The Role of the Hypothalamic-Pituitary-Adrenal Axis in Post-Traumatic Stress Disorder
Introduction. Post-traumatic stress disorder (PTSD) develops after a traumatic event such as exposure to actual or threatened death, serious injury, or sexual violence.1 DSM V defines PTSD as avoidance, intrusion, negative alterations in cognition or mood, and alterations in arousal and reactivity for more than one month.1 70.4% of the global population is exposed to trauma and 3.9% develop PTSD.2 Currently, treatment in the United States consists of the FDA-approved SSRIs paroxetine or sertraline in conjunction with psychotherapy; however, many studies have found that this is treatment regimen is not effective for most patients.3 One potential target is the immune system – specifically, the hypothalamic-pituitary-adrenal (HPA) axis – as individuals with PTSD expressed elevated proinflammatory molecules.3 Methods. Rodent models were used to study the effects of eliminating various elements of the HPA axis on behavior and marker molecules. Rodents would undergo a procedure, such as a splenectomy, or would be given an antagonist agent that blocked a certain pathway. Through this process, the roles of several pathways were tested, including norepinephrine4,5, cortisol4,7, adrenal glands8,and FKBP5 chaperone protein6. Results. Studies showed that norepinephrine played an important role in stress response after 21 days, but not after 7 days.4 In contrast, cortisol was found to have a bigger role in stress response after 7 days, but not after 21 days.4 A similar study found that a history of social defeat in mice resulted in a sensitized norepinephrine response and a habituated corticosterone response, further supporting that the initial stress response is mediated by glucocorticoids whereas later effects are mediated by norepinephrine.5 Adrenalectomized mice that did not have the ability to produce cortisol were found to have fewer circulating monocytes; this could be attributed to the fact that monocytes are recruited by microglial cells, which need cortisol to be activated.7 Wild-type mice exposed to stress were found to have significantly thinner zona fasciculata, which is where cortisol is produced.8 In another study, stress-exposed mice were found to have downregulated FKBP5 in the hypothalamus, indicating that not enough cortisol was bound to glucocorticoid receptors to allow FKBP5 to be released.6 Conclusion. In PTSD, the hypothalamic-pituitary-adrenal axis is dysregulated, resulting in low levels of cortisol and an immune system that is in a proinflammatory state. There are several components of the HPA axis that could serve as potential targets for future therapy of PTSD, including glucocorticoid/beta-adrenergic receptors, chaperone proteins, cortisol, and norepinephrine. Recently, more studies have been conducted to test the efficacy of steroid injections after a traumatic event to prevent development of PTSD. This is a promising avenue of research that could potentially reveal a more efficacious treatment for PTSD than currently existing therapeutics.
- Center for Substance Abuse Treatment (US). Trauma-Informed Care in Behavioral Health Services. Rockville (MD): Substance Abuse and Mental Health Services Administration (US); 2014. (Treatment Improvement Protocol (TIP) Series, No. 57.) Exhibit 1.3-4, DSM-5 Diagnostic Criteria for PTSD. Available from: https://www.ncbi.nlm.nih.gov/books/NBK207191/box/part1_ch3.box16/
- Grasser LR, Burghardt P, Daugherty AM, Amirsadri A, Javanbakht A. Inflammation and trauma-related psychopathology in Syrian and Iraqi refugees. Behav Sci. 2020;10(4):75. doi: 10.3390/bs10040075
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- Li, Yu., Jiang, W., Li, Z., Zhang, C., Huang, C., Yang, J., & Kong, G. Repetitive restraint stress changes spleen immune cell subsets through glucocorticoid receptor or β-adrenergic receptor in a stage dependent manner. Biochemical and biophysical research communications. 2018;495(1):1108-1114. doi: 10.1016/j.bbrc.2017.11.148
- Finnell JE, Moffitt CM, Hesser LA, Harrington E, Melson MN, Wood CS, Wood SK. The contribution of the locus coeruleus-norepinephrine system in the emergence of defeat-induced inflammatory priming. Brain, Behavior, and Immunity. 2019;79:102-113. doi: 10.1016/j.bbi.2019.01.021
- Algamal M, Ojo JO, Lungmus CP, et al. Chronic hippocampal abnormalities and blunted HPA axis in an animal model of repeated unpredictable stress. Frontiers in Behavioral Neuroscience. 2018;12. doi:10.3389/fnbeh.2018.00150
- Niraula A, Wang Y, Godbout JP, Sheridan JF. Corticosterone production during repeated social defeat causes monocyte mobilization from the bone marrow, glucocorticoid resistance, and neurovascular adhesion molecule expression. The Journal of Neuroscience. 2018;38(9):2328-2340. doi: 10.1523/jneurosci.2568-17.2018
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