Age-related changes in the dog hypothalamic-pituitary-adrenocortical system: Neuroendocrine activity and corticosteroid receptors

doi:10.1016/0960-0760(91)90168-5

The Journal of Steroid Biochemistry and Molecular Biology

Volume 40, Issues 1–3, 1991, Pages 63-69

https://doi.org/10.1016/0960-0760(91)90168-5 Get rights and content

Abstract

Aging is associated with a progressive dysfunctioning of the hypothalamic-pituitary-adrenocortical (HPA) axis. We have studied the response of the HPA axis to stress and a hormonal (ovine corticotropin releasing factor (o-CRF) challenge in young (1.5-2 years) and aged (> 11 years) dogs. Compared to the young dogs, the aged animals displayed an increased basal concentration of both ACTH and cortisol. In addition, in response to an o-CRF challenge (1 μg/kg i.v.) or an electric footshock (1 mA, alternatively on/off for 2 s) or immobilization (45 min) stress, the aged dogs showed significantly larger increments in ACTH and cortisol. Following the challenge test, the young and aged dogs reached their respective basal hormone levels at the same time, except for the o-CRF test. In the latter case, in contrast to the young controls, the aged dogs still showed an increased plasma cortisol level compared to the pre-challenge basal hormone concentration. Concerning the effect of aging on the brain and hypophyseal corticosteroid receptors, a selective decline (minus 50–75%) in mineralocorticoid receptor (MR) was observed in all measured brain regions (dorsal and ventral hippocampus, septum, hypothalamus) and anterior pituitary, whereas no change was found in brain glucocorticoid receptor (GR) number. The GR level in the anterior pituitary was even increased by 70%. In light of the role that MR and GR seem to play in the regulation of the HPA axis, it is concluded that the diminished MR number in the aged dog brain may underly the increased basal hormone levels and the elevated responsiveness of the HPA axis in these animals. The observation that the stress-induced elevations of cortisol and ACTH were not prolonged at senescence suggests that the GR-induced negative feedback action of glucocorticoids is not altered, which is in line with the unchanged brain GR numbers in the aged dogs.

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However, other potential reasons for these findings include the mode and dosage of spironolactone administration (single dose vs. continuous administration over six-weeks; high versus low-dose). Importantly, aging might also affect the association between MR function and cognition because animal studies have demonstrated largely reduced MR expression in the hippocampus of aged dogs (Choi et al., 2008; Reul et al., 1991). However, when comparing young (mean age 25.4 ± 4.6 years) and elderly (mean age 63.2 ± 8.2 years) healthy individuals we found – as expected – that young participants performed significantly better than elderly individuals in memory tasks.
The steroid hormone cortisol is released in response to stress and exerts its effects in the brain via two different receptors: the mineralocorticoid receptor (MR) and the glucocorticoid receptor (GR). This review - dedicated to Dirk Hellhammer - focusses on the role of MR on cognitive and emotional function in healthy individuals and in stress-associated disorders such as major depressive disorder (MDD) or borderline personality disorder (BPD).
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In contrast to studies in healthy participants, age played a moderating role on the effects of MR stimulation on cognition in depressed patients. In young depressed patients, MR stimulation exerted beneficial effects on verbal memory and executive function, whereas in elderly depressed patients MR stimulation led to impaired verbal learning and visuospatial memory. Similar to healthy controls, BPD patients showed enhanced emotional empathy but not cognitive empathy after MR stimulation. Accordingly, this make MR an interesting target for potential pharmacological augmentation of psychotherapy in BPD.
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Stress compromises learning and memory via the elevated adrenal glucocorticoid output that occurs during stressful episodes [21,22]. In AD patients, the concurrent loss of hippocampal neurons and the reduction in the number of corticosteroid receptors disinhibits the hypothalamic-pituitary-adrenal (HPA) axis function [23]. Thus, progressive failure of the negative feedback regulation of the HPA axis facilitates sustained glucocorticoid release [24], which causes excitotoxicity [25] and hippocampal atrophy [26].
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Furthermore, polymorphisms of the MR gene have been associated with depression (DeRijk et al., 2008), dysfunction of the MR has been demonstrated in treatment-resistant depression (Juruena et al., 2010; 2009b, 2013), and administration of a MR agonist as add-on to standard antidepressants accelerated the response to antidepressants (Otte et al., 2010). Furthermore, preclinical studies have demonstrated that MR expression in the brain is reduced in aging (Choi et al., 2008; Reul et al., 1991). Finally, studies in humans have shown diminished MR function in aging (Otte et al., 2003).
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Steroid control of higher brain functionsAge-related changes in the dog hypothalamic-pituitary-adrenocortical system: Neuroendocrine activity and corticosteroid receptors

Abstract

Cell

Psychoneuroendocrinology

Prog. Horm. Res.

Neurobiol. Aging

Brain Res.

J. Biol. Chem.

Neurobiol. Aging

Aging and anti-aging effects of hormones

J. Geront.

Cloning of human mineralocorticoid receptor complementary DNA: structural and functional kindhsip with the glucocorticoid receptor

Science

Molecular cloning of a mineralocorticoid (type 1) receptor complementary DNA from rat hippocampus

Molec. Endocr.

Autoradiographic studies with 3H-dexamethasone in the rat brain and pituitary

The c-erb-A gene encodes a thyroid hormone receptor

Nature

Specificity of adrenal steroid receptor system in the rat hippocampus

Endocrinology

Two receptor systems for corticosterone in rat brain: microdistribution and differential occupation

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Binding characteristics of mineralocorticoid and glucocorticoid receptors in dog brain and pituitary

Endocrinology

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On the role of brain type 1 and type 2 corticosteroid receptors in neuroendocrine regulation

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Effects of glucocorticoids and norepinephrine on the excitability in the hippocampus

Science

Antiglucocorticoid RU 38486 attenuates retention of a behaviour and disinhibits the hypothalamic-pituitary-adrenal axis at different brain sites

Neuroendocrinology

Steroid control of higher brain functions
Age-related changes in the dog hypothalamic-pituitary-adrenocortical system: Neuroendocrine activity and corticosteroid receptors

Autoradiographic studies with ³H-dexamethasone in the rat brain and pituitary

Mineralocorticoid receptor-mediated effects on membrane properties of rat CA₁ pyramidal neurons in vitro