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Increased corticotropin-releasing hormone immunoreactivity in monoamine-containing pontine nuclei of depressed suicide men

Molecular Psychiatry volume 8, pages 324–332 (2003)Cite this article

Abstract

A number of clinical investigations and postmortem brain studies have provided evidence that excessive corticotropin-releasing hormone (CRH) secretion and neurotransmission is involved in the pathophysiology of depressive illness, and several studies have suggested that the hyperactivity in CRH neurotransmission extends beyond the hypothalamus involving several extra-hypothalamic brain regions. The present study was designed to test the hypothesis that CRH levels are increased in specific brainstem regions of suicide victims with a diagnosis of major depression. Frozen tissue sections of the pons containing the locus coeruleus and caudal raphe nuclei from 11 matched pairs of depressed suicide and control male subjects were processed for radioimmunocytochemistry using a primary antiserum to CRH and a [125]I-IgG secondary antibody. The optical density corresponding to the level of CRH-immunoreactivity (IR) was quantified in specific pontine regions from the film autoradiographic images. The level of CRH-IR was increased by 30% in the locus coeruleus, 39% in the median raphe and 45% in the caudal dorsal raphe in the depressed suicide subjects compared to controls. No difference in CRH-IR was found in the dorsal tegmentum or medial parabrachial nucleus between the subject groups. These findings reveal that CRH-IR levels are specifically increased in norepinephrine- and serotonin-containing pontine nuclei of depressed suicide men, and thus they are consistent with the hypothesis that CRH neurotransmission is elevated in extra-hypothalamic brain regions of depressed subjects.

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References

  1. Gibbons JL, McHugh PR . Plasma cortisol in depressive illness. J Psychiatr Res 1962; 1: 162–171.

    Article  CAS  Google Scholar 

  2. Carpenter WT, Bunney WE . Adrenal cortical activity in depressive illness. Am J Psychiatry 1971; 128: 31–40.

    Article  Google Scholar 

  3. Sachar EJ, Hellman L, Fukushima DK, Gallagher TF . Cortisol production in depressive illness. A clinical and biochemical clarification. Arch Gen Psychiatry 1970; 23: 289–298.

    Article  CAS  Google Scholar 

  4. Carroll BJ, Curtis GC, Davies BM, Mendels J, Sugerman AA . Urinary free cortisol excretion in depression. Psychol Med 1976; 6: 43–50.

    Article  CAS  Google Scholar 

  5. Linkowski P, Mendlewicz J, LeClercq R, Brasseur M, Hubain P, Goldstein J et al. The 24 hour profile of adrenocorticotropin and cortisol in major depressive illness. J Clin Endocrinol Methods 1985; 61: 429–438.

    Article  CAS  Google Scholar 

  6. Gold PW, Loriaux DL, Roy A, Kling MA, Calabrese JR, Kellner CH et al. Responses to corticotropin-releasing hormone in the hypercortisolism of depression and Cushing's disease. N Engl J Med 1986; 314: 1329–1335.

    Article  CAS  Google Scholar 

  7. Holsboer F, Von Bardeleben U, Gerken A, Stalla GK, Müller OA . Blunted corticotropin and normal cortisol response to human corticotropin-releasing factor in depression. N Engl J Med 1984; 311: 1127.

    CAS  PubMed  Google Scholar 

  8. Kathol RG, Jaeckle RS, Lopez JF, Meller WH . Consistent reduction of ACTH responses to stimulation with CRH, vasopressin and hypoglycaemia in patients with major depression. Br J Psychiatry 1989; 155: 468–478.

    Article  CAS  Google Scholar 

  9. Nemeroff CB, Widerlöv E, Bissette G, Walléus H, Karlsson I, Eklund K et al. Elevated concentrations of CSF corticotropin-releasing factor-like immunoreactivity in depressed patients. Science 1984; 226: 1342–1344.

    Article  CAS  Google Scholar 

  10. Banki CM, Bissette G, Arató M, O'Conner L, Nemeroff CB . CSF corticotropin-releasing factor-like immunoreactivity in depression and schizophrenia. Am J Psychiatry 1987; 144: 873–877.

    Article  CAS  Google Scholar 

  11. Arató M, Banki CM, Bissette G, Nemeroff CB . Elevated CSF CRF in suicide victims. Biol Psychiatry 1989; 25: 355–359.

    Article  Google Scholar 

  12. Raadsheer FC, Hoogendijk WJG, Stam FC, Tilders FJH, Swaab DF . Increased numbers of corticotropin-releasing hormone expressing neurons in the hypothalamic paraventricular nucleus of depressed patients. Neuroendocrinology 1994; 60: 436–444.

    Article  CAS  Google Scholar 

  13. Raadsheer FC, van Heerikhuize JJ, Lucassen PJ, Hoogendijk WJG, Tilders FJH, Swaab DF . Corticotropin-releasing hormone mRNA levels in the paraventricular nucleus of patients with Alzheimer's disease and depression. Am J Psychiatry 1995; 152: 1372–1376.

    Article  CAS  Google Scholar 

  14. Nemeroff CB, Owens MJ, Bissette G, Andorn AC, Stanley M . Reduced corticotropin releasing factor binding sites in the frontal cortex of suicide victims. Arch Gen Psychiatry 1988; 45: 577–579.

    Article  CAS  Google Scholar 

  15. Kling MA, Roy A, Doran AR, Calabrese MR, Rubinow DR, Whitfield HJ et al. Cerebrospinal fluid immunoreactive corticotropin-releasing hormone and adrenocorticotropin secretion in Cushing's disease and major depression: Potential clinical implications. J Clin Endocrinol Methods 1991; 72: 260–271.

    Article  CAS  Google Scholar 

  16. Roy A, Pickar D, Paul SM, Doran A, Chrousos GP, Gold PW . CSF corticotropin-releasing hormone in depressed patients and normal control subjects. Am J Psychiatry 1987; 144: 641–645.

    Article  CAS  Google Scholar 

  17. Pitts AF, Samuelson SD, Meller WH, Bissette G, Nemeroff CB, Kathol RG . Cerebrospinal fluid corticotropin-releasing hormone vasopressin, and oxytocin concentrations in treated patients with major depression and controls. Biol Psychiatry 1995; 38: 330–335.

    Article  CAS  Google Scholar 

  18. Charlton BG, Cheetham SC, Horton RW, Katona CLE, Crompton MR, Ferrier IN . Corticotropin-releasing factor immunoreactivity in post-mortem brain from depressed suicides. J Psychopharmacol 1988; 2: 13–18.

    Article  CAS  Google Scholar 

  19. Leake A, Perry EK, Perry RH, Fairbairn AF, Ferrier IN . Cortical concentrations of corticotropin-releasing hormone and its receptor in Alzheimer type dementia and major depression. Biol Psychiatry 1990; 28: 603–608.

    Article  CAS  Google Scholar 

  20. Hucks D, Lowther S, Crompton MR, Katona CLE, Horton RW . Corticotropin-releasing factor binding sites in cortex of depressed suicides. Psychopharmacology (Berl) 1997; 134: 174–178.

    Article  CAS  Google Scholar 

  21. Valentino RJ, Wehby RG . Corticotropin-releasing factor: evidence for a neurotransmitter role in the locus ceruleus during hemodynamic stress. Neuroendocrinology 1988; 48: 674–677.

    Article  CAS  Google Scholar 

  22. Valentino RJ, Page ME, Curtis AL . Activation of noradrenergic locus coeruleus neurons by hemodynamic stress is due to local release of corticotropin-releasing factor. Brain Res 1991; 555: 25–34.

    Article  CAS  Google Scholar 

  23. Melia KR, Duman RS . Involvement of corticotropin-releasing factor in chronic stress regulation of the brain noradrenergic system. Proc Natl Acad Sci USA 1991; 88: 8382–8386.

    Article  CAS  Google Scholar 

  24. Kirby LG, Rice KC, Valentino RJ . Effects of corticotropin-releasing factor on neuronal activity in the serotonergic dorsal raphe nucleus. Neuropsychopharmacology 2000; 22: 148–162.

    Article  CAS  Google Scholar 

  25. Price ME, Curtis AL, Kirby LG, Valentino RJ, Lucki I . Effects of corticotropin-releasing factor on brain serotonergic activity. Neuropsychopharmacology 1998; 18: 492–502.

    Article  CAS  Google Scholar 

  26. Lowry CA, Rodda JE, Lightman SL, Ingram CD . Corticotropin-releasing factor increases in vitro firing rates of serotonergic neurons in the rat dorsal raphe nucleus: evidence for activation of a topographically organized mesolimbocortical serotonergic system. J Neurosci 2000; 20: 7728–7736.

    Article  CAS  Google Scholar 

  27. Ordway GA, Streator Smith K, Haycock JW . Elevated tyrosine hydroxylase in the locus coeruleus of suicide victims. J Neurochem 1994; 62: 680–685.

    Article  CAS  Google Scholar 

  28. Klimek V, Stockmeier CA, Overholser J, Meltzer HY, Kalka S, Dilley G et al. Reduced levels of norepinephrine transporters in the locus coeruleus in major depression. J Neurosci 1997; 17: 8451–8458.

    Article  CAS  Google Scholar 

  29. Wong ML, Kling MA, Munson PJ, Listwak S, Licinio J, Prolo P et al. Pronounced and sustained central hypernoradrenergic function in major depression with melancholic features: relation to hypercortisolism and corticotropin-releasing hormone. Proc Natl Acad Sci USA 2000; 97: 325–330.

    Article  CAS  Google Scholar 

  30. Stockmeier CA, Shapiro LA, Dilley GE, Kolli TN, Friedman L, Rajkowska G . Increase in serotonin-1A autoreceptors in the midbrain of suicide victims with major depression—postmortem evidence for decreased serotonin activity. J Neurosci 1998; 18: 7394–7401.

    Article  CAS  Google Scholar 

  31. Drevets WC, Frank E, Price JC, Kupfer DJ, Holt D, Greer PJ et al. PET imaging of serotonin 1A receptor binding in depression. Biol Psychiatry 1999; 46: 1375–1387.

    Article  CAS  Google Scholar 

  32. Arango V, Underwood MD, Boldrini M, Tamir H, Kassir SA, Hsiung SC et al. Serotonin 1A receptors, serotonin transporter binding and serotonin transporter mRNA expression in the brainstem of depressed suicide victims. Neuropsychopharmacology 2001; 25: 892–903.

    Article  CAS  Google Scholar 

  33. Austin MC, Rhodes JL, Lewis DA . Differential distribution of corticotropin-releasing hormone immunoreactive axons in monoaminergic nuclei of the human brainstem. Neuropsychopharmacology 1997; 17: 326–341.

    Article  CAS  Google Scholar 

  34. Ruggiero DA, Underwood MD, Rice PM, Mann JJ, Arango V . Corticotropin-releasing hormone and serotonin interact in the human brainstem: behavioral implications. Neuroscience 1999; 91: 1343–1354.

    Article  CAS  Google Scholar 

  35. Ng MC, Iacopino AM . Quantitative measurement of neuronal calbindin-D28K by radioimmunocytochemistry. Mol Brain Res 1995; 32: 82–86.

    Article  CAS  Google Scholar 

  36. Mitchell AJ . The role of corticotropin-releasing factor in depressive illness: a critical review. Neurosci Biobehav Rev 1998; 22: 635–651.

    Article  CAS  Google Scholar 

  37. Berrettini WH, Nurnberger JI, Zerbe RL, Gold PW, Chrousos GP, Tomai T . CSF neuropeptides in euthymic bipolar patients and controls. Br J Psychiatry 1987; 150: 208–212.

    Article  CAS  Google Scholar 

  38. Banki CM, Karmacsi L, Bissette G, Nemeroff CB . CSF corticotropin-releasing hormone and somatostatin in major depression: response to antidepressant treatment and relapse. Eur Neuropsychopharmacol 1992; 2: 107–113.

    Article  CAS  Google Scholar 

  39. De Bellis MD, Gold PW, Geracioti TD, Listwak SJ, Kling MA . Association of fluoxetine treatment with reductions in CSF concentration of corticotropin-releasing hormone and arginine vasopressin in patients with major depression. Am J Psychiatry 1993; 150: 656–657.

    Article  CAS  Google Scholar 

  40. Heuser I, Bissette G, Dettling M, Schweiger U, Gotthardt U, Schmider J et al. Cerebrospinal fluid concentrations of corticotropin-releasing hormone, vasopressin, and somatostatin in depressed patients and healthy controls: response to amitriptyline treatment. Depress Anxiety 1998; 8: 71–79.

    Article  CAS  Google Scholar 

  41. Price JL, Amaral DG . An autoradiographic study of the projections of the central nucleus of the monkey amygdala. J Neurosci 1981; 1: 1242–1259.

    Article  CAS  Google Scholar 

  42. Veazey RB, Amaral DG, Cowan WM . The morphology and connections of the posterior hypothalamus in the cynomolgus monkey (Macaca fascicularis). II. Efferent connections. J Comp Neurol 1982; 207: 135–156.

    Article  CAS  Google Scholar 

  43. Arnsten AFT, Goldman-Rakic PS . Selective prefrontal cortical projections to the region of the locus coeruleus and raphe nuclei in the rhesus monkey. Brain Res 1984; 306: 9–18.

    Article  CAS  Google Scholar 

  44. An X, Bandler R, Ongur D, Price JL . Prefrontal cortical projections to longitudinal columns in the midbrain periaqueductal gray in macaque monkeys. J Comp Neurol 1998; 401: 455–479.

    Article  CAS  Google Scholar 

  45. Freedman LJ, Insel TR, Smith Y . Subcortical projections of area 25 (subgenual cortex) of the macaque monkey. J Comp Neurol 2000; 421: 172–188.

    Article  CAS  Google Scholar 

  46. Chiba T, Kayahara T, Nakano K . Efferent projections of infralimbic and prelimbic areas of the medial prefrontal cortex in the Japanese monkey Macaca fuscata. Brain Res 2001; 888: 83–101.

    Article  CAS  Google Scholar 

  47. Paull WK, Phelix CF, Copeland M, Palmiter P, Gibbs FP, Middleton C . Immunohistochemical localization of corticotropin-releasing factor (CRF) in the hypothalamus of the squirrel monkey, Saimiri sciureus. Peptides 1984; 5: 45–51.

    Article  CAS  Google Scholar 

  48. Lewis DA, Foote SL, Cha CI . Corticotropin-releasing factor immunoreactivity in monkey neocortex: an immunohistochemical analysis. J Comp Neurol 1989; 290: 599–613.

    Article  CAS  Google Scholar 

  49. Bassett JL, Foote SL . Distribution of corticotropin-releasing factor-like immunoreactivity in squirrel monkey (Saimiri sciureus) amygdala. J Comp Neurol 1992; 323: 91–102.

    Article  CAS  Google Scholar 

  50. Smagin GN, Swiergiel AH, Dunn AJ . Corticotropin-releasing factor administered into the locus coeruleus, but not the parabrachial nucleus, stimulates norepinephrine release in the prefrontal cortex. Brain Res Bull 1995; 36: 71–76.

    Article  CAS  Google Scholar 

  51. Finlay JM, Jedema HP, Rabinovic AD, Mana MJ, Zigmond MJ, Sved AF . Impact of corticotropin-releasing hormone on extracellular norepinephrine in prefrontal cortex after chronic cold stress. J Neurochem 1997; 69: 144–150.

    Article  CAS  Google Scholar 

  52. Page ME, Abercrombie ED . Discrete local application of corticotropin-releasing factor increases locus coeruleus discharge and extracellular norepinephrine in rat hippocampus. Synapse 1999; 33: 304–313.

    Article  CAS  Google Scholar 

  53. Jedema HP, Finlay JM, Sved AF, Grace AA . Chronic cold exposure potentiates CRH-evoked increases in electrophysiologic activity of locus coeruleus neurons. Biol Psychiatry 2001; 49: 351–359.

    Article  CAS  Google Scholar 

  54. Chappell PB, Smith MA, Kilts CD, Bissette G, Ritchie J, Nemeroff CB . Alterations in corticotropin-releasing factor-like immunoreactivity in discrete rat brain regions after acute and chronic stress. J Neurosci 1986; 6: 2908–2914.

    Article  CAS  Google Scholar 

  55. Zobel AW, Nickel T, Künzel HE, Ackl N, Sonntag A, Ising M et al. Effects of the high-affinity corticotropin-releasing hormone receptor 1 antagonist R121919 in major depression: the first 20 patients treated. J Psychiatr Res 2000; 34: 171–181.

    Article  CAS  Google Scholar 

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Acknowledgements

This work was supported by USPHS Grants MH57011 and MH45156. The authors thank Drs Gretchen Haas, Carol Sue Johnston, Cameron Carter and Matcheri Keshavan for their participation in the diagnostic conferences.

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Authors and Affiliations

  1. Department of Psychiatry, University of Pittsburgh, School of Medicine, Pittsburgh, 15213, PA, USA

    M C Austin & H A Murphy

  2. Department of Family Medicine and Clinical Epidemiology, University of Pittsburgh, School of Medicine, Pittsburgh, 15213, PA, USA

    J E Janosky

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Correspondence to M C Austin.

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Austin, M., Janosky, J. & Murphy, H. Increased corticotropin-releasing hormone immunoreactivity in monoamine-containing pontine nuclei of depressed suicide men. Mol Psychiatry 8, 324–332 (2003). https://doi.org/10.1038/sj.mp.4001250

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