Kappa Opioid Regulation of Dopamine in Dysphoria and Addiction

Thesis (Ph.D.)--University of Washington, 2014Stress-induced release of dynorphin and subsequent activation of the kappa opioid receptor (KOR) has been hypothesized to mediate the dysphoric component of stress. Evidence suggests that this dysphoria can alternately block or potentiate the rewarding properties of addictive drugs, while also directly inducing aversion. These effects have historically been described as being mediated by the ability of KOR activation to inhibit dopamine release within the nucleus accumbens. However, a growing body of evidence suggests that this model is overly simplistic. This dissertation focuses on improving our understanding of how KOR signaling pathways within dopamine neurons can mediate the aversive, anhedonic, and proaddictive properties of stress. We first attempt to understand if changes in dopamine signaling can model bivalent, KOR-induced changes in cocaine reward. These experiments show that a combination of KOR effects on the somatodendritic and terminal compartments of dopamine neurons induce similar shift in the activity of core-projecting dopamine neurons as are seen in the behavior of mice during a conditioned place preference experiment. We then proceed to demonstrate that activation of KOR within dopamine neurons of the VTA is both necessary and sufficient for mediating the aversive properties of KOR activation. Surprisingly, however, we find that it is phosphorylation of the receptor and subsequent activation of p38 MAPK, and not KOR-induced inhibition of dopamine release, that is the key mediator of this behavior