Noradrenergic dysregulation in the pathophysiology of PTSD

doi:10.1016/j.expneurol.2016.05.014

Experimental Neurology

Volume 284, Part B, October 2016, Pages 181-195

https://doi.org/10.1016/j.expneurol.2016.05.014 Get rights and content

Highlights

•
Noradrenaline dysregulation plays a critical role in the pathophysiology of PTSD.
•
Noradrenaline and CRF may interact in regulating amygdala versus mPFC activation.
•
The α₁ adrenergic receptor antagonist prazosin decreases many symptoms of PTSD.
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Other alterations in noradrenergic signaling may also contribute to PTSD symptoms.
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Evidence suggests heterogeneity in the role of noradrenergic dysregulation in PTSD.

Abstract

A central role for noradrenergic dysregulation in the pathophysiology of post-traumatic stress disorder (PTSD) is increasingly suggested by both clinical and basic neuroscience research. Here, we integrate recent findings from clinical and animal research with the earlier literature. We first review the evidence for net upregulation of the noradrenergic system and its responsivity to stress in individuals with PTSD. Next, we trace the evidence that the α₁ noradrenergic receptor antagonist prazosin decreases many of the symptoms of PTSD from initial clinical observations, to case series, to randomized controlled trials. Finally, we review the basic science work that has begun to explain the mechanism for this efficacy, as well as to explore its possible limitations and areas for further advancement. We suggest a view of the noradrenergic system as a central, modifiable link in a network of interconnected stress–response systems, which also includes the amygdala and its modulation by medial prefrontal cortex. Particular attention is paid to the evidence for bidirectional signaling between noradrenaline and corticotropin-releasing factor (CRF) in coordinating these interconnected systems. The multiple different ways in which the sensitivity and reactivity of the noradrenergic system may be altered in PTSD are highlighted, as is the evidence for possible heterogeneity in the pathophysiology of PTSD between different individuals who appear clinically similar. We conclude by noting the importance moving forward of improved measures of noradrenergic functioning in clinical populations, which will allow better recognition of clinical heterogeneity and further assessment of the functional implications of different aspects of noradrenergic dysregulation.

Introduction

Our understanding of the role of noradrenergic signaling in the pathophysiology of PTSD has emerged from a process of repeatedly integrating research results and clinical observations. Drawing on both direct and indirect evidence that increased central nervous system (CNS) noradrenergic tone may underlie many of the symptoms of post-traumatic stress disorder (PTSD), we hypothesized that blockade of noradrenergic transmission might be able to treat the nightmares that posed one of the most impairing and treatment-resistant symptoms observed in this patient population. Clinical case series followed by formal clinical trials confirmed that in particular prazosin, a clinically available antagonist of the postsynaptic α₁ noradrenergic receptor, was effective for both night and daytime symptoms of PTSD. Here, we will review this initial evidence as well as the ongoing exploration of the mechanism for these effects in animal models, in order to develop an overall conceptualization of the role of increased noradrenergic tone in the pathophysiology of PTSD.

Section snippets

Noradrenaline and the biologic response to stress

Noradrenaline, along with its methylation product, adrenaline, is perhaps the paradigmatic example of a neuromodulatory neurotransmitter system. Peripherally, noradrenaline (abbreviated here as NA, and also known as norepinephrine or NE) was first known for its ability to effect a rapid and coordinated response from multiple end organs in response to acute stress, forming a central component of the idea of a sympathoadrenal system that coordinated the ‘fight or flight’ response (Johnson et al.,

Evidence of increased sympathetic or noradrenergic tone in the peripheral nervous system

Initial indications of increased noradrenergic signaling in PTSD came from evidence of increased peripheral sympathetic nervous system activity (Krystal and Neumeister, 2009, Michopoulos et al., 2015, Strawn and Geracioti, 2008, Zoladz and Diamond, 2013). In 1982, Blanchard and colleagues observed significantly higher heart rate (HR) and systolic blood pressure (SBP) in 11 Veterans with PTSD as compared with 11 age- and sex-matched controls (Blanchard et al., 1982). The temporal plots of their

Motivation for and initial clinical experience with prazosin in PTSD

The initial use of prazosin for PTSD was motivated by a need for new treatments to address nighttime symptoms of PTSD. Sleep disturbances in general and recurrent trauma nightmares with distressed awakenings in particular have long been recognized as a hallmark of PTSD (Ross et al., 1989). These symptoms are often particularly resistant to treatment, with persistent sleep complaints present in approximately half of even those considered “complete responders” to evidence-based psychotherapy for

Integrative view of basic science and clinical results in understanding the role of NA in the CNS and the pathophysiology of PTSD

The clinical impact of α₁ noradrenergic receptor blockade in PTSD and commonly comorbid disorders suggests that increased noradrenergic tone plays an important role in their pathophysiology. These findings can inform us as we integrate earlier and more recent basic science results regarding the role of noradrenaline in CNS function, and how alterations in these systems contribute to clinical symptoms. For the sake of brevity, we focus here on the role of NA in the activation and intensity of

Conclusions

Together, clinical and basic research results both point to dysregulation in an interacting web of brain stress–response systems as fundamental to the pathophysiology of PTSD, and potentially to several of its highly comorbid conditions. They suggest that noradrenaline plays some essential role in the perpetuation and/or expression of clinical symptoms, and that blocking in particular the α₁ AR can prevent or significantly decrease the expression of many – but not all – of the symptoms of PTSD.

Acknowledgments and disclosures

The writing of this manuscript was supported by the Department of Veterans Affairs Office of Academic Affiliations Advanced Fellowship Program in Mental Illness Research and Treatment, the Medical Research Service of the Puget Sound Veterans Affairs Health Care System, the Puget Sound Veterans Affairs Health Care System Mental Illness Research, Education, and Clinical Center (MIRECC) and the Department of Defense (W81XWH-12-2-0094).

Dr. Raskind is a paid advisory board member for Pfizer

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Published by Elsevier Inc.

Review ArticleNoradrenergic dysregulation in the pathophysiology of PTSD

Highlights

Abstract

Introduction

Section snippets

Noradrenaline and the biologic response to stress

Evidence of increased sympathetic or noradrenergic tone in the peripheral nervous system

Motivation for and initial clinical experience with prazosin in PTSD

Integrative view of basic science and clinical results in understanding the role of NA in the CNS and the pathophysiology of PTSD

Conclusions

Acknowledgments and disclosures

Biol. Psychiatry

Neurobiol. Stress

Brain Res.

Psychoneuroendocrinology

Psychiatry Res.

Biol. Psychol.

Brain Res.

Brain Res.

Biol. Psychiatry

Neuropharmacology

Eur. J. Pharmacol.

Behav. Res. Ther.

Neurobiol. Learn. Mem.

Psychoneuroendocrinology

J. Psychosom. Res.

Biol. Psychol.

Neurosci. Biobehav. Rev.

Brain Res.

Biol. Psychiatry

Int. J. Psychophysiol.

J. Anxiety Disord.

Biol. Psychiatry

Psychoneuroendocrinology

J. Chem. Neuroanat.

Brain Res.

Neuropsychopharmacology

Psychoneuroendocrinology

Pharmacol. Ther.

Neuron

Biol. Psychiatry

Potential pleiotropic beneficial effects of adjuvant melatonergic treatment in posttraumatic stress disorder

J. Pineal Res.

Comparing the effect of prazosin and hydroxyzine on sleep quality in patients suffering from posttraumatic stress disorder

Neuropsychobiology

Nightcap: laboratory and home-based evaluation of a portable sleep monitor

Psychophysiology

Mental stress increases sympathetic nerve activity during sustained baroreceptor stimulation in humans

Hypertension

Through the looking glass: differential noradrenergic modulation of prefrontal cortical function

Neural Plast.

Serial CSF corticotropin-releasing hormone levels and adrenocortical activity in combat veterans with posttraumatic stress disorder

Am. J. Psychiatry

The autonomic brain: an activation likelihood estimation meta-analysis for central processing of autonomic function

J. Neurosci.

Alpha-2 receptor agonists for the treatment of posttraumatic stress disorder

Drugs Context

Psychopharmacological strategies in the management of posttraumatic stress disorder (PTSD): what have we learned?

Curr. Psychiatry Rep.

Autonomic arousal during actigraphically estimated waking and sleep in male veterans with PTSD

J. Trauma. Stress.

The development of a clinician-administered PTSD scale

J. Trauma. Stress.

A psychophysiological study of post traumatic stress disorder in Vietnam veterans

Psychiatry Q.

Changes in plasma norepinephrine to combat-related stimuli among Vietnam veterans with posttraumatic stress disorder

J. Nerv. Ment. Dis.

A brainstem atlas of catecholaminergic neurons in man, using melanin as a natural marker

J. Comp. Neurol.

Elevated CSF corticotropin-releasing factor concentrations in posttraumatic stress disorder

Am. J. Psychiatr.

Positron emission tomography measurement of cerebral metabolic correlates of yohimbine administration in combat-related posttraumatic stress disorder

Arch. Gen. Psychiatry

Control of sleep and wakefulness

Physiol. Rev.

A meta-analytic examination of basal cardiovascular activity in posttraumatic stress disorder

Psychosom. Med.

Chronic cold stress increases excitatory effects of norepinephrine on spontaneous and evoked activity of basolateral amygdala neurons

Int. J. Neuropsychopharmacol.

Noradrenergic modulation of basolateral amygdala neuronal activity: opposing influences of alpha-2 and beta receptor activation

Review Article
Noradrenergic dysregulation in the pathophysiology of PTSD