Psychosocial stress is an important risk factor for psychiatric disorders such as depression and anxiety. There has been increasing interest in targeting kappa opioid receptors (KOR) as a novel therapeutic target. Agonists for KOR have been reported to induce dysphoria and regulate the hypothalamic-pituitary-adrenal axis (HPA). New evidence suggests that there is a major gap in our understanding of the aversive properties of KOR. Studies showing that KOR mediates effects of stress on behavior primarily focus on short term effects of stress (15 min). However, after two days of psychosocial stress KOR loses its aversive properties. We hypothesize that this long term effect of psychosocial stress induces a neuroadaptation that fundamentally alters the effects of KOR. This is a critical idea because the field is working on the assumption that KOR antagonists have antidepressant properties. Our hypothesis suggests that KOR agonists will have stronger antidepressant properties for individuals exposed to long term psychosocial stress. Kappa opioid receptors inhibit serotonergic tone by inhibiting the activity of dorsal raphe nucleus (DRN) serotonin neurons. Increased serotonergic tone is linked to increased sensitivity to threat and increased inhibition o the HPA axis, and psychosocial stress can increase baseline activity of DRN serotonin neurons. By studying monogamous California mice, we are one of the only lab groups with the capability to study the effects of social defeat in both males and females. Females exposed to defeat exhibit social avoidance to non- threatening social stimuli. We hypothesize that defeat stress results in desensitization of the inhibitory effects of KOR on the DRN, which facilitates social avoidance. We predict that this effect is greater in females than males. If KOR inhibition of the DRN is stronger in stressed males, then social avoidance show be diminished and baseline corticosterone levels should be high. This is exactly what we have observed. Intriguingly, women diagnosed with depression have been reported to show stronger avoidance of social cues while recent work suggests that elevated baseline cortisol levels are more likely to occur in men with depression. First we use place preference studies to examine how defeat stress affects the aversive and rewarding properties of KOR. Second, we use multilabel immunohistochemistry to examine KOR induced changes in extracellular signal regulated kinase (ERK) and p38 MAP kinase (p38) in serotonin neurons in the dorsal raphe nucleus (DRN). These pathways are activated by KOR. Finally, we use site specific manipulations to test whether changes in serotonergic signaling mediate the effects of KOR on aversion, social interaction, and corticosterone.

Public Health Relevance

Emerging evidence indicates psychosocial stress induces neuroadaptations that alter the behavioral effects of kappa opioid receptors (KOR). The proposed studies examine the novel hypothesis that KOR may have antidepressant properties in individuals exposed to psychosocial stress.

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
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Biobehavioral Regulation, Learning and Ethology Study Section (BRLE)
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Simmons, Janine M
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University of California Davis
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