Therapeutic Potential of Kappa Antagonists in the Adjunctive Treatment of Psychotic Depression

University Of Washington, Seattle WA

Investigators

Linked publications & trials

Abstract

Project Summary Extensive research has established that kappa opioid receptor (KOR) antagonists can block the dysphoria, anxiety and cognitive disruptions caused by behavioral stress exposure and that KOR agonists produce strong anxiogenic, aversive and psychotomimetic effects in humans and animal models of human behaviors. Our current understanding is that the dynorphin-KOR system produces its depressive effects on mood and cognition through actions on the serotonergic (5HT) projections from Dorsal Raphe Nucleus (DRN) to the Nucleus Accumbens (NAc) and Ventral Tegmental Area (VTA). In addition, published results show that the dynorphin-KOR system regulates the dopaminergic (DA) inputs from the VTA to NAc. The studies proposed in Project 1 would use a combination of optogenetic and mouse genetic approaches to test the hypothesis that endogenous dynorphins, locally released within the DRN-VTA-NAc circuit during stress-exposure, produce aversion behaviors and disrupt cognition.