A switch in kappa opioid receptor signaling from inhibitory to excitatory induced by stress in a subset of cortically-projecting dopamine neurons

The kappa opioid receptor (KOR) has shown potential as a therapeutic target for several neuropsychiatric disorders including major depressive disorder, pain, and substance use disorder. In vivo signaling of G protein coupled receptors like the KOR is generally thought to change in magnitude but not sign in such behavior states. Here we investigated KOR modulation of ventral tegmental area (VTA) neurons following an acute, behaviorally aversive manipulation. We found this switches KOR signaling from inhibitory to excitatory in a subset of VTA dopamine neurons. Brief corticotrophin releasing factor (CRF) exposure ex vivo rapidly induces a similar switch in KOR signaling, specifically in dorsal medial prefrontal cortex (dmPFC) projecting neurons, but not nucleus accumbens or basolateral amygdala projecting neurons. These KOR mediated excitations depend on G protein activation, but where somatodendritic VTA KORs activate a K ⁺ conductance to hyperpolarize dopamine neurons in control conditions, depolarizations require HCN channel function. One behavioral impact of this change is a loss of the aversiveness of intra-VTA KOR activation, providing direct evidence that rapid changes in GPCR signaling pathways can be triggered by activity at other GPCRs and significantly alter behavioral responses driven by neuromodulators.