Stress-induced reinstatement of drug seeking: 20 years of progress

Mantsch, John R; Baker, David A; Funk, Douglas; Lê, Anh D; Shaham, Yavin

doi:10.1038/npp.2015.142

Cited by 438Neurotransmitter Receptor Influence on BehaviorSubstance Abuse Treatment and OutcomesNeuropeptides and Animal Physiology

Stress-induced reinstatement of drug seeking: 20 years of progress

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Mantsch, John R, Baker, David A, Funk, Douglas, Lê, Anh D, Shaham, Yavin·2016·Neuropsychopharmacology

DOI 10.1038/npp.2015.142PMC PMC4677117

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Abstract

In human addicts, drug relapse and craving are often provoked by stress. Since 1995, this clinical scenario has been studied using a rat model of stress-induced reinstatement of drug seeking. Here, we first discuss the generality of stress-induced reinstatement to different drugs of abuse, different stressors, and different behavioral procedures. We also discuss neuropharmacological mechanisms, and brain areas and circuits controlling stress-induced reinstatement of drug seeking. We conclude by discussing results from translational human laboratory studies and clinical trials that were inspired by results from rat studies on stress-induced reinstatement. Our main conclusions are (1) The phenomenon of stress-induced reinstatement, first shown with an intermittent footshock stressor in rats trained to self-administer heroin, generalizes to other abused drugs, including cocaine, methamphetamine, nicotine, and alcohol, and is also observed in the conditioned place preference model in rats and mice. This phenomenon, however, is stressor specific and not all stressors induce reinstatement of drug seeking. (2) Neuropharmacological studies indicate the involvement of corticotropin-releasing factor (CRF), noradrenaline, dopamine, glutamate, kappa/dynorphin, and several other peptide and neurotransmitter systems in stress-induced reinstatement. Neuropharmacology and circuitry studies indicate the involvement of CRF and noradrenaline transmission in bed nucleus of stria terminalis and central amygdala, and dopamine, CRF, kappa/dynorphin, and glutamate transmission in other components of the mesocorticolimbic dopamine system (ventral tegmental area, medial prefrontal cortex, orbitofrontal cortex, and nucleus accumbens). (3) Translational human laboratory studies and a recent clinical trial study show the efficacy of alpha-2 adrenoceptor agonists in decreasing stress-induced drug craving and stress-induced initial heroin lapse.

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Meta-analyses indicate that mindfulness reduces physiological stress markers that can trigger craving and relapse in people with OUD.
“Meta-analyses suggest mindfulness decreases physiologic markers of stress, which can trigger craving and relapse among people with OUD (Hyman et al., 2007; Koob et al., 2014; Mantsch et al., 2016; Pascoe et al., 2017; Ribiero et al., 2005).”
From Feasibility and acceptability of mindful recovery opioid use care continuum (M-ROCC): A concurrent mixed methods study (2021) · cites this paper as Mantsch et al., 2016
Stress-induced reinstatement of drug-seeking is generalizable to other substances, including food.
“The phenomenon of stress-induced reinstatement of drug-seeking is generalizable to other substances, including food [170].”
From Food Addiction and Psychosocial Adversity: Biological Embedding, Contextual Factors, and Public Health Implications (2020) · cites this paper as [170]

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Untitled work
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“In support of this, longitudinal studies confirm that PTSD increases risk for SUD [4] and animal studies have shown that stressors are able to potently drive drugseeking [7].”
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Noradrenaline in the bed nucleus of the stria terminalis is critical for stress-induced reactivation of morphine-conditioned place preference in rats
Wang, X., Cen, X., & Lü, L. (2001) · European Journal of Pharmacology · doi:10.1016/s0014-2999(01)01487-x · Cited by 112 · see citing works
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Authors: Mantsch, J. R., Baker, D. A., Funk, D., Lê, A. D., & Shaham, Y.
Affiliations: Marquette University (US)
University of Toronto (CA)
National Institute on Drug Abuse (US)
Corresponding author: Mantsch, John R
Shaham, Yavin
ORCID: Mantsch, John R
Funk, Douglas
Shaham, Yavin
Venue: Neuropsychopharmacology
Publisher: Springer Science and Business Media LLC
Published: 2015-05-15
Volume: 41
Issue: 1
Pages: 335-356
ISSN: 0893-133X (ISSN-L)
1740-634X
DOI: 10.1038/npp.2015.142
PMC: PMC4677117
OpenAlex: W2248682259
Cited by: 438
References: 300
Citations by year: 2026: 24 · 2025: 22 · 2024: 30 · 2023: 40 · 2022: 43 · 2021: 52 · 2020: 45 · 2019: 46 · 2018: 52 · 2017: 46 · 2016: 32 · 2015: 6
FWCI: 5.39
Type: journal article
Language: en
Open access: green
www.ncbi.nlm.nih.gov
Licence: www.springer.com/tdm (tdm)
Locations: Neuropsychopharmacology (publishedVersion)
PubMed Central (publishedVersion)
PubMed (publishedVersion)
e-Publications@Marquette (Marquette University) (submittedVersion)
Funders: National Institutes of Health
National Institute on Drug Abuse (R01DA038663)
Topics: Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
Health Sciences › Medicine › Epidemiology › Substance Abuse Treatment and Outcomes
Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuropeptides and Animal Physiology
Keywords: stress-induced reinstatement, drug-seeking behavior, drug relapse, drug craving, stress, heroin, cocaine, methamphetamine, nicotine, alcohol, conditioned place preference, corticotropin-releasing factor, norepinephrine, dopamine, glutamate, bed nucleus of the stria terminalis, central amygdala, mesocorticolimbic dopamine system, alpha-2 adrenergic agonists, translational research, addiction
MeSH terms: Animals, Brain, Conditioning, Psychological, Glucocorticoids, Humans, Nerve Net, Self Administration, Illicit Drugs, Stress, Psychological, Behavior, Addictive, Drug-Seeking Behavior

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Stress-induced reinstatement of drug seeking: 20 years of progress

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