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The HPA and immune axes in stress: the involvement of the serotonergic system

Published online by Cambridge University Press:  16 April 2020

B.E. Leonard
B.E. Leonard*
Affiliation:
Pharmacology Department, National University of Ireland, Galway, Ireland Brain and Behaviour Institute, University of Maastricht, Maastricht, The Netherlands
*
E-mail address: belucg@iol.ie (B.E. Leonard)
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Abstract

The impact of acute and chronic stress on the hypothalamic-pituitary-adrenal (HPA) axis is reviewed and evidence presented that corticotrophin releasing factor (CRF) is the stress neurotransmitter which plays an important role in the activation of the central sympathetic and serotonergic systems. The activity of CRF is expressed through specific receptors (CRF 1 and 2) that are antagonistic in their actions and widely distributed in the limbic regions of the brain, as well as in the hypothalamus, and on immune cells.

The mechanism whereby chronic stress, via the CRF induced activation of the dorsal raphe nucleus, can induce a change in the serotonergic system, involves an increase in the 5HT2A and a decrease in the 5HT1A receptor mediated function. Such changes contribute to the onset of anxiety and depression. In addition, the hypersecretion of glucocorticoids that is associated with chronic stress and depression desensitises the central glucocorticoid receptors to the negative feedback inhibition of the HPA axis. This indirectly results in the further activation of the HPA axis.

The rise in pro-inflammatory cytokines that usually accompanies the chronic stress response results in a further stimulation of the HPA axis thereby adding to the stress response. While CRF would appear to play a pivotal role, evidence is provided that simultaneous changes in the serotonergic and noradrenergic systems, combined with the activation of peripheral and central macrophages that increase the pro-inflammatory cytokine concentrations in the brain and blood, also play a critical role in predisposing to anxiety and depression. Neurodegenerative changes in the brain that frequently occur in the elderly patient with major depression, could result from the activation of indoleaminedioxygenase (IDO), a widely distributed enzyme that converts tryptophan via the kynenine pathway to for the neurotoxic end product quinolinic acid.

Keywords

HPA axisCorticosteroidsPro-inflammatory cytokinesSerotoninNoradrenalineKynurenine pathwayNeurodegeneration

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Type
Research Article
Information
European Psychiatry , Volume 20 , Issue S3 , October 2005 , pp. S302 - S306
Copyright
Copyright © Elsevier SAS 2005

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References

Aber, N., Berliner, S., Tamir, A.The State of leucocyte adhesiveness/aggregation in the peripheral blood: a new and independent marker of mental stress. Stress Med 1991; 7: 75–78CrossRefGoogle Scholar
Arborelius, L., Owens, M.J., Plotsky, P.M., Nemeroff, C.B.The role of CRF in depression and anxiety disorders. J Endocrinol 1999; 160: 1–12CrossRefGoogle ScholarPubMed
Coplan, J.D., Andrews, M.W., Rosenblum, L.A.Persistent elevations of CSF concentrations of CRF in adult non human primates exposed to early life stressors: implications for pathophysiology ofmood and anxiety disorders. Proc Nat Acad Sci USA 1996; 93:1619–1623CrossRefGoogle Scholar
Dallman, M.F., Jones, M.T.Corticosteroid feedback of ACTH secretion on subsequent stress responses in the rat. Endocrinol 1973; 92: 1367–1375CrossRefGoogle ScholarPubMed
Dinan, T.G.Glucocorticoids and the genesis of depressive illness: a psychobiological model. Brit J Psychiat 1994; 164: 365–371CrossRefGoogle ScholarPubMed
Dinan, T.G., Lavelle, E., Scott, L.V.Desmopressin normalises the blunted ACTH response to CRF in melancholic depression: evidence of enhanced vasopressinergic responsivity. J Clin Endocrinol Metab 1999; 84: 2238–2246CrossRefGoogle Scholar
Dunn, A.The role of IL-1 and TNF alpha in the neurochemical and neuroendocrine responses to endotoxin. Brain Res Bull 1992; 29: 807–872CrossRefGoogle ScholarPubMed
Graeff, F.G., Silveira, M.C., Nogueira, R.L.Role of amygdale and periaqueductal gray in anxiety and depression. Behav Brain Res 1993; 58: 123–131CrossRefGoogle Scholar
Gray, T.S.Amygdaloid CRF pathways: role in autonomic, neuroendocrine and behavioural responses to stress. Ann NY Acad Sci 1993; 697: 53–60CrossRefGoogle ScholarPubMed
Gutman, D.A., Owens, M.J., Nemeroff, C.B.CRF receptor and glucocorticoid receptor antagonists: new approaches to antidepressant treatment. In: den Boer, J.A., George, M.S., ter Horst, G.T. editors. Current and future developments in psychopharmacology Amsterdam: Pub. Benecke NI; 2005.pp. 133–158Google Scholar
Habib, K.E., Weld, K.P., Rice, K.C.Oral administration of CRF receptor antagonists significantly attenuates behavioural, neuroendocrine and autonomic responses to stress in primates. Proc Nat Acad Sci USA 2000; 97:6070–6084CrossRefGoogle ScholarPubMed
Heilig, M., Koob, G.F., Ekman, R.CRF and NPY: role in emotional integration. Trends Pharmacol Sci 1994; 17: 80–85Google ScholarPubMed
Inoue, T., Tsuchiya, K., Koyama, T.Regional changes in dopamine and 5-hydroxytryptamine activation with various intensity of physical and psychological stress in rat brain. Pharmacol Biochem Behav 1994; 49: 911–920CrossRefGoogle ScholarPubMed
Irwin, M., Hauger, R.L., Jones, L.Sympathetic nervous system mediates central CRF induced suppression of natural killer cell cytotoxicity. J Pharmacol Exp Ther 1991; 255: 101–107Google Scholar
Irwin, M., Smith, T.L., Gillin, J.C.Low natural killer cytotoxicity in major depression. Life Sci 1987; 41: 2127–2133CrossRefGoogle ScholarPubMed
Kant, G.J., Leu, J.R., Anderson, S.M.Effects of chronic stress on plasma corticosterone, ACTH and prolactin. Physiol Behav 1987; 40: 775–779CrossRefGoogle ScholarPubMed
Kishimoto, T., Radulovic, J., Radulovic, M.Deletion of CRF 2 receptor reveals an anxiolytic role for CRF 2 receptor. Nature Genet 2000; 24: 415–419CrossRefGoogle Scholar
Leonard, B.E.Brain cytokines and the psychopathology of depression. In: Leonard, B.E. editor. Antidepressants. Basel: Birkhaeuser; 2001. pp. 109–120.CrossRefGoogle ScholarPubMed
Levine, S., Wiener, S.G., Coe, C.L.Temporal and social factors influencing behavioural and hormonal responses to separation of mother and infant squirrel monkeys. Psychoneuroendocrinol 1993; 18: 297–306CrossRefGoogle ScholarPubMed
Lesch, K.P.5HT1A receptor responsivity in anxiety disorders and depression. Prog Neuropsychopharmacol Biol Psychiat 1991; 15: 723–733CrossRefGoogle Scholar
Lin, D., Diorio, J., Tannenbaum, B.Maternal care, hippocampal glucocortcoid receptors and HPA responses to stress. Science 1997; 277: 1654–1662Google Scholar
Lopez, J.F., Chalmers, D.L., Little, K.Y.Regulation of serotonin IA, glueocorticoid and mineralocorticoid receptors in the rat and human hippocampus: implications for neurobiology of depression. Biol Psychiat 1998; 43: 547–573CrossRefGoogle Scholar
Maes, M., Smith, R., Scharpe, S.The monocyte-T-lymphocyte hypothesis of major depression. Psychoneuroendocrinol 1995; 20: 111–116CrossRefGoogle ScholarPubMed
Meaney, M.J., Airken, D.H., van Berkel, C.Effect of neonatal handling on age-related impairments associated with the hippocampus. Science 1988; 239: 766–768CrossRefGoogle ScholarPubMed
Myint, A.M., Kim, Y.-K.Cytokine-serotonin system interaction through IDO: a neurodegeneration hypothesis of depression. Med Hypothesis 2003; 61: 519–525CrossRefGoogle ScholarPubMed
Plotsky, P.M., Meaney, M.J.Early postnatal experience alters hypothalamic CRF mRNA mediated content and stress induced release in adult rats. Mol Brain Res 1993; 18: 195–200CrossRefGoogle Scholar
Post, R.M., Gold, P., Rubinow, D.R.Peptides in the CSF of neuropsychiatric patients: an approach to CNS peptide function. Life Sci 1982; 31: 1–15CrossRefGoogle ScholarPubMed
Ramboz, S., Ossting, R., Amara, D.A.Serotonin receptor 1A knock-out: an animal model of anxiety related disorder. Proc Nat Acad Sci USA 1998;95:14476–14481CrossRefGoogle Scholar
Sapolsky, R.M., Plotsky, P.M.Hypercortisolism and its possible neural bases. Biol Psychiat 1980; 27: 937–952CrossRefGoogle Scholar
Schaefer, M., Moussa, S.A., Stein, C.CRF in antinociception and inflammation. Eur J Pharmacol 1997; 323: 1–10CrossRefGoogle Scholar
Smith, G.W., Aubry, J.M., Dellu, F.CRF1 receptor deficient mice display decreased anxiety, impaired stress response and aberrant neuroendocrine development. Neuron 1998; 20: 1093–1102CrossRefGoogle Scholar
Song, C., Earley, B., Leonard, B.E.Behavioural, neurochemical and immunological responses to CRF administration. Ann NY Acad Sci 1995; 771: 55–72CrossRefGoogle ScholarPubMed
Stanton, M.E., Gutierrez, Y.R., Levine, S.Maternal deprivation potentiates pituitary-adrenal stress response in infant rats. Behav Neurosci 1988; 10: 69–70Google Scholar
Vaughan, J., Donaldson, C., Bittencourt, J.Urocortin, a mammalian neuropeptide related to fish urotensin I and to CRF. Nature 1995; 378: 287–292CrossRefGoogle Scholar
Watanabe, Y., Sakai, R.R., McEwan, B.S.Stress and antidepressant effects on hippocampal and cortical 5HTIA and 5HT2A receptors and transport sites for serotonin. Brain Res 1993; 615: 87–94CrossRefGoogle Scholar
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