Mechanisms Underlying the Adverse Consequences of Stress: A Role for the Dynorphin/Kappa Opioid Receptor System, p38α MAPK, and the Serotonin Transporter

Abstract

Unlike the proadaptive effects of acute stress exposure, repeated stress exposure results in maladaptive responses by mechanisms that are not completely understood. These maladaptive responses can lead to debilitating diseases such as depression, anxiety, and drug addiction. During a stressful event, the dynorphins, a family of endogenous opioids, are released and subsequently bind to and active the kappa opioid receptor (KOR), but how the dynorphin/KOR system mediates these adverse behaviors remains unknown. My dissertation sought to further our understanding of the role of the dynorphin/KOR system in stress-induced aversion and stress-induced potentiation of cocaine conditioned place preference (cocaine-CPP), and to elucidate downstream molecular targets. First, I attempted to understand the behavioral mechanisms underlying stress-induced potentiation of cocaine-CPP by modulating the temporal relation between cocaine treatment and stress exposure. I determined that stress-induced potentiation of cocaine-CPP was through modulation of cocaine or cocaine-associated cues, and not through modulation of associative learning or memory recall mechanisms. From this, I hypothesized that stress-induced aversion mediates potentiation of drug reward through modulation of drug or drug-associated cues. I next set out to determine whether the signal transduction mechanisms underlying stress-induced aversion and stress-induced potentiation of cocaine-CPP are the same. I determined that, like stress-induced aversion, stress-induced potentiation of drug reward is mediated by GRK3 and p38α MAPK in serotonergic neurons. These results support the hypothesis that stress-induced activation of the dynorphin/KOR system mediates the aversive component of stress to produce potentiation of drug reward. Finally, I investigated potential downstream targets of p38α MAPK in order to further understand the molecular processes underlying the adverse consequences of repeated stress exposure. I demonstrated that stress-induced KOR activation increases the surface expression of the serotonin transporter (SERT) specifically in the ventral striatum in a GRK3 and p38α MAPK dependent manner, and hypothesize that this regulation leads to a hyposertonergic tone. Future work elucidating the downstream effects of hyposerotonergic tone in the ventral striatum is required, but the current thesis advances the knowledge base regarding the role of the dynorphin/KOR system and serotonin in the adverse consequences of repeated stress exposure.