ACTH, cortisol, and corticosterone output after ovine corticotropin-releasing factor challenge during depression and after recovery

Holsboer, Florian; Gerken, A.; Stalla, G. K.; Müller, Otto

doi:10.1016/0006-3223(85)90057-5

Cited by 91 publications

(23 citation statements)

References 31 publications

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“…Dysregulation of the hypothalamic-pituitary-adrenocortical (HPA) axis is the most consistent biochemical change observed in patients suffering from major depression (Holsboer et al, 1985;Linkowski et al, 1985). High incidence of depression in Cushing's syndrome and antidepressant action of cortisol synthesis inhibitors and an antagonist of corticotropin-releasing hormone (CRH) receptors (Jeffcoate et al, 1979;Murphy 1997;O'Brien et al, 2001;Zobel et al, 2000) support the hypothesis that the hyperactivity of HPA is involved in the pathogenesis of this disorder.…”

Section: Introductionmentioning

confidence: 99%

Regulation of the Human Corticotropin-Releasing-Hormone Gene Promoter Activity by Antidepressant Drugs in Neuro-2A and AtT-20 Cells

Budziszewska

Jaworska-Feil

Tetich

et al. 2004

Neuropsychopharmacol

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Major depression is frequently associated with hyperactivity of the hypothalamic-pituitary-adrenal (HPA) axis. Clinically effective therapy with antidepressant drugs normalizes the disturbed activity of HPA axis, in part, by decreasing corticotropin-releasing hormone (CRH) synthesis, but the mechanism of this action is poorly recognized. In order to find out whether antidepressants directly affect CRH gene promoter activity, we studied their effect on undifferentiated and differentiated Neuro-2A cells, and for comparison the effect of the selected antidepressants on AtT-20 cells was also determined. The cells were stably transfected with a human CRH promoter fragment (À663 to þ 124 bp) linked to the chloramphenicol acetyltransferase (CAT) reporter gene. The regulation of CRH gene promoter activity is similar in Neuro-2A cells, both intact and differentiated, and in AtT-20 cell line, and cAMP/PKA-dependent pathway plays an important role in the stimulation of CRH gene. It was found that imipramine, amitryptyline, desipramine, fluoxetine, and mianserin, present in the culture medium for 5 days, in a concentration-dependent manner inhibited basal hCRH gene promoter activity in undifferentiated Neuro-2A cells, while other drugs under study (citalopram, tianeptine, moclobemide, venlafaxine, reboxetine, mirtazapine, and milnacipram) were inactive. In the differentiated cells, all examined antidepressants, except moclobemide (no effect) and tianeptine (increase), inhibited hCRH gene transcription. Moreover, in differentiated cells, the drugs acted stronger and were effective at lower concentrations. Forskolin-induced CAT activity was attenuated by imipramine and fluoxetine and to a lesser degree by amitriptyline and desipramine in differentiated cells, whereas other drugs were inactive. Moreover, imipramine and fluoxetine, but not tianeptine, showed moderate inhibitory effect on CRH gene promoter activity also in AtT-20 cell line, commonly used in CRH gene regulation studies. These results indicate that neuron-like differentiated Neuro-2A cells are a better model than pituitary and intact neuroblastoma to investigate the mechanism of psychotropic drug action. Inhibition of CRH gene promoter activity by antidepressant drugs may be a molecular mechanism by which these drugs inhibit the activity of HPA axis.

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Section: Introductionmentioning

confidence: 99%

Regulation of the Human Corticotropin-Releasing-Hormone Gene Promoter Activity by Antidepressant Drugs in Neuro-2A and AtT-20 Cells

Budziszewska

Jaworska-Feil

Tetich

et al. 2004

Neuropsychopharmacol

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“…The long delay may reflect long-term central nervous system biological adaptations occurring during the daily administrations. A common biological alteration in patients with major depression is the activation of the hypothalamicpituitary-adrenal (HPA) axis, manifested as hypersecretion of adrenocorticotropic hormone (ACTH) and cortisol and an abnormal cortisol response to dexamethasone and corticotropin-releasing hormone (CRH) administration (Gold et al, 1988;Holsboer and Barden, 1996;Holsboer et al, 1985;Raadsher et al, 1994). Correspondingly, the hyperactivity of the HPA axis in depressed patients was corrected during clinically effective therapy with antidepressant drugs (Barden et al, 1995;Holsboer et al, 1985).…”

Section: Introductionmentioning

confidence: 99%

Hyperforin-Containing Extracts of St John's Wort Fail to Alter Gene Transcription in Brain Areas Involved in HPA Axis Control in a Long-Term Treatment Regimen in Rats

Butterweck

Winterhoff²,

Herkenham

2003

Neuropsychopharmacol

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We previously showed that a methanolic extract of St John's wort (SJW) (Hypericum) and hypericin, one of its active constituents, both have delayed regulation of genes that are involved in the control of the hypothalamic-pituitary-adrenal (HPA) axis. Hyperforin, another constituent of SJW, is active in vitro and has been proposed to be the active constituent for therapeutic efficacy in depression. We therefore examined if hyperforin has delayed effects on HPA axis control centers similar to those of Hypericum and hypericin. We used in situ hybridization histochemistry to examine in rats the effects of short-term (2 weeks) and long-term (8 weeks) oral administration of two hyperforin preparations, fluoxetine (positive control), and haloperidol (negative control) on the expression of genes involved in the regulation of the HPA axis. Fluoxetine (10 mg/kg) given daily for 8 weeks, but not 2 weeks, significantly decreased levels of corticotropinreleasing hormone (CRH) mRNA by 22% in the paraventricular nucleus (PVN) of the hypothalamus and tyrosine hydroxylase (TH) mRNA by 23% in the locus coeruleus. Fluoxetine increased levels of mineralocorticoid (MR) (17%), glucocorticoid (GR) (18%), and 5-HT 1A receptor (21%) mRNAs in the hippocampus at 8, but not 2, weeks. Comparable to haloperidol (1 mg/kg), neither the hyperforinrich CO 2 extract (27 mg/kg) nor hyperforin-trimethoxybenzoate (8 mg/kg) altered mRNA levels in brain structures relevant for HPA axis control at either time point. These data suggest that hyperforin and hyperforin derivatives are not involved in the regulation of genes that control HPA axis function.

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“…In addi tion, CRH neurons have been hypothesized to be in volved in the pathophysiological response of the HPA axis in various stress-related human pathologies, e.g. depres sion [6,7], This hypothesis is largely based on reports showing that in depressed patients: (i) 24-hour cortisol excretion was elevated [8]; (ii) the HPA axis was often unable to respond appropriately to exogenous corticoste roids, as measured by the dexamethasone suppression test [9], and (iii) ACTH responses to test doses of ovine CRH [10][11][12][13][14][15] or human CRH [16][17][18] were blunted. These blunted responses in depressed patients have been inter preted as an index of CRH hyperexposure because rats that were chronically exposed to CRH develop a reduced CRH receptor efficacy, resulting in blunted ACTH re sponses to a CRH challenge [19].…”

Section: Introductionmentioning

confidence: 99%

Increased Numbers of Corticotropin-Releasing Hormone Expressing Neurons in the Hypothalamic Paraventricular Nucleus of Depressed Patients

et al. 1994

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The hypothalamo-pituitary-adrenal (HPA) axis is known to be activated in depressed patients. Although direct evidence is lacking, this activation is hypothesized to be due to hyperactivity of corticotropin-releasing hormone (CRH) neurons of the hypothalamic paraventricular nucleus (PVN). Recent immunocytochemical studies in experimental animals and in humans showed that the number of CRH-expressing neurons correlated with the activity of these neurons. In addition, colocalization of AVP in CRH neurons has been shown to be an index for the secretory activity. Therefore, we estimated the total number of CRH-immunoreactive neurons and their fraction showing colocalization with AVP in the PVN of 10 control subjects and of 6 depressed patients who were diagnosed to be suffering from a major depression or a bipolar disorder. The mean total number of CRH-expressing neurons of the 6 depressed patients was four times higher, and the number of CRH neurons co-expressing AVP was almost three times higher than those in the control group. We also determined the two activity parameters of CRH neurons in the PVN of 2 subjects with a depressive organic mood syndrome or a depressive disorder not otherwise specified. In these two ‘non-major depressed’ subjects, the activity parameters of CRH neurons were comparable to those of control subjects. Our observations strongly support the hypothesis that CRH neurons in the PVN are hyperactivated in major depressed patients. This hyperactivity might be causally related to at least part of the symptomatology of depression.

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ACTH, cortisol, and corticosterone output after ovine corticotropin-releasing factor challenge during depression and after recovery

Cited by 91 publications

References 31 publications

Regulation of the Human Corticotropin-Releasing-Hormone Gene Promoter Activity by Antidepressant Drugs in Neuro-2A and AtT-20 Cells

Regulation of the Human Corticotropin-Releasing-Hormone Gene Promoter Activity by Antidepressant Drugs in Neuro-2A and AtT-20 Cells

Hyperforin-Containing Extracts of St John's Wort Fail to Alter Gene Transcription in Brain Areas Involved in HPA Axis Control in a Long-Term Treatment Regimen in Rats

Increased Numbers of Corticotropin-Releasing Hormone Expressing Neurons in the Hypothalamic Paraventricular Nucleus of Depressed Patients

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