Kappa‐Opioid Receptors Modulate Innate and Learned Responses to Positive and Negative Reinforcers

Abstract

There are few effective and approved treatments for Substance Use Disorders (SUDs) but clinical and preclinical research has shown therapeutic potential for Kappa-opioid receptor (KOR) antagonists. The leading theory of the KOR system's role in SUD posits that chronic substance use augments expression and release of the aversive KOR ligand, dynorphin, which produces a dysphoric state. In this model, upregulation of dynorphin/KOR activity drives continued substance use through a negative reinforcement mechanism whereby substances are consumed to alleviate the negative affective state. While systemic KOR antagonists have been shown to reduce drug consumption in several preclinical models, direct effects on positive and negative reinforcement schedules have not been systematically investigated. In the present study we investigate the effects of systemic antagonism of KORs by nor-Binaltorphimine (NorBNI) on acquisition and maintenance of operant responding reinforced by presentation of sucrose (positive reinforcement) or removal of footshock (negative reinforcement). Based on the prevailing theory that KOR activation is aversive and drives negative reinforcement in addiction, we hypothesized that antagonism of the system would result in decreased responding under the negative reinforcement contingency and have no effect on positive reinforcement. Male C57BL/6J mice received 10 mg/kg intraperitoneal injections of the long-acting KOR antagonist NorBNI or 10 ml/kg saline 24 hours prior to their first session. Animals acquired a discriminated operant response for a positive or negative reinforcer (separate cohorts) whereby a cue light above the active nose-poke (presented on a variable time schedule) served as a discriminative stimulus indicating when a nose-poke would result in the receipt of sucrose or the removal of a series of shocks. Contrary to our hypothesis, mice that received NorBNI showed increased performance during acquisition of both positive and negative reinforcement contingencies compared to saline control mice. These results suggest a novel role of the KOR system in learning that is independent of the valence of the stimulus. We also found differential innate responses to sucrose and footshock prior to operant conditioning suggesting a key role of the system in encoding information about stimuli both aversive and non-aversive. These results call for a reevaluation of the role of KOR signaling in behavioral control and how this system influences drug taking behaviors.