Stress-restress: Effects on ACTH and fast feedback
Abstract
Glucocorticoid secretion is tightly regulated by negative feedback. Glucocorticoid feedback has been found to be altered in depression and post-traumatic stress disorder (PTSD). While hyposensitive glucocorticoid feedback has been found in depression, hypersensitive or enhanced negative feedback was described in PTSD. Enhanced negative feedback, can be seen as a sensitization of the inhibitory elements of HPA axis, and stress-restress or time dependent sensitization (TDS) model, has been suggested as an animal model for PTSD. We have studied the effects of this model on the HPA axis to determine whether it will produce increased sensitivity to negative feedback as found in PTSD patients. Adult Sprague-Dawley male rats were exposed to a single session of prolonged stress (restraint followed by a forced swim and exposure to ether vapors) and briefly restressed 7 days later. The effects of single prolonged stress on plasma ACTH and corticosterone responses (0, 5, and 30 min) and on glucocorticoid fast feedback (cortisol vs. saline pretreatment) were assessed in two studies. Animals exposed to single prolonged stress showed enhanced negative feedback in comparison to naive animals (F = 4.6371, df = 3, p = .0107), but there was no difference in ACTH or corticosterone responses during the restress. Pretreatment with cortisol, in the first stress session, did not prevent the development of the enhanced fast feedback when restressed. This can be seen as a sensitization of the inhibitory elements of HPA axis, suggesting that stress-restress paradigm might serve as a good animal model for HPA abnormalities found in PTSD patients.
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After an undisturbed period of 7 or 14 days, rats exposed to SPS show enhanced negative feedback on the hypothalamic-pituitary-adrenal (HPA) axis.
“Exposure to SPS involves three different stress paradigms and, after an undisturbed period of 7 or 14 days, rats show enhanced negative feedback on the hypothalamic-pituitary-adrenal (HPA) axis and an exaggerated acoustic startle response (ASR) (Liberzon et al, 1997;Khan and Liberzon, 2004;Kohda et al, 2007).”
From Cannabinoids prevent the development of behavioral and endocrine alterations in a rat model of intense stress (2012) · cites this paper as Liberzon et al, 1997
After an undisturbed period of 7 or 14 days, rats exposed to SPS show an exaggerated acoustic startle response (ASR).
“Exposure to SPS involves three different stress paradigms and, after an undisturbed period of 7 or 14 days, rats show enhanced negative feedback on the hypothalamic-pituitary-adrenal (HPA) axis and an exaggerated acoustic startle response (ASR) (Liberzon et al, 1997;Khan and Liberzon, 2004;Kohda et al, 2007).”
From Cannabinoids prevent the development of behavioral and endocrine alterations in a rat model of intense stress (2012) · cites this paper as Liberzon et al, 1997
SPS rats show enhanced negative feedback of the HPA axis function in response to glucocorticoid administration.
“Rats subjected to SPS (SPS rats) show enhanced negative feedback of the hypothalamic-pituitary-adrenal (HPA) axis function in response to glucocorticoid administration (Liberzon et al, 1997(Liberzon et al, , 1999)).”
From Effects of Single Prolonged Stress and D-Cycloserine on Contextual Fear Extinction and Hippocampal NMDA Receptor Expression in a Rat Model of PTSD (2008) · cites this paper as Liberzon et al, 1997
Cites
The Neuroendocrinology of Stress and Aging: The Glucocorticoid Cascade Hypothesis
Sapolsky, R. M., Krey, L. C., & McEwen, B. S. (1986) · Science of Aging Knowledge Environment · doi:10.1126/sageke.2002.38.cp21 · Cited by 2,288 · see citing works
Effect of Neonatal Handling on Age-Related Impairments Associated with the Hippocampus
Meaney, M. J., Aitken, D. H., van Berkel, C., Bhatnagar, S., & Sapolsky, R. M. (1988) · Science · doi:10.1126/science.3340858 · Cited by 1,074 · see citing works
Sapolsky, R. M., Krey, L. C., & McEwen, B. S. (1984) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.81.19.6174 · Cited by 758 · see citing works
Elevated CSF corticotropin-releasing factor concentrations in posttraumatic stress disorder
(1997) · American Journal of Psychiatry · doi:10.1176/ajp.154.5.624 · Cited by 721 · see citing works
Selective Retention of Corticosterone by Limbic Structures in Rat Brain
McEwen, B. S., Weiss, J. M., & Schwartz, L. S. (1968) · Nature · doi:10.1038/220911a0 · Cited by 713 · see citing works
Neuroendocrine Regulation in Depression
Carroll, B. J. (1976) · Archives of General Psychiatry · doi:10.1001/archpsyc.1976.01770090041003 · Cited by 638 · see citing works
Cullinan, W. E., Herman, J. P., & Watson, S. J. (1993) · Journal of Comparative Neurology · doi:10.1002/cne.903320102 · Cited by 541 · see citing works
Low Urinary Cortisol Excretion in Patients with Posttraumatic Stress Disorder
Yehuda, R., Southwick, S. M., Nussbaum, G., Wahby, V. S., Giller, E. L., & Mason, J. W. (1990) · The Journal of Nervous and Mental Disease · doi:10.1097/00005053-199006000-00004 · Cited by 528 · see citing works
(1993) · American Journal of Psychiatry · doi:10.1176/ajp.150.1.83 · Cited by 517 · see citing works
Differences in Corticosterone and Dexamethasone Binding to Rat Brain and Pituitary<sup>1</sup>
DE KLOET, R., WALLACH, G., & McEWEN, B. S. (1975) · Endocrinology · doi:10.1210/endo-96-3-598 · Cited by 453 · see citing works
Makino, S., Gold, P. W., & Schulkin, J. (1994) · Brain Research · doi:10.1016/0006-8993(94)91862-7 · Cited by 400 · see citing works
Allostasis, amygdala, and anticipatory angst
Schulkin, J., McEwen, B. S., & Gold, P. W. (1994) · Neuroscience & Biobehavioral Reviews · doi:10.1016/0149-7634(94)90051-5 · Cited by 380 · see citing works
Criteria for rationally evaluating animal models of postraumatic stress disorder
Yehuda, R., & Antelman, S. M. (1993) · Biological Psychiatry · doi:10.1016/0006-3223(93)90001-t · Cited by 301 · see citing works
Loss of Glucocorticoid Fast Feedback in Depression
Young, E. A. (1991) · Archives of General Psychiatry · doi:10.1001/archpsyc.1991.01810320017003 · Cited by 299 · see citing works
Self-citationNeuroendocrine Aspects of Primary Endogenous Depression
Rubín, R. T. (1987) · Archives of General Psychiatry · doi:10.1001/archpsyc.1987.01800160032006 · Cited by 287 · see citing works
The corticotropin-releasing hormone test in patients with posttraumatic stress disorder
Smith, M. A., Davidson, J. R. T., Ritchie, J., Kudler, H. S., Lipper, S., Chappell, P. B., & Nemeroff, C. B. (1989) · Biological Psychiatry · doi:10.1016/0006-3223(89)90050-4 · Cited by 234 · see citing works
van Dijken, H. H., de Goeij, D. C. E., Sutanto, W., Mos, J., de Kloet, E. R., & Tilders, F. J. H. (2008) · Neuroendocrinology · doi:10.1159/000126512 · Cited by 181 · see citing works
van Dijken, H. H., Mos, J., der Heyden, J. A. M. V., & Tilders, F. J. H. (1992) · Physiology & Behavior · doi:10.1016/0031-9384(92)90375-c · Cited by 162 · see citing works
Herman, J. P., Cullinan, W. E., Young, E. A., Akil, H., & Watson, S. J. (1992) · Brain Research · doi:10.1016/0006-8993(92)91680-d · Cited by 138 · see citing works
Self-citationAntelman, S. M. (1988) · Drug Development Research · doi:10.1002/ddr.430140102 · Cited by 137 · see citing works
Decreased Sensitivity to Glucocorticoid Fast Feedback in Chronically Stressed Rats
Young, E. A., Akana, S. F., & Dallman, M. F. (2008) · Neuroendocrinology · doi:10.1159/000125388 · Cited by 130 · see citing works
Self-citationCorticosterone binding to hippocampus: nuclear and cytosol bindingin vitro
McEwen, B. S., & Wallach, G. (1973) · Brain Research · doi:10.1016/0006-8993(73)90143-1 · Cited by 116 · see citing works
Arana, G. W., Workman, R. J., & Baldessarini, R. J. (1984) · American Journal of Psychiatry · doi:10.1176/ajp.141.12.1619 · Cited by 98 · see citing works
Dexamethasone bioavailability: Implications for DST research
Lowy, M. T., & Meltzer, H. Y. (1987) · Biological Psychiatry · doi:10.1016/0006-3223(87)90155-7 · Cited by 83 · see citing works
Negative Feedback Regulation following Administration of Chronic Exogenous Corticosterone
Young, E. A., Kwak, S., & Kottak, J. (1995) · Journal of Neuroendocrinology · doi:10.1111/j.1365-2826.1995.tb00665.x · Cited by 59 · see citing works
Self-citationvan Dijken, H. H., Tilders, F. J. H., Olivier, B., & Mos, J. (1992) · Psychopharmacology · doi:10.1007/bf02247714 · Cited by 56 · see citing works
One stressful event blocks multiple actions of diazepam for up to at least a month
Antelman, S. M., Knopf, S., Kocan, D. J., Edwards, D. J., Ritchie, J. C., & Nemeroff, C. B. (1988) · Brain Research · doi:10.1016/0006-8993(88)91204-8 · Cited by 48 · see citing works
Hypercortisolemia, hippocampal glucocorticoid receptors, and fast feedback.
Young, E. A., & Vázquez, D. M. (1996) · PubMed · Cited by 42 · see citing works
Self-citationReader, S. C. J., Alaghband‐Zadeh, J., Daly, J. R., & Robertson, W. R. (1982) · Journal of Endocrinology · doi:10.1677/joe.0.0920443 · Cited by 38 · see citing works
Anticonvulsant and other effects of diazepam grow with time after a single treatment
Antelman, S. M., Kocan, D. J., Edwards, D. J., et al. (1989) · Pharmacology Biochemistry and Behavior · doi:10.1016/0091-3057(89)90425-5 · Cited by 23 · see citing works
Glucocorticoid Binding Sites in Rat Brain: Subcellular and Anatomical Localizations
McEwen, B. S. (1973) · Progress in brain research · doi:10.1016/s0079-6123(08)64068-6 · Cited by 19 · see citing works
Normal glucocorticoid fast feedback following chronic 50% corticosterone pellet treatment
Young, E. A. (1995) · Psychoneuroendocrinology · doi:10.1016/0306-4530(95)00012-7 · Cited by 11 · see citing works
Self-citation
Flagged first, then by citations
Cited by
Sorted by citations
Heim, C., Newport, D. J., Wagner, D., Wilcox, M. M., Miller, A. H., & Nemeroff, C. B. (2002) · Depression and Anxiety · doi:10.1002/da.10015 · Cited by 433 · see citing works
Neural circuits mediating stress
López, J. F., Akil, H., & Watson, S. J. (1999) · Biological Psychiatry · doi:10.1016/s0006-3223(99)00266-8 · Cited by 373 · see citing works
Liberzon, López, Flagel, Vázquez, & Young (1999) · Journal of Neuroendocrinology · doi:10.1046/j.1365-2826.1999.00288.x · Cited by 308 · see citing works
Behavioral methods to study anxiety in rodents
Lezak, K. R., Missig, G., & Carlezon Jr, W. A. (2017) · Dialogues in Clinical Neuroscience · doi:10.31887/dcns.2017.19.2/wcarlezon · Cited by 290 · see citing works
Sleep and REM sleep disturbance in the pathophysiology of PTSD: the role of extinction memory
Pace-Schott, E. F., Germain, A., & Milad, M. R. (2015) · Biology of Mood & Anxiety Disorders · doi:10.1186/s13587-015-0018-9 · Cited by 255 · see citing works
Kohda, K., Harada, K., Kato, K., Hoshino, A., Motohashi, J., Yamaji, T., Morinobu, S., Matsuoka, N., & Kato, N. (2007) · Neuroscience · doi:10.1016/j.neuroscience.2007.05.041 · Cited by 252 · see citing works
Yamamoto, S., Morinobu, S., Fuchikami, M., Kurata, A., Kozuru, T., & Yamawaki, S. (2008) · Neuropsychopharmacology · doi:10.1038/sj.npp.1301605 · Cited by 224 · see citing works
Topiramate attenuates exaggerated acoustic startle in an animal model of PTSD
Khan, S., & Liberzon, I. (2004) · Psychopharmacology · doi:10.1007/s00213-003-1634-4 · Cited by 192 · see citing works
Self-citationMechanisms of action of antidepressants: from neurotransmitter systems to signaling pathways
Taylor, C., Fricker, A. D., Devi, L. A., & Gomes, I. (2005) · Cellular Signalling · doi:10.1016/j.cellsig.2004.12.007 · Cited by 186 · see citing works
Importance of early environment in the development of post-traumatic stress disorder-like behaviors
Imanaka, A., Morinobu, S., Toki, S., & Yamawaki, S. (2006) · Behavioural Brain Research · doi:10.1016/j.bbr.2006.06.012 · Cited by 154 · see citing works
Neuroimaging of fear-associated learning
Greco, J. A., & Liberzon, I. (2016) · Neuropsychopharmacology · doi:10.1038/npp.2015.255 · Cited by 145 · see citing works
Self-citationEffect of paroxetine on enhanced contextual fear induced by single prolonged stress in rats
Takahashi, T., Morinobu, S., Iwamoto, Y., & Yamawaki, S. (2006) · Psychopharmacology · doi:10.1007/s00213-006-0545-6 · Cited by 138 · see citing works
Noble, L. J., Gonzalez, I. J., Meruva, V. B., Callahan, K. A., Belfort, B. D., Ramanathan, K. R., Meyers, E., Kilgard, M. P., Rennaker, R. L., & McIntyre, C. K. (2017) · Translational Psychiatry · doi:10.1038/tp.2017.191 · Cited by 121 · see citing works
Ganon-Elazar, E., & Akirav, I. (2012) · Neuropsychopharmacology · doi:10.1038/npp.2011.204 · Cited by 120 · see citing works
Thrivikraman, K. V., Nemeroff, C. B., & Plotsky, P. M. (2000) · Brain Research · doi:10.1016/s0006-8993(00)02405-7 · Cited by 105 · see citing works
Epigenetic mechanisms in stress and adaptation
Mifsud, K. R., Gutièrrez-Mecinas, M., Trollope, A. F., Collins, A., Saunderson, E. A., & Reul, J. M. H. M. (2011) · Brain, Behavior, and Immunity · doi:10.1016/j.bbi.2011.06.005 · Cited by 100 · see citing works
Ganon-Elazar, E., & Akirav, I. (2013) · Psychoneuroendocrinology · doi:10.1016/j.psyneuen.2013.01.014 · Cited by 98 · see citing works
Shafia, S., Vafaei, A. A., Samaei, S. A., Bandegi, A. R., Rafiei, A., Valadan, R., Hosseini-Khah, Z., Mohammadkhani, R., & Rashidy-Pour, A. (2017) · Neurobiology of Learning and Memory · doi:10.1016/j.nlm.2017.01.009 · Cited by 89 · see citing works
Lisboa, S. F., Vila-Verde, C., Rosa, J., Uliana, D. L., Stern, C. A. J., Bertoglio, L. J., Resstel, L. B., & Guimaraes, F. S. (2019) · Psychopharmacology · doi:10.1007/s00213-018-5127-x · Cited by 54 · see citing works
Late glucocorticoid receptor antagonism changes the outcome of adult life stress
Ding, J., da Silva, M. S., Lingeman, J., Chen, X., Shi, Y., Han, F., & Meijer, O. C. (2019) · Psychoneuroendocrinology · doi:10.1016/j.psyneuen.2019.05.014 · Cited by 26 · see citing works
Arai, A., Hirota, Y., Miyase, N., Miyata, S., Young, L. J., Osako, Y., Yuri, K., & Mitsui, S. (2016) · Behavioural Brain Research · doi:10.1016/j.bbr.2016.08.022 · Cited by 21 · see citing works
Lim, H.-S., Lee, S. H., Seo, H., Lee, H.-H., Yoon, K., Kim, Y.-U., Park, M.-K., Chung, J. H., Lee, Y.-S., Lee, D. H., et al. (2022) · Biomedicine & Pharmacotherapy · doi:10.1016/j.biopha.2022.113716 · Cited by 10 · see citing works
Chang, S.-H., Chang, Y.-M., Chen, H.-Y., Shaw, F.-Z., & Shyu, B.-C. (2023) · Neurobiology of Stress · doi:10.1016/j.ynstr.2023.100569 · Cited by 5 · see citing works
- Authors
- Liberzon, I., Krstov, M., & Young, E. A.
- Affiliations
- United States Department of Veterans Affairs (US)
- University of Michigan (US)
- Corresponding author
- Liberzon, Israel
- Venue
- Psychoneuroendocrinology
- Publisher
- Elsevier BV
- Published
- 1997-08
- Volume
- 22
- Issue
- 6
- Pages
- 443-453
- ISSN
- 0306-4530 (ISSN-L)
- OpenAlex
- W2039047753
- Cited by
- 556
- References
- 32
- Citations by year
- 2026: 22 · 2025: 35 · 2024: 21 · 2023: 26 · 2022: 28 · 2021: 25 · 2020: 33 · 2019: 40 · 2018: 36 · 2017: 28 · 2016: 35 · 2015: 32 · 2014: 31 · 2013: 27 · 2012: 15
- FWCI
- 1.78
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Psychoneuroendocrinology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (5r29mh045232-05)
- National Institute of Mental Health (MH-00427, MH 45232)
- Topics
- Life Sciences › Neuroscience › Behavioral Neuroscience › Stress Responses and Cortisol
- Social Sciences › Psychology › Clinical Psychology › Posttraumatic Stress Disorder Research
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Adrenal Hormones and Disorders
- Keywords
- post-traumatic stress disorder, glucocorticoid negative feedback, hypothalamic-pituitary-adrenal axis, ACTH, corticosterone, long-term stress, animal model of PTSD
- MeSH terms
- Adrenocorticotropic Hormone, Animals, Corticosterone, Feedback, Hydrocortisone, Hypothalamo-Hypophyseal System, Immunoassay, Male, Restraint, Physical, Stress Disorders, Post-Traumatic, Stress, Psychological, Rats, Sprague-Dawley, Rats
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