Novel Pharmacological Targets of Post-Traumatic Stress Disorders

Abstract

Post-traumatic stress disorder (PTSD) is a psychopathological condition with a heterogeneous clinical picture that is complex and challenging to treat. Its multifaceted pathophysiology still remains an unresolved question and certainly contributes to this issue. The pharmacological treatment of PTSD is mainly empirical and centered on the serotonergic system. Since the therapeutic response to prescribed drugs targeting single symptoms is generally inconsistent, there is an urgent need for novel pathogenetic hypotheses, including different mediators and pathways. This paper was conceived as a narrative review with the aim of debating the current pharmacological treatment of PTSD and further highlighting prospective targets for future drugs. The authors accessed some of the main databases of scientific literature available and selected all the papers that fulfilled the purpose of the present work. The results showed that most of the current pharmacological treatments for PTSD are symptom-based and show only partial benefits; this largely reflects the limited knowledge of its neurobiology. Growing, albeit limited, data suggests that the hypothalamic-pituitary-adrenal axis, opioids, glutamate, cannabinoids, oxytocin, neuropeptide Y, and microRNA may play a role in the development of PTSD and could be targeted for novel treatments. Indeed, recent research indicates that examining different pathways might result in the development of novel and more efficient drugs.

Keywords: PTSD; cannabinoids; glutamate; hypothalamic-pituitary-adrenal axis; microRNA; opioids; oxytocin; pharmacological treatment.

Figure 1

The hypothalamic-pituitary-adrenal axis. Corticotropin Releasing Factor (CRF) binds CRF1 receptors, which are linked to the inflammatory process and depressive-like behavior.

Figure 2

MDMA acts as an inhibitor of NET, DAT, SERT and of VMAT2, resulting in increased levels of the three monoamines DA, NE, and 5HT. The latter consequently increases the blood levels of prolactin, DHEA, oxytocin, and cortisol. MDMA also binds D1-D2 receptors and acts as an agonist of H1, 5HT2A, and B receptors. Its effects are also explained by the interaction with TAAR1, alpha2, and Sigma1. S- and R-ketamines increase glutamate release into the synaptic cleft, activating AMPAR and contributing to further synaptogenesis and dendritogenesis. S-ketamine binds NMDARs expressed in GABAergic interneurons, leading to a depolarization of cortical excitatory neurons. This depolarization causes glutamate and BDNF release, which bind to TrkB receptors. TrkB activates the mTORC1 signaling pathway, leading to the upregulation of synaptogenesis and dendritogenesis. S-ketamine binds to extrasynaptic NMDARs, disinhibiting mTORC1 signaling by deactivating eEFK2. Binding to mu-opioid receptors may facilitate antidepressant effects. R-ketamine affects microglial signaling and, by increasing BDNF release through TrkB, activates the ERK signaling pathway, resulting in synaptogenesis and dendritogenesis.

Figure 3

Different activities of oxytocin implicated in PTSD through its anti-inflammatory and fear memory modulation properties.

Figure 4

Neuropeptide Y (NPY) and its different receptors (Y1, Y2, Y4, Y5). Y1, Y2, Y4, and Y5, localized in different CNS areas and bound by NPY produced by CNS and sympathetic neurons, are important not only for food intake and energy homeostasis but also for cognition, anxiety, and mood regulation. Sensation and pain are regulated by CNS and enteric neurons that bind Y1, Y2, and Y4 localized in spinal cord sensory neurons. Y1 and Y2, located in the Gut system and bound by CNS and enteric NPY, regulate blood pressure, mucosal immunity, and gut mobility.