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bioRxiv · 10.1101/2025.08.09.669424

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

Margolis, E. B.
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Abstract

BackgroundThe kappa opioid receptor (KOR) has shown potential as a therapeutic target for several neuropsychiatric disorders including major depressive disorder, chronic pain, and substance use disorder. Signaling of G protein coupled receptors (GPCRs) like the KOR is generally thought to change in magnitude, not valence, with behavior states. Here we investigated KOR modulation of ventral tegmental area (VTA) neurons following an acute, behaviorally aversive manipulation. MethodsKOR agonist responses were measured with whole cell recordings in acute brain slices containing the VTA from male and female rats. Slices were made <1 hr, 3 days or 5 days after a foot shock or sham session. Slices from untreated rats were used to determine the mechanism of action. Recordings were also made in neurons labeled by the retrograde tracer DiI to evaluate circuit specificity. Place conditioning to intra-VTA KOR agonist injections was performed in sham vs shock rats. ResultsAfter acute stress KOR activation excited a subset of VTA dopamine neurons. In slices from untreated animals, brief corticotrophin releasing factor (CRF) exposure ex vivo rapidly induced a similar switch in KOR signaling. This effect was observed specifically in dorsal medial prefrontal cortex (dmPFC) projecting VTA neurons, but not in other projections. Behaviorally, foot shock stress produced a loss of conditioned place aversion to intra-VTA KOR activation. ConclusionsAfter acute aversive stress, KOR activation in the VTA excites, rather than inhibits, dmPFC-projecting VTA dopamine neurons. This change can be generated by activating the CRF system and interferes with the aversiveness of VTA KOR activation.

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Margolis, E. B.. 2025-08-10. A switch in kappa opioid receptor signaling from inhibitory to excitatory induced by stress in a subset of cortically-projecting dopamine neurons. https://doi.org/10.1101/2025.08.09.669424

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