Kappa opioid receptors delay sucrose self-administration by modulating dopamine ramps before operant responding

Chronic consumption of drugs of abuse increases sensitivity of the dynorphin/kappa opioid receptor (KOR) stress system, which reduces striatal dopamine signaling and promotes drug taking. However, there is mixed evidence on how KOR-modulation of dopamine affects operant behavior in the absence of addiction. To address this gap, we injected dLight1.2 in the nucleus accumbens of male and female C57BL/6J mice and trained them to self-administer sucrose. Mice were injected with the KOR agonist U50,488H, with or without the KOR antagonist aticaprant, prior to each session. U50,488H did not affect dopamine responses during the lever press and did not alter total presses or consumption. The primary effects of KOR activation were to delay initiation of lever pressing, and to diminish the rapid ramp-up in dopamine seen before lever presses. The first lever press of each session was preceded by the largest dopamine ramp; however, ramp size did not correlate with latency under any condition. We further tested whether KOR-modulation of dopamine ramps affects behavior throughout the session. We found that the total amount of dopamine activity 10 seconds before the lever press predicted when the next lever press would occur, specifically after U50,488H injection. When the phasic peaks were subtracted from this to quantify a slower dopamine ramp, time to the next lever press could be predicted and this effect was strongest after U50,488H injection. As U50,488H reduces basal dopamine signaling, we propose that dopamine ramps prior to behavior have a larger signal-to-noise ratio during KOR activation. This relatively greater increase in dopamine from baseline could increase the salience of the decision to perform reward-associated actions, which may play a role in habitual behaviors like drug taking.