Abstract
Background: Hypersecretion of corticotropin-releasing hormone (CRH) in the brain has
been implicated in stress-related human pathologies. We developed a transgenic mouse
line overexpressing CRH (CRH-OE) exclusively in neural tissues to assess the effect
of long-term CRH overproduction on regulation of the hypothalamic-pituitary-adrenal
(HPA) axis.
Methods: Male transgenic CRH-OE2122 mice on a C57BL/6J background were used. Littermate wildtype mice served as control
animals. Basal plasma corticotropin and corticosterone concentrations were measured,
and adrenal gland weight was determined. A dexamethasone suppression test measured
the effects of long-term CRH hypersecretion on negative feedback control. Additionally,
we measured plasma corticosterone concentrations in reaction to stress.
Results: CRH-OE2122 mice showed elevated basal plasma corticosterone concentrations, hypertrophy of the
adrenal gland, and dexamethasone nonsuppression. Basal plasma ACTH concentrations
of wildtype and CRH-OE2122 mice did not differ significantly. In reaction to stress, CRH-OE2122 mice showed a normal corticosterone response.
Conclusions: The HPA axis abnormalities observed in CRH-OE2122 mice suggest that long-term hypersecretion of CRH in the brain can be a main cause
of HPA axis dysregulation. The alterations in HPA axis regulation are reminiscent
of changes reported in major depressive disorder. As such, these CRH -OE2122 mice may model the neuroendocrine changes observed in major depressive disorder.
Keywords
To read this article in full you will need to make a payment
Purchase one-time access:
Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online accessOne-time access price info
- For academic or personal research use, select 'Academic and Personal'
- For corporate R&D use, select 'Corporate R&D Professionals'
Subscribe:
Subscribe to Biological PsychiatryAlready a print subscriber? Claim online access
Already an online subscriber? Sign in
Register: Create an account
Institutional Access: Sign in to ScienceDirect
References
- Overexpression of the neural growth-associated protein GAP-453 induces nerve sprouting in the adult nervous system of transgenic mice.Cell. 1995; 83: 269-278
- Corticotropin-releasing hormone (CRH) directly stimulates corticosterone secretion by the rat adrenal gland.Endocrinology. 1991; 128: 1198-1200
- Effects of cortisol treatment on brain and adrenal corticotropin-releasing hormone (CRH) content and other parameters regulated by CRH.Regul Pept. 1990; 31: 83-92
- Cerebrospinal fluid neuropeptides in mood disorder and dementia.J Affect Disord. 1992; 25: 39-45
- Endocrine profile and neuroendocrine challenge tests in transgenic mice expressing antisense RNA against the glucocorticoid receptor.Neuroendocrinology. 1997; 66: 212-220
- Circadian rhythm of melatonin, corticosterone and phagocytosis.J Pineal Res. 2001; 30: 180-187
- Non-invasive, quantitative assessment of the anatomical phenotype of corticotropin-releasing factor-overexpressing mice by MRI.NMR Biomed. 2001; 14: 210-216
- Clinical applications of the dexamethasone suppression test for endogenous depression.Pharmacopsychiatria. 1982; 15: 19-25
- The dexamethasone suppression test for melancholia.Br J Psychiatry. 1982; 140: 292-304
- The neuroendocrinology of depression and chronic stress.Br Med Bull. 1996; 52: 597-617
- The concepts of stress and stress system disorders—overview of physical and behavioral homeostasis.JAMA. 1992; 267: 1244-1252
- Dexamethasone suppression of corticosteroid secretion.Psychoneuroendocrinology. 2000; 25: 151-167
- Animal models of CRH excess and CRH receptor deficiency display altered adaptations to stress.Peptides. 2001; 22: 733-741
- Repeated stress-induced activation of corticotropin-releasing factor neurons enhances vasopressin stores and colocalization with corticotropin-releasing factor in the median eminence of rats.Neuroendocrinology. 1991; 53: 150-159
- Overexpression of corticotropin-releasing hormone in transgenic mice and chronic stress-like autonomic and physiological alterations.in: Dirks A Corticotropin-Releasing Hormone, Stress and Anxiety—Physiological, Neuroendocrine and Behavioral Studies. PhD thesis, Utrecht University, The Netherlands2001: 97-116
- Reduced startle reactivity and plasticity in transgenic mice overexpressing corticotropin-releasing hormone.Biol Psychiatry. 2002; 51: 583-590
- Salivary cortisol levels and their correlation with plasma ACTH levels in depressed patients before and after the DST.Am J Psychiatry. 1991; 148: 505-508
- Psychological stress increases hippocampal mineralocorticoid receptor levels.J Neurosci. 2001; 21: 4822-4829
- Neuropeptides and the hypothalamicpituitary-adrenocortical (HPA) system.World J Biol Psychiatry. 2000; 1: 105-111
- Regulation of pituitary corticotropin releasing hormone (CRH) receptors by CRH.Endocrinology. 1993; 133: 1708-1714
- CRF receptor regulation and sensitization of ACTH responses to acute ether stress during chronic intermittent immobilization stress.Brain Res. 1990; 532: 34-40
- Splanchnicotomy increases adrenal sensitivity to ACTH in nonstressed rats.Am J Physiol. 1997; 273: E363-E368
- The central mechanism of hypothalamic-pituitary-adrenocortical system hyperfunction in depressed patients.Psychiatry Clin Neurosci. 2000; 54: 227-234
- Cerebrospinal fluid immunoreactive corticotropin-releasing hormone and adrenocorticotropin secretion in Cushing’s disease and major depression.J Clin Endocrinol Metabol. 1991; 72: 260-271
- Prenatal stress alters circadian activity of hypothalamo-pituitary- adrenal axis and hippocampal corticosteroid receptors in adult rats of both genders.J Neurobiol. 1999; 40: 302-315
- Modulation of basal and corticotropin-releasing factor-stimulated proopiomelanocortin gene expression by vasopressin in rat anterior pituitary.Endocrinology. 1989; 125: 2957-2966
- Source of corticotropin-releasing hormone-like innervation of the adrenal glands of fetal and postnatal sheep.Brain Res. 1997; 767: 87-91
- Regulation of serotonin(1A), glucocorticoid, and mineralocorticoid receptor in rat and human hippocampus.Biol Psychiatry. 1998; 43: 547-573
- Endogenous serine protease inhibitor modulates epileptic activity and hippocampal long-term potentiation.J Neurosci. 1997; 17: 4688-4699
- Penetration of dexamethasone into brain glucocorticoid targets is enhanced in mdr1A P-glycoprotein knockout mice.Endocrinology. 1998; 139: 1789-1793
- Expression in brain of amyloid precursor protein mutated in the alpha-secretase site causes disturbed behavior, neuronal degeneration and premature death in transgenic mice.EMBO J. 1996; 15: 1265-1274
- Expression of Thy-1 in the nervous system of the rat and mouse.Immunol Ser. 1989; 45: 121-148
- Adrenal gland enlargement in major depression. A computed tomographic study.Arch Gen Psychiatry. 1992; 49: 384-387
- Reduced corticotropin releasing factor binding sites in the frontal cortex of suicide victims.Arch Gen Psychiatry. 1988; 45: 577-579
- Elevated concentrations of CSF corticotropin-releasing factor-like immunoreactivity in depressed patients.Science. 1984; 226: 1342-1344
- Differences in plasma ACTH and cortisol between depressed patients and normal controls.Biol Psychiatry. 1985; 20: 1055-1072
- Cerebrospinal fluid corticotropin-releasing hormone, vasopressin, and oxytocin concentrations in treated patients with major depression and controls.Biol Psychiatry. 1995; 38: 330-335
- Corticotropin-releasing hormone-like axons in the adrenal glands of fetal and postnatal sheep.J Auton Nerv Syst. 1996; 59: 87-90
- Increased numbers of corticotropin-releasing hormone expressing neurons in the hypothalamic paraventricular nucleus of depressed patients.Neuroendocrinology. 1994; 60: 436-444
- Adrenal gland volume in major depression. Increase during the depressive episode and decrease with successful treatment.Arch Gen Psychiatry. 1995; 52: 213-218
- Vasopressin and the regulation of hypothalamic-pituitary-adrenal axis function.Life Sci. 1998; 62: 1985-1998
- Development of Cushing’s syndrome in corticotropin-releasing factor transgenic mice.Endocrinology. 1992; 130: 3378-3386
- Effects of antidepressant treatment on corticotropin-induced cortisol responses in patients with melancholic depression.Psychiatry Res. 1997; 73: 27-32
- Rat corticotropin-releasing hormone gene.Mol Endocrinol. 1987; 1: 363-370
- Physiological role of corticotropin-releasing factor in the control of adrenocorticotropin-mediated corticosterone release from the rat adrenal gland.Endocrinology. 1992; 130: 282-288
- Changes in CRH-expression and in stress-related FOS-IR in transgenic mice over-expressing CRH.in: Dirks A Corticotropin-Releasing Hormone, Stress and Anxiety—Physiological, Neuroendocrine and Behavioral Studies. PhD thesis, Utrecht University, The Netherlands2001: 129-150
- Tissue-specific control elements of the Thy-1 gene.EMBO J. 1990; 9: 833-840
- The effect of repeated human corticotropin releasing hormone administration on dexamethasone suppressed pituitary adrenocortical activity in healthy subjects.Biol Psychiatry. 1997; 42: 882-888
- Neuron-specific transgene expression of Bcl-XL but not Bcl-2 genes reduced lesion size after permanent middle cerebral artery occlusion in mice.Neurosci Lett. 1999; 268: 119-122
- Pronounced and sustained central hypernoradrenergic function in major depression with melancholic features.Proc Natl Acad Sci USA. 2000; 97: 325-330
- Cortisol regulation in posttraumatic stress disorder and major depression.Biol Psychiatry. 1996; 40: 79-88
- Hormonal evidence for altered responsiveness to social stress in major depression.Neuropsychopharmacology. 2000; 23: 411-418
Article info
Publication history
Accepted:
January 15,
2002
Received in revised form:
December 31,
2001
Received:
September 21,
2001
Identification
Copyright
© 2002 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.
