KOR Control over Addiction Processing: An Exploration of the Mesolimbic Dopamine Pathway
Drug addiction is a complex, persistent, and chronically relapsing neurological disorder exacerbated by acute and chronic stress. It is well known that the dynorphin/kappa opioid receptor (KOR) system regulates stress perception and responsivity, while th
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Contents 1 Introduction 2 KOR Interactions with the Dopamine System 2.1 KOR-Mediated Regulation of Dopamine Release 2.2 KOR-Mediated Regulation of Dopamine Uptake 2.3 KOR-Mediated Regulation of D2/D3 Receptors 3 Behavioral Effects of KOR Activation in Humans and Animal Models 4 Involvement of KOR in Addiction Processing and Stress 4.1 KOR and Alcohol Use Disorder 4.2 KOR and Substance Use Disorder 4.3 Acute and Chronic Stress Impact on Dynorphin/KOR System 4.4 Stress-Induced Development of Drug Addiction 5 Conclusion References
Abstract
Drug addiction is a complex, persistent, and chronically relapsing neurological disorder exacerbated by acute and chronic stress. It is well known that the dynorphin/kappa opioid receptor (KOR) system regulates stress perception and responsivity, while the mesolimbic dopamine system plays a role in reward and reinforcement associated with alcohol and substance use disorders. Interestingly,
P. M. Estave Department of Physiology and Pharmacology, Wake Forest School of Medicine, Winston-Salem, NC, USA M. B. Spodnick · A. N. Karkhanis (*) Department of Psychology, Developmental Exposure Alcohol Research Center, Center for Developmental and Behavioral Neuroscience, Binghamton University – SUNY, Binghamton, NY, USA e-mail: [email protected] # The Author(s), under exclusive license to Springer Nature Switzerland AG 2020 Handbook of Experimental Pharmacology, https://doi.org/10.1007/164_2020_421
P. M. Estave et al.
the dopamine and dynorphin/KOR systems are highly integrated in mesolimbic areas, with KOR activation leading to inhibition of dopamine release, further altering the perception of reinforcing and aversive stimuli. Chronic or repeated exposure to stress or drugs potentiates KOR function ultimately contributing to a hypodopaminergic state. This hypodopaminergic state is one of the hallmarks of hyperkatifeia, defined as the hypersensitivity to emotional distress that is exacerbated during drug withdrawal and abstinence. The relationship between stress and drug addiction is bidirectional; repeated/chronic stress promotes pro-addictive behaviors, and repeated cycles of drug exposure and withdrawal, across various drug classes, produces stress. Neuroadaptations driven by this bidirectional relationship ultimately influence the perception of the reinforcing value of rewarding stimuli. In this chapter, we address the involvement of the dopamine and dynorphin/KOR systems and their interactions in shaping reinforcement value processing after drug and stress exposure, as well as a combinatorial impact of both drugs and stress. Keywords
Alcohol use disorder · Dopamine · Dynorphins · Kappa opioid receptor · Nucleus accumbens · Substance use disorder
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Introduction
The dynorphin/kappa opioid receptor (KOR) system is a main player involved in regulating stress responsivity, mood, and reinforcement learning. Previous literature suggests that KOR and its interaction with dopamine modulates motivated behaviors as well as aversion and negative affective states – all of which contribut
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