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Cited by 381Posttraumatic Stress Disorder ResearchStress Responses and CortisolNeurotransmitter Receptor Influence on Behavior

The effects of stress exposure on prefrontal cortex: Translating basic research into successful treatments for post-traumatic stress disorder

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Arnsten, Amy F.T., Raskind, Murray A., Taylor, Fletcher B., Connor, Daniel F.·2015·Neurobiology of Stress
DOI 10.1016/j.ynstr.2014.10.002PMC PMC4244027
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Abstract

Research on the neurobiology of the stress response in animals has led to successful new treatments for Post-Traumatic Stress Disorder (PTSD) in humans. Basic research has found that high levels of catecholamine release during stress rapidly impair the top-down cognitive functions of the prefrontal cortex (PFC), while strengthening the emotional and habitual responses of the amygdala and basal ganglia. Chronic stress exposure leads to dendritic atrophy in PFC, dendritic extension in the amygdala, and strengthening of the noradrenergic (NE) system. High levels of NE release during stress engage low affinity alpha-1 adrenoceptors, (and likely beta-1 adrenoceptors), which rapidly reduce the firing of PFC neurons, but strengthen amygdala function. In contrast, moderate levels of NE release during nonstress conditions engage higher affinity alpha-2A receptors, which strengthen PFC, weaken amygdala, and regulate NE cell firing. Thus, either alpha-1 receptor blockade or alpha-2A receptor stimulation can protect PFC function during stress. Patients with PTSD have signs of PFC dysfunction. Clinical studies have found that blocking alpha-1 receptors with prazosin, or stimulating alpha-2A receptors with guanfacine or clonidine can be useful in reducing the symptoms of PTSD. Placebo-controlled trials have shown that prazosin is helpful in veterans, active duty soldiers and civilians with PTSD, including improvement of PFC symptoms such as impaired concentration and impulse control. Open label studies suggest that guanfacine may be especially helpful in treating children and adolescents who have experienced trauma. Thus, understanding the neurobiology of the stress response has begun to help patients with stress disorders.

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  • Changes in neural circuitry caused by chronic stress are believed to underlie the deficits in learning/memory, mood, motivation, and reward seeking that are characteristic of depression and related disorders.

    “these changes in neural circuitry are believed to underlie the deficits in learning/memory, mood, motivation, and reward seeking that are characteristic of depression and related disorders (10, 67–74)”

    From Psychedelics and Other Psychoplastogens for Treating Mental Illness. (2021) · cites this paper as [72]

    In “Chronic stress accentuates these actions” (page not provided), the paper links stress-related circuit changes to impaired working memory and describes persistent changes in circuits regulating behavior and emotion. It does not link those changes to deficits in motivation or reward seeking, or establish the full set of deficits as characteristic of depression and related disorders. (LLM, conf=0.86)

    Experimental — accuracy not yet measured

  • Guanfacine has been especially useful in treating traumatized or abused children, who often have PFC dysfunction reflected in symptoms of impaired self-control.

    “Guanfacine has been especially useful in treating traumatized or abused children, who often have PFC dysfunction reflected in symptoms of impaired self-control.”

    From Guanfacine’s mechanism of action in treating prefrontal cortical disorders: Successful translation across species (2020) · cites this paper as Arnsten et al., 2015

    The Abstract says open-label studies suggest guanfacine may be especially helpful for children and adolescents who have experienced trauma. The sections on treatment and symptoms in children link traumatic stress to PFC dysfunction and impaired impulse control. But the claim presents guanfacine's usefulness as established, whereas the paper says the pediatric evidence is preliminary and notes that there are no controlled trials. (LLM, conf=0.86)

    Experimental — accuracy not yet measured

  • Prazosin reduces flashbacks.

    “Prazosin reduces flashbacks, improves concentration and thinking, and reduces substance abuse, signs of improved PFC function.”

    From Stress weakens prefrontal networks: molecular insults to higher cognition (2015) · cites this paper as [111]

    In the section on prazosin treatment for adults with PTSD (page unavailable), the review reports reduced nightmares and improvement in the broader reexperiencing symptom cluster. It does not report a reduction in flashbacks specifically, so the claim is more specific than the evidence in our copy. (LLM, conf=0.80)

    Experimental — accuracy not yet measured

  • Prazosin reduces substance abuse.

    “Prazosin reduces flashbacks, improves concentration and thinking, and reduces substance abuse, signs of improved PFC function.”

    From Stress weakens prefrontal networks: molecular insults to higher cognition (2015) · cites this paper as [111]

    In “The use of the alpha-1 receptor antagonist, prazosin, for adults with PTSD” (page not provided), the paper says prazosin may help reduce substance abuse. It cites preliminary trials showing reduced alcohol craving and use in people without PTSD, so the unqualified claim that prazosin reduces substance abuse overstates the evidence reported. (LLM, conf=0.87)

    Experimental — accuracy not yet measured

  • The α1-AR antagonist prazosin is in widespread use to treat PTSD in veterans, active duty soldiers and civilians.

    “The α1-AR antagonist prazosin is now in widespread use to treat PTSD in veterans, active duty soldiers and civilians (reviewed in ref. 111).”

    From Stress weakens prefrontal networks: molecular insults to higher cognition (2015) · cites this paper as [111]

    The section on prazosin for adults with PTSD identifies it as an alpha-1 blocker and reviews treatment studies in veterans, active-duty soldiers, and civilians (page not provided). It does not establish that prazosin was in widespread clinical use in those groups; the cited passages describe trials rather than prescribing prevalence. (LLM, conf=0.84)

    Experimental — accuracy not yet measured

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Cited by

Sorted by citations

Authors
Arnsten, A. F. T., Raskind, M. A., Taylor, F. B., & Connor, D. F.
Affiliations
  • Yale University (US)
  • VA Puget Sound Health Care System (US)
  • University of Connecticut (US)
Corresponding author
Arnsten, Amy F.T.
ORCID
Venue
Neurobiology of Stress
Publisher
Elsevier BV
Published
2015-01
Volume
1
Pages
89-99
ISSN
2352-2895 (ISSN-L)
DOI
10.1016/j.ynstr.2014.10.002
PMC
PMC4244027
OpenAlex
W1987605932
Cited by
381
References
38
Citations by year
2026: 36 · 2025: 39 · 2024: 36 · 2023: 33 · 2022: 35 · 2021: 34 · 2020: 39 · 2019: 39 · 2018: 29 · 2017: 29 · 2016: 23 · 2015: 9
FWCI
24.06
Type
journal article
Language
en
Open access
Licence
Locations
  • Neurobiology of Stress (publishedVersion, cc-by-nc-sa)
  • PubMed Central (publishedVersion, cc-by-nc-sa)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
National Institute on Aging (DP1AG047744)
Topics
  • Social Sciences › Psychology › Clinical Psychology › Posttraumatic Stress Disorder Research
  • Life Sciences › Neuroscience › Behavioral Neuroscience › Stress Responses and Cortisol
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
Keywords
post-traumatic stress disorder, prefrontal cortex, chronic stress, noradrenergic system, alpha1-adrenoceptors, catecholamines, amygdala, dendritic atrophy, prazosin, guanfacine, clonidine, stress response, children and adolescents, veterans, impulse control

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