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Review ArticleReview Article

Drug Addiction: Hyperkatifeia/Negative Reinforcement as a Framework for Medications Development

George F. Koob
Robert Dantzer, ASSOCIATE EDITOR
Pharmacological Reviews January 2021, 73 (1) 163-201; DOI: https://doi.org/10.1124/pharmrev.120.000083
George F. Koob
National Institute on Alcohol Abuse and Alcoholism and National Institute on Drug Abuse, National Institutes of Health, Bethesda, Maryland
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Robert Dantzer
Roles: ASSOCIATE EDITOR
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Abstract

Compulsive drug seeking that is associated with addiction is hypothesized to follow a heuristic framework that involves three stages (binge/intoxication, withdrawal/negative affect, and preoccupation/anticipation) and three domains of dysfunction (incentive salience/pathologic habits, negative emotional states, and executive function, respectively) via changes in the basal ganglia, extended amygdala/habenula, and frontal cortex, respectively. This review focuses on neurochemical/neurocircuitry dysregulations that contribute to hyperkatifeia, defined as a greater intensity of negative emotional/motivational signs and symptoms during withdrawal from drugs of abuse in the withdrawal/negative affect stage of the addiction cycle. Hyperkatifeia provides an additional source of motivation for compulsive drug seeking via negative reinforcement. Negative reinforcement reflects an increase in the probability of a response to remove an aversive stimulus or drug seeking to remove hyperkatifeia that is augmented by genetic/epigenetic vulnerability, environmental trauma, and psychiatric comorbidity. Neurobiological targets for hyperkatifeia in addiction involve neurocircuitry of the extended amygdala and its connections via within-system neuroadaptations in dopamine, enkephalin/endorphin opioid peptide, and γ-aminobutyric acid/glutamate systems and between-system neuroadaptations in prostress corticotropin-releasing factor, norepinephrine, glucocorticoid, dynorphin, hypocretin, and neuroimmune systems and antistress neuropeptide Y, nociceptin, endocannabinoid, and oxytocin systems. Such neurochemical/neurocircuitry dysregulations are hypothesized to mediate a negative hedonic set point that gradually gains allostatic load and shifts from a homeostatic hedonic state to an allostatic hedonic state. Based on preclinical studies and translational studies to date, medications and behavioral therapies that reset brain stress, antistress, and emotional pain systems and return them to homeostasis would be promising new targets for medication development.

Significance Statement The focus of this review is on neurochemical/neurocircuitry dysregulations that contribute to hyperkatifeia, defined as a greater intensity of negative emotional/motivational signs and symptoms during withdrawal from drugs of abuse in the withdrawal/negative affect stage of the drug addiction cycle and a driving force for negative reinforcement in addiction. Medications and behavioral therapies that reverse hyperkatifeia by resetting brain stress, antistress, and emotional pain systems and returning them to homeostasis would be promising new targets for medication development.

Footnotes

  • This paper received no external funding.

  • https://doi.org/10.1124/pharmrev.120.000083.

  • U.S. Government work not protected by U.S. copyright
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Pharmacological Reviews: 73 (1)
Pharmacological Reviews
Vol. 73, Issue 1
1 Jan 2021
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Review ArticleReview Article

Hyperkatifeia/Negative Reinforcement in Drug Addiction

George F. Koob
Pharmacological Reviews January 1, 2021, 73 (1) 163-201; DOI: https://doi.org/10.1124/pharmrev.120.000083

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Review ArticleReview Article

Hyperkatifeia/Negative Reinforcement in Drug Addiction

George F. Koob
Pharmacological Reviews January 1, 2021, 73 (1) 163-201; DOI: https://doi.org/10.1124/pharmrev.120.000083
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  • Article
    • Abstract
    • I. Introduction
    • II. Addiction: Definition and Theoretical Framework
    • III. Within-System/Between-System Neurobiological Substrates for Hyperkatifeia Associated with Opioid and Alcohol Withdrawal
    • IV. Within-System Neurobiological Substrates for Hyperkatifeia Associated with Opioid and Alcohol Withdrawal
    • V. Between-System Neurobiological Substrates for Hyperkatifeia Associated with Opioid and Alcohol Withdrawal
    • VI. Antistress Neurotransmitters/Neuromodulators and Hyperkatifeia
    • VII. Hyperkatifeia and Sex Differences
    • VIII. Pain, Hyperkatifeia, and Addiction
    • IX. Individual Differences in Hyperkatifeia
    • X. The Case for Hyperkatifeia as a Target for Medications Development
    • Acknowledgments
    • Authorship Contributions
    • Footnotes
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