Kappa opioid receptors as modulators of novelty processing

Abstract

A long-standing notion is that kappa opioid receptors (KOPR) are part of negative valence brain systems that contribute to anhedonia and aversive motivated behaviors. Overactivation of KOPR systems has been posited to play are role in drug withdrawal aversion and the motivation to alleviate drug withdrawal [1]. Additionally, KOPRs, like the other opioid receptors, also have analgesic effects. The combination of its low abuse potential (due to its presumed aversive effects), coupled with its therapeutic potential, has made KOPR an appealing target for pain management and addiction treatment. There are many studies corroborating the use of KOPR agonists and antagonists to improve negative affective states [2]. But there is also literature indicating that KOPR modulation can instead produce anxiety, increase drug intake, or have no effect [3]. Despite the expansive literature, until now the hypothesis that KOPRs selectively contribute to negative valence processing and behavioral responses to aversive stimuli had not been directly tested. In their article published in this issue of Neuropsychopharmacology, Farahbakhsh et al. have directly tested this theory using positive and negative reinforcement procedures [4].Based on a priori valence processing frameworks [5], the authors hypothesized that if KOPR activity mediates responses to aversive stimuli, antagonism would selectively impair negative reinforcement learning but have no effect on positive reinforcement learning. Using daily operant conditioning sessions with either positive (sucrose) or negative (footshock) reinforcement, the authors tested whether systemic KOPR antagonism with norBNI would affect the ability of mice to recognize visual light cues and perform the "correct" response to either receive the positive reinforcer or avoid the negative reinforcer. Surprisingly, KOPR antagonism enhanced positive reinforcement learning by increasing the speed and accuracy with which mice responded to sucrose-predictive cues compared to saline controls. There were no differences in maximum performance or total amount consumed between the saline and norBNI groups, suggesting that KOPRs do not directly modulate the reward value per se. Complementing the positive reinforcer results, KOPR antagonism also increased the rate of negative reinforcement learning.Together, these findings suggest that KOPR modulates learning rate independent of presumed valence of the unconditioned stimulus. These results indicate that the negative valence theory cannot explain KOPR's role in behavioral modulation. To clarify how KOPR blockade affects the processing of reinforcement learning, the authors performed crossover experiments, where mice that were previously trained with saline pretreatment were exposed to the task after norBNI pretreatment. They found that KOPR antagonism only enhanced positive reinforcement learning