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Cited by 34Neurotransmitter Receptor Influence on BehaviorNeuropeptides and Animal PhysiologyOpioid Use Disorder Treatment

Modulation of drug choice by extended drug access and withdrawal in rhesus monkeys: implications for negative reinforcement as a driver of addiction and target for medications development

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Negus, S. Stevens, Banks, Matthew L.·2018·Pharmacology Biochemistry and Behavior
DOI 10.1016/j.pbb.2017.04.006PMC PMC5651207
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Abstract

Chronic drug exposure is hypothesized to recruit negative reinforcement processes that increase the magnitude and alter the mechanisms of drug reinforcement. Candidate substrates of negative reinforcement include increased signaling via stress-related neurotransmitters such as corticotropin releasing factor (CRF, acting at CRF receptors) or dynorphin (acting at kappa opioid receptors) and/or decreased signaling via reward-related neurotransmitters such as dopamine. Determinants of drug reinforcement can be examined with choice procedures, in which subjects choose between a drug of interest (e.g. heroin or cocaine) and a non-drug alternative reinforcer (e.g. food). This review summarizes evidence collected from studies of drug choice in rhesus monkeys to address the negative reinforcement hypothesis. In monkeys choosing between heroin and food, chronic heroin exposure and subsequent withdrawal produces a robust increase in heroin choice. This withdrawal-associated increase in heroin choice is blocked by morphine and by other mu opioid agonists used to treat opioid use disorder (methadone, buprenorphine); however, withdrawal-associated increases in heroin choice are not reliably blocked by antagonists of CRF or kappa opioid receptors or by an indirect dopamine agonist. In monkeys choosing between cocaine and food, chronic cocaine exposure and withdrawal fail to increase cocaine choice or alter sensitivity of cocaine choice to treatment with candidate therapeutics including an indirect dopamine agonist and a kappa opioid receptor antagonist. These results support a role for negative reinforcement in self-administration of heroin but not cocaine. The constellation of neurobiological changes that constitutes the negative reinforcing stimulus in opioid-dependent rhesus monkeys remains to be determined.

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  • In rhesus monkeys, extended opioid exposure and subsequent opioid withdrawal increased the reinforcing strength of heroin in choice responding, supporting negative reinforcement as a source of motivation.

    “Studies did show that changes in choice responding in rhesus monkeys during extended opioid exposure and subsequent opioid withdrawal reflected an increase in the reinforcing strength of heroin in a manner that supports the hypothesis that negative reinforcement is a source of motivation (Negus and Banks, 2018).”

    From Drug Addiction: Hyperkatifeia/Negative Reinforcement as a Framework for Medications Development (2021) · cites this paper as Negus and Banks, 2018

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Authors
Negus, S. S., & Banks, M. L.
Affiliations
Virginia Commonwealth University (US)
Corresponding author
Negus, S. Stevens
ORCID
Venue
Pharmacology Biochemistry and Behavior
Publisher
Elsevier BV
Published
2018-01
Volume
164
Pages
32-39
ISSN
0091-3057 (ISSN-L)
DOI
10.1016/j.pbb.2017.04.006
PMC
PMC5651207
OpenAlex
W2605971169
Cited by
34
References
5
Citations by year
2026: 1 · 2025: 4 · 2024: 2 · 2023: 1 · 2022: 4 · 2021: 6 · 2020: 5 · 2019: 8 · 2018: 1 · 2017: 2
FWCI
0.54
Type
journal article
Language
en
Open access
Licence
Locations
  • Pharmacology Biochemistry and Behavior (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • NIH
  • National Institute on Drug Abuse (R01 DA026946)
Topics
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuropeptides and Animal Physiology
  • Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Opioid Use Disorder Treatment
Keywords
negative reinforcement, drug selection, heroin, cocaine, opioid withdrawal, opioid use disorder, kappa opioid receptor, corticotropin-releasing factor, dopamine, self-administration, rhesus monkeys, mu-opioid receptor agonists, methadone, buprenorphine, addiction treatment
MeSH terms
Animals, Choice Behavior, Cocaine, Heroin, Disease Models, Animal, Food, Heroin Dependence, Humans, Macaca mulatta, Narcotic Antagonists, Opioid-Related Disorders, Reinforcement, Psychology, Substance Withdrawal Syndrome, Cocaine-Related Disorders

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