ArticleNeuropsychopharmacology : official publication of the American College of Neuropsychopharmacology2018
κ-Opioid Receptor Activation in Dopamine Neurons Disrupts Behavioral Inhibition.
Article in Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 29 papers.
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Who cites it
29 citing papers in PubMed, 50 citations in OpenAlex.
- Dissecting the contribution of mu and kappa opioid receptor signalling in effort and delay-related cost/benefit decision making.Psychopharmacology · 2026Article
- Kappa opioid receptor antagonism in neuropsychiatry: from molecular mechanisms to clinical prospects.European archives of psychiatry and clinical neuroscience · 2026Review
- Kappa Opioid Receptors Control a Stress-Sensitive Brain Circuit and Drive Cocaine Seeking.The Journal of neuroscience : the official journal of the Society for Neuroscience · 2025Article
- κ-Opioid Receptor Agonists as Robust Pain-Modulating Agents: Mechanisms and Therapeutic Potential in Pain Modulation.Journal of clinical medicine · 2025Review
- An integrated microfluidic and fluorescence platform for probing in vivo neuropharmacology.Neuron · 2025Article
- Dezocine modulates the reinstatement of conditioned place preference in morphine-dependent rats via the dopamine reward circuitry.Frontiers in neuroscience · 2025Article
- Limitations and potential of κOR biased agonists for pain and itch management.Neuropharmacology · 2024Review
- Article
- Endogenous Opioids in the Homeostatic Regulation of Hunger, Satiety, and Hedonic Eating: Neurobiological Foundations.Advances in neurobiology · 2024Review
- Kappa Opioid Receptors Reduce Serotonin Uptake and Escitalopram Efficacy in the Mouse Substantia Nigra Pars Reticulata.International journal of molecular sciences · 2023Article
- Quantitative Systems Pharmacology and Biased Agonism at Opioid Receptors: A Potential Avenue for Improved Analgesics.International journal of molecular sciences · 2022Review
- Comparative effects of cannabinoid CB1 receptor agonist and antagonist on timing impulsivity induced by d-amphetamine in a differential reinforcement of low-rate response task in male rats.Psychopharmacology · 2022Article
- Article
- Traumatic Stress-Induced Vulnerability to Addiction: Critical Role of the Dynorphin/Kappa Opioid Receptor System.Frontiers in pharmacology · 2022Review
- The Role of Dynorphin and the Kappa Opioid Receptor in Schizophrenia and Major Depressive Disorder: A Translational Approach.Handbook of experimental pharmacology · 2022Review
- Release of endogenous dynorphin opioids in the prefrontal cortex disrupts cognition.Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology · 2021Article
- A midbrain dynorphin circuit promotes threat generalization.Current biology : CB · 2021Article
- Early life stress dysregulates kappa opioid receptor signaling within the lateral habenula.Neurobiology of stress · 2020Article
- Crosstalk Between Kappa Opioid and Dopamine Systems in Compulsive Behaviors.Frontiers in pharmacology · 2020Review
- Functions of p38 MAP Kinases in the Central Nervous System.Frontiers in molecular neuroscience · 2020Review
Corrections and comments
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Authors and funding
8 authors at 2 institutions in 2 countries.
Funding
Abstract
The dynorphin/κ-opioid receptor (KOR) system has been previously implicated in the regulation of cognition, but the neural circuitry and molecular mechanisms underlying KOR-mediated cognitive disruption are unknown. Here, we used an operational test of cognition involving timing and behavioral inhibition and found that systemic KOR activation impairs performance of male and female C57BL/6 mice in the differential reinforcement of low response rate (DRL) task. Systemic KOR antagonism also blocked stress-induced disruptions of DRL performance. KOR activation increased 'bursts' of incorrect responses in the DRL task and increased marble burying, suggesting that the observed disruptions in DRL performance may be attributed to KOR-induced increases in compulsive behavior. Local inactivation of KOR by injection of the long-acting antagonist nor-BNI in the ventral tegmental area (VTA), but not the infralimbic prefrontal cortex (PFC) or dorsal raphe nucleus (DRN), prevented disruption of DRL performance caused by systemic KOR activation. Cre-dependent genetic excision of KOR from dopaminergic, but not serotonergic neurons, also blocked KOR-mediated disruption of DRL performance. At the molecular level, we found that these disruptive effects did not require arrestin-dependent signaling, because neither global deletion of G-protein receptor kinase 3 (GRK3) nor cell-specific deletion of GRK3/arrestin-dependent p38α MAPK from dopamine neurons blocked KOR-mediated DRL disruptions. We then showed that nalfurafine, a clinically available G-biased KOR agonist, could also produce DRL disruptions. Together, these studies demonstrate that KOR activation in VTA dopamine neurons disrupts behavioral inhibition in a GRK3/arrestin-independent manner and suggests that KOR antagonists could be beneficial for decreasing stress-induced compulsive behaviors.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.