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. 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 experience switches KOR signaling from inhibitory to excitatory in a subset of VTA dopamine neurons. Brief corticotrophin releasing factor (CRF) exposure 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 hyperpolarization-activated cyclic nucleotide-gated channel (HCN) 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 signaling coupling of one GPCR can be triggered by activity at other GPCRs thus significantly altering behavioral responses driven by neuromodulators.