Noradrenergic and serotonergic mechanisms in the neurobiology of posttraumatic stress disorder and resilience

Abstract

Posttraumatic stress disorder (PTSD) is characterized mainly by symptoms of re-experiencing, avoidance and hyperarousal as a consequence of catastrophic and traumatic events that are distinguished from ordinary stressful life events. Although extensive research has already been done, the etiology of PTSD remains unclear. Research on the impact of trauma on neurobiological systems can be expected to inform the development of treatments that are directed specifically to symptoms of PTSD. During the past 25 years there has been a dramatic increase in the knowledge about noradrenergic and serotonergic mechanisms in stress response, PTSD and more recently in resilience and this knowledge has justified the use of antidepressants with monoaminergic mechanisms of action for patients with PTSD. Nevertheless, available treatments of PTSD are only to some extent effective and enhanced understanding of the neurobiology of PTSD may lead to the development of improved treatments for these patients. In the present review, we aim to close existing gaps between basic research in psychopathology, neurobiology and treatment development with the ultimate goal to translate basic research into clinically relevant findings which may directly benefit patients with PTSD.

Figure 1

Acute and repeated stressors disrupt frontal-cortical control over limbic-striatal circuits which constitute the brain stress circuit, increase mesolimbic dopaminergic transmission and increase prefrontal cortex (PFC) norepinephrine (NE) and serotonin (5-HT) transmission. The prevailing neurocircuitry model of PTSD which has been developed from theoretical considerations, research in animals and expanded to human imaging studies emphasizes the role of the amygdala, as well as its interactions with the ventral/medial prefrontal cortex (vmPFC), hippocampus and anterior cingulate cortex. The model hypothesizes hyperresponsivity of the amygdala to threat-related stimuli and deficient ventro-medial PFC function but also evidence for generalized hypervigilance in PTSD.

Figure 2

Correlation between psychologic symptoms of dissociation at baseline predict significantly less NPY release during stress in a group of N=25 active duty U.S. Navy personnel participating in survival school training.

Figure 3

The effects of the sympathetic nervous system are mediated via release of neurotransmitters and neuropeptides from sympathetic neurons. NPY and tyrosinhydroxylase are likely to modulate NPY and/or norepinephrine (NE) release whereby NE seems to moderate the flight and fight response during stress whereas NPY contributes to dampen down the effects of NE during stress response.

Figure 4

Positron emission tomography study of 5-HT1A receptors with the radioligand [18F]Trans-4-fluoro-N-2-[4-(2-methoxyphenyl)piperazin-1-yl]ethyl]-N-(2-pyridyl)cyclohexanecarboxamide (FCWAY), a selective 5-HT1A receptor antagonist ligand. No difference in receptor expression was found in PTSD or PTSD and depression vs. healthy control subjects.

Figure 5

The occurrence of a traumatic event and/or chronic stress leads to increased synaptic 5-HT levels in the amygdala and cortical regions, as well as alterations in dopamine release in the ventral striatum (VST). These effects are at least partially mediated by 5-HT1B receptors. A PTSD-resilience model that implicates a central role for the 5-HT1B receptor would assume that PTSD patients, in contrast to resilient people are unable to downregulate 5-HT_1B receptors which will lead to amygdala hyperresponsiveness because of reduced 5-HT activity which may disinhibit excitatory activity by reducing the stimulation of 5HT₁A receptors located on pyramidal cells where they inhibit action potential formation, and of 5-HT₃ receptors, that are located on GABAergic interneurons where they stimulate GABA release, alterations in dopamine release in the VST and changes in ventromedial prefrontal cortex (vmPFC) function resulting in inadequate top-down governance over the amygdala by the vmPFC which is characteristic for PTSD.