Kappa Opioid Receptor Activity Underlies Individual Differences in Motivated Behaviors

Abstract

Since the discovery of the kappa opioid receptor (KOR) and its endogenous ligand, dynorphin, the KOR system has held the curiosity of basic and clinical researchers across disciplines. Recent advances in technologies for measuring and manipulating KOR activity, along with the development of several clinically viable KOR compounds, have poised the field for breakthrough discoveries and treatments. As paradigms shift, it is paramount that lessons from the prior literature are synthesized and passed forward to inform future studies, thus optimizing the ability to translate understanding of the KOR system into evidenced based pharmacotherapeutics. To this end, we directly assess long-standing hypotheses of the KOR field, namely that it is a negative valence system that drives negative reinforcement and that it is persistently upregulated during long term periods of abstinence after chronic alcohol intake. Through this work, we find discrepancies that undermine the canon that the KOR system solely plays a role in negative affective states. Instead, we find that it is involved in valence-independent behaviors through increased exploration of, and motivation for, novel stimuli. We do find evidence that the system remains upregulated during abstinence, but hypotheses on the mechanism by which this would be maintained (i.e. through differential gene expression) are once again undermined by the empirical results. Rather, we find an experience-dependent relationship between transcription and function that calls into question the interpretation of many foundational works in neurobiology. Despite these complexities and discrepancies in KOR function, we find that individual differences in KOR activity can still be leveraged to optimize therapeutic outcomes in the treatment of alcohol use disorder, highlighting the utility of a precision medicine approach. By calling into question many long-standing hypotheses on KOR/dynorphin function, we highlight missing links in our understanding and apply these new findings to maximize therapeutic efficacy and inform the next generation of KOR research.