Recent progress in understanding the pathophysiology of post-traumatic stress disorder: implications for targeted pharmacological treatment

Abstract

Post-traumatic stress disorder (PTSD) is a common and chronic anxiety disorder that can result after exposure to a traumatic event. Though our understanding of the aetiology of PTSD is incomplete, several neurobiological systems have been implicated in the pathophysiology and vulnerability towards developing PTSD after trauma exposure. We aimed to provide a concise review of benchmark findings in important neurobiological systems related to the aetiology and maintenance of PTSD symptomology. Specifically, we discuss functional aetiologies in the noradrenergic, serotonergic, endogenous cannabinoid and opioid systems as well as the hypothalamic-pituitary adrenal (HPA) axis. This article provides a succinct framework to appreciate the current understanding of neurobiological mechanisms related to the pathophysiology of PTSD and how these findings may impact the development of future, targeted pharmacological treatments for this debilitating disorder.

Fig. 1

Post-traumatic stress disorder (PTSD) patients, overall, have lower serotonin 5-HT_1B receptor density in the anterior cingulate cortex (ACC), hippocampus (HC) and pallidum as well as other regions implicated in PTSD [70]. Specific alterations in 5-HT_1B receptor density in PTSD have been shown, using the 5-HT_1B selective radioligand [11C]P943, to be linked to specific domains of PTSD symptomology. Decreased 5-HT_1B receptor binding in the ACC has been shown to increase re-experiencing symptoms. Decreased 5-HT_1B receptor binding in the HC has been shown to increase numbing symptoms. Decreased 5-HT_1B receptor binding in the pallidum has been shown to increase anxious arousal, re-experiencing, and numbing symptoms [193]

Fig. 2

Chemical structures of endogenous compounds that bind to cannabinoid receptors

Fig. 3

Plasma anandamide (AEA) levels are decreased in post-traumatic stress disorder (PTSD) patients (0.72 ± 0.12 pmol/mL) relative to healthy control subjects without trauma history (hippocampus [HC]; 2.74 ± 0.85 pmol/mL, t = 2.47, degrees of freedom [df] = 17, p = 0.024)

Fig. 4

MRI scans and positron emission tomography (PET) images of kappa opiate receptors in the brain of a healthy individual. For both left and right panels, the left column shows the axial slice, the middle column shows the coronal slice and the right column shows the sagittal slice. The PET images of the receptors confirm their known distribution in the human brain, with high levels in a circuit implicated in post-traumatic stress disorder, which includes the amygdala, hippocampus and ventromedial prefrontal cortex. Left panel: Top row: MRI images. Middle row: 0–10 min summed PET image. Bottom row: 60–120 min summed PET image. Right panel: Top row: MRI images. Middle row: corresponding binding potential (BPND images estimated using a simplified reference tissue model [SRTM]). Bottom row: corresponding BPND images estimated using the SRTM2; it is slightly less noisy than the SRTM, as would be expected.