a mixture of depressed mood and increased preference for palatable food, as is often observed in eating disorders characterized by dysfunctional 'emotional eating.'…”