Fig. 1. Serotonin neuron kappa opioid receptors mediate stress potentiation of cocaine reward and can be mimicked by optogenetic inhibition.

A Breeding scheme used to excise KOR gene from SERT-expressing neurons. B Schematic of rFSS potentiation of cocaine CPP protocol. Mice were subjected to rFSS on day 1 and day 2 prior to cocaine conditioning. C Stress potentiation of cocaine preference scores for control and KOR^SERT cKO mice with or without prior stress (n = 9–10). D Cartoon depicting DRN injection of inhibitory opsin (AAV5-DIO-SwiChR-EYFP) and cannula placement in a SERT-cre mouse. Below: image showing EYFP expression in the DRN. Scale bar = 50 µm. E Schematic of optogenetic CPA protocol. During optogenetic conditioning, the mouse was confined to one chamber where it received opto-inhibition of SERT^DRN neurons. F Serotonin inhibition preference scores (postconditioning-preconditioning preference for opto-paired chamber) for control and SwiChR-inhibition conditioned groups (n = 5–7). G Representative image showing expression of transcripts for SERT (Slc6a4), VGluT3 (Slc17a8), and KOR (Oprk1) in the medial DRN. Right insets: higher magnification of rectangular regions showing colocalization in cells of the dorsal, ventral, and lateral aspects of the DRN (DRD, DRV, DRL, respectively). Scale bar = 200, 200, 25 µm. H Quantitation of cells co-expressing two transcripts, expressed as percentage cells in the denominator indicated (n = 3). I Quantitation of Slc6a4⁺ cells co-expressing Oprk1 or both Oprk1 and Slc17a8 in each subregion, expressed as percentage of Slc6a4⁺ cells per subregion.