Corticotropin-releasing factor (CRF), a 41 amino acid-containing neuropeptide, acts both as a hypothalamic releasing factor, controlling ACTH and corticosteroid secretion, and at extrahypothalamic CNS sites to mod ulate mammalian organisms' responses to stress. In this article, the evidence that CRF-containing neurons within the CNS are hyperactive in patients with depression is reviewed. The evidence, taken together, suggests that during depressive episodes, CRF is hypersecreted, resulting in both pituitary-adrenal axis hyperactivity and certain of the signs and symptoms of depression, including decreased appetite, decreased libido and disturbed sleep. There is also evidence that treatments for depression, including antidepressant medications and electroconvulsive therapy, reduce CRF hypersecretion within the CNS. Finally, evidence suggests that alterations in CRF-containing neurons and receptors are responsible for the widely held ob servation that early untoward life events increase an individual's vulnerability for affective disorders. These findings have a number of implications for treatment of the mood disorders, including the suggestion that the pharmacological manipulation of CRF receptors may provide a novel avenue for the treatment of de pression. NEUROSCIENTIST 3:186-194, 1997
Chalmers DT, Lovenberg TW, Grigonadis DE, Behan DP, DeSouza EB. Corticotrophin-releasing factor receptors: from molecular biology to drug design. Trends Pharmacol Sci1996;17:166-172.
2.
Vale W., Speiss J., Rivier C., Rivier J.Characterization of a 41-residue ovine hypothalamic peptide that stimulates secretion of corticotropin and beta-endorphin. Science1981;213:1394-1397.
3.
Owens MJ, Nemeroff CBPhysiology and pharmacology of corticotropin-releasing factor. Pharmacol Rev1991;43:425-473.
4.
Swanson LW, Sawchenko PE, Rivier J., et al. Organization of ovine corticotropin-releasing factor immunoreactive cells and fibers in the rat brain: an immunohistochemical study. Neuroendocnnology1983;36:165-186.
5.
Lightman SL, Harbuz MS, Knight RA, Chowdrey HSCRF mRNA m normal and stress conditions. Ann N Y Acad Sci1993; 697:142-154.
6.
Sawchenko PE , Arias CA, Mortrud MTLocal tetrodotoxin blocks chronic stress effects on corticotropin-releasing factor and vasopressm messenger ribonucleic acids in hypophysiotropic neurons. J Neuroendocnnol1993;5:341-348.
7.
Plotsky PM, Thnvikraman KV, Meaney MJCentral and feedback regulation of hypothalamic corticotropm-releasing factor secretion. In: Chadwick DJ, Marsh J, Ackrill K, editors. Ciba Foundation symposium on corticotropin-releasmg factor . London: Wiley1993;59-84.
8.
Gray TSLimbic pathways and neurotransmitters as mediators of autonomic and neuroendocrine responses to stress. In: Brown MR, Koob GF, Rivier C, editors. Stress: neurobiology and neuroendocrinology. New York: Dekker1991;73-89.
9.
Imaki T., Vale W.Chlordiazepoxide attenuates stress-induced accumulation of corticotropin-releasing factor mRNA in the paraventricular nucleus. Brain Res1993;623:223-228.
10.
Nappi RE, Rivest S.Ovulatory cycle influences the stimulatory effect of stress on the expression of corticotropm-releasmg factor receptor messenger nbonucleic acid in the paraventricular nucleus of the female rat hypothalamus. Endocrinology1995;136:4073-4083.
11.
Valentino RJ , Foote SL, Page METhe locus coeruleus as a site for integrating corticotropin-releasing factor and noradrenergic mediation of stress responses . Ann N Y Acad Sci1993; 697:173-188.
12.
Curtis AL, Pavcovich LA, Grigonadis DE, Valentino RJPrevious stress alters corticotropin-releasing factor neurotransmission in the locus coeruleus. Neuroscience1995;65:541-550.
13.
Koob GF, Hemnchs SC, Pich EM, et al. The role of corticotropm-releasmg factor in behavioural responses to stress. In: Chadwick DJ, Marsh J, Ackrill K, editors. Ciba Foundation symposium on corticotropin-releasing factor . London: Wiley1993;277-295.
14.
Weiss JM, Stout J., Aaron M., et al. Experimental studies of depression and anxiety: role of locus coeruleus and corticotropin-releasmg factor. Brain Res Bull1994;35:561-572.
15.
Borosody MK , Weiss JMInfluence of corticotropin-releasing hormone on electrophysiological activity of locus coeruleus neurons. Brain Res1996;724:149-168.
16.
Chappell PB , Smith MA, Kilts CD, et al. Alterations in CRF-like immunoreactivity in discrete rat brain regions after acute and chronic stress. J Neurosci1986;6:2908-2914.
17.
Butler PD, Weiss JM, Stout JC, et al. Corticotropin-releasing factor produces fear-enhancing and behavioral activating effects followmg infusion into the locus coeruleus. J Neurosci1990;10:176-183.
18.
Menzaghi F. , Heinrichs SC, Pich EM, Weiss F., Koob GFThe role of limbic and hypothalamic corticotropin-releasing factor in behavioral responses to stress. Ann N Y Acad Sci1993;697:142-154.
19.
Wiersma AD, Baaun AD, Bohus B., Koolhaas JMBehavioural activation produced by CRH but not alpha-helical CRH when microinfused into the central nucleus of the amygdala under stress-free conditions . Psychoneuroendocnnology1995;20:423-432.
20.
Swiergial AH , Takahashi LK, Kalin NHAttenuation of stress-mduced behavior by antagonism of corticotropin-releasing factor receptors in the central nucleus of the amygdala in the rat. Brain Res1993;623:229-234.
21.
Wiersma A., Bohus B., Koolhaas JMCorticotropm-releasmg hormone microinfusion in the central amygdala diminishes a cardiac parasympathetic outflow under stress-free conditions . Brain Res1993;625:219-227.
22.
Kalin NH, Takahashi LK, Chen FLRestraint stress increases corticotropin-releasing hormone mRNA content in the amygdala and paraventricular nucleus. Brain Res1994;656:182-186.
23.
Boadle-Biber MC, Singh VB, Corley KC, Phan TH, Dilts RPEvidence that corticotropin-releasing factor within the extended amygdala mediates the activation of tryptophan hydroxylase produced by sound stress in the rat. Brain Res1993;628:105-114.
24.
de Goeij Dce , Jezova D., Tilders Fjh.Repeated stress enhances vasopressm synthesis m corticotropin releasing factor neurons in the paraventricular nucleus. Brain Res1992;577:165-168.
Irwin M.Stress-induced immune suppression. Ann N Y Acad Sci1993;697:203-217.
27.
Kalin NHBehavioral and endocnne studies of CRH in primates. In: DeSouza EB, Nemeroff CB, editors. CRF: basic and chemical studies of a neuropeptide. Boca Raton, FL: CRC Press1990;275-289.
28.
Vaughan J., Donaldson C., Bittencourt J., et al. Urocortm, a mammalian neuropeptide related to fish urotensin I and to corticotropm-releasing factor. Nature1995;378:287-292.
29.
Imaki T., Wang XQ, Tamotsu S., et al. Stress-induced activation of neuronal activity and corticotropin-releasing factor gene expression in the paraventricular nucleus is modulated by glucocorticoids in rats. J Clin Invest1995;96:231-238.
30.
Young EA, Akana S., Dullman MFDecreased sensitivity to glucocorticoid fast feedback in chronically stressed rats. Neuroendocrinology1990;51:536-542.
Hauger RL, Millan MA, Catt KJ, Aguilera G.Differential regulation of brain and pituitary corticotropin-releasing factor receptors by corticosterone. Endocrinology1987;120:1527-1533.
33.
Luo X., Kiss A., Makara G., Lolait SJ, Aguilera G.Stress-specific regulation of corticotropin releasing hormone receptor expression in the paraventricular and supraoptic nuclei of the hypothalamus in the rat . J Neuroendocnnol1994;6:689-696.
34.
Rivest S., Laflamme N., Nappi REImmune challenge and immobilization stress induce transcription of the gene encoding the CRF receptor in selective nuclei of the rat hypothalamus . J Neurosci1995;15:2680-2695.
35.
Martins JM, Kastin AJ, Banks WAUnidirectional specific and modulated brain to blood transport of corticotropin-releasing hormone. Neuroendocnnol1996;63:338-348.
36.
Schatzberg AF , Nemeroff CBTextbook of psychopharmacology . Washington DC: American Psychiatric Press1995.
37.
Raadsheer FC , van Heerikhuize JJ, Lucassen PJ, et al. Corticotropin-releasing hormone mRNA levels in the paraventricular nucleus of patients with Alzheimer's disease and depression. Am J Psychiat1995 ;152:1372-1376.
38.
De Bellis MD , Gold PW, Gerarioti TD et al. Fluoxetine significantly reduces cerebrospinal fluid corticotropin-releasing factor and arginine vasopressin concentrations in patients with major depression. Am J Psychiatry1993;150:656-657.
39.
Nemeroff CB , Bissette G., Akil H., et al. Neuropeptide concentrations in the cerebrospmal fluid of depressed patients treated with electroconvulsive therapy: corticotropin-releasing factor, beta-endorphm and somatostatm. Brit J Psychiatry1991;158:59-63.
40.
Veith RC, Lewis N., Langohr JI, et al. Effect of desipramine on cerebropsmal fluid concentrations of corticotropin-releasing factor in human subjects. Psychiatry Res1992;46:1-8.
41.
Holsboer F. , Barden N.Antidepressants and hypothalamic-pituitary-adrenocortical regulation. Endocr Rev1996;17:187-205.
Stedman's Medical Dictionary. Baltimore: Williams & Wilkins. 1982.
44.
Chrousos GP, Gold PWThe concepts of stress and stress systems disorders. JAMA1992;267:1244-1252.
45.
Gold PW, Goodwm FK, Chrousos GPClinical and biochemical manifestations of depression. Relation to the neurobiology of stress. N Engl J Med1988 ;319:413-420.
46.
Heuser Ije, Holsboer F.The CRH-stimulation test in affective and anxiety disorder: comparison to physical stress. Clin Neuropharmacol1992 ;15(Suppl 1):159A-160A.
47.
Paykel E.Causal relationships between clinical depression and life events. In: Barrett JE, editor. Stress and mental disorder. New York: Raven Press1979.
48.
Breslau N., Davis GCChronic stress and major depression. Arch Gen Psychiatry1986;43:309-314.
49.
Kendler KS, Kessler RC, Neale MC, et al. The prediction of major depression in women: toward an integrated etiologic model. Am J Psychiatry1993;150:1139-1148.
50.
Brown GWThe social etiology of depression: London studies. In: Depue RA, editor. The psychobiology of the depressive disorders : implications for the effects of stress. New York: Academic Press1979;263-290.
51.
Nemeroff CB , Owens MJ, Owens CA, Ehlers C., Robbms T., Levine S.The neurobiological consequences of early traumatic experience : focus on corticotropin-releasing factor. Eur Neuropsychopharmacol1994;4:514-516.
52.
Ladd CO, Owens, MJ, Nemeroff CBPersistent changes in corticotropin-releasing factor neuronal systems induced by maternal deprivation. Endocrinology1996 ;137:1212-1218.
53.
Coplan JD, Andrews MW, Rosenblum LA, et al. Persistent elevations of cerebrospmal fluid concentrations of corticotropin-releasing factor in adult nonhuman primates exposed to early-life stressors: Implications for the pathophysiology of mood and anxiety disorders . Proc Natl Acad Sci U S A1996; 93:1619-1623.
54.
Cratty MS, Ward HE, Johnson EA, Azzaro AJ, Birkle DLPrenatal stress increases corticotropm-releasing factor (CRF) content and release in rat amygdala minces. Brain Res1995;675: 297-302.
