Central 6-hydroxydopamine lesions decrease mineralocorticoid, but not glucocorticoid receptor gene expression in the rat hippocampus

doi:10.1016/0304-3940(92)90363-C

Neuroscience Letters

Volume 142, Issue 2, 17 August 1992, Pages 159-162

https://doi.org/10.1016/0304-3940(92)90363-C Get rights and content

Abstract

The role of hippocampal noradrenergic inputs in the modulation of corticosteroid receptor expression has been investigated. Adult male rats were given central 6-hydroxydopamine (6-OHDA) and the expression of hippocampal mineralocorticoid (MR) and glucocorticoid (GR) receptor mRNA was examined after two weeks by in situ hybridization histochemistry. Expression of MR mRNA was significantly decreased in all subregions of the hippocampus except CA2, but 6-OHDA lesions had no effect on GR mRNA expression. These data reveal differential regulation of the two receptor types by noradrenergic inputs.

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Stress and corticosterone alter synaptic plasticity in a rat model of Parkinson's disease
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Citation Excerpt :
It is also possible that GR/MR signaling in the motor system interact to regulate negative feedback and influence motor outcome [28] and thus affect the rate of neuronal degeneration. While previous studies have investigated the effects of 6-OHDA noradrenergic system lesions with GR mRNA expression [43,84] the present study is the first to evaluate changes of nigrostriatal 6-OHDA lesion on this central component of the HPA axis. The GR upregulation in response to stress and CORT elevation may represent a protective or adaptive mechanism in response to elevated CORT conditions.
As a major influence on neuronal function and plasticity, chronic stress can affect the progression and symptoms of neurodegenerative conditions, such as Parkinson’s disease (PD). Here we investigated the influence of unilateral dopamine depletion and stress on dopamine-related hallmarks of stress response and neuronal plasticity in a rat model of PD. Animals received either restraint stress or a combination of adrenalectomy and corticosterone (CORT) supplementation to clamp circulating glucocorticoid levels for three weeks prior to unilateral nigrostriatal dopamine depletion. Rats were tested in skilled and non-skilled motor function up to three weeks post-lesion. Midbrain mRNA expression assessments included markers of dopamine function and neuroplasticity, such as tyrosine hydroxylase (TH), synaptophysin (SYN), calcyon, and glucocorticoid receptor (GR). Along with impaired motor performance, stress and clamped CORT partially preserved TH expression in both substantia nigra (SN) and ventral tegmental area (VTA), but differentially modulated the expression of SYN, calcyon, and GR mRNA in midbrain and cortical areas. Stress reduced synaptophysin mRNA expression in SN/VTA, and elevated calcyon mRNA optical density in both non-lesion and lesion hemispheres. Stress and CORT increased GR mRNA in the non-lesion SN/VTA, while in the lesion hemisphere GR mRNA was only elevated by CORT. In the motor cortex and striatum, however, GR was higher in both hemispheres under both experimental conditions. These findings suggest that stress and stress hormones differentially affect dopaminergic function and neuroplasticity in a rat model of PD. The findings suggest a role for stress in motor and non-motor symptoms of PD and stress response.
Differential regulation of corticosteroid receptors by monoamine neurotransmitters and antidepressant drugs in primary hippocampal culture
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Hyperactivity of the hypothalamic–pituitary–adrenal axis is a characteristic feature of depressive illness. The centrally located corticosteroid receptors, the glucocorticoid and mineralocorticoid receptors, are thought to be important modulators of this axis and changes in the levels of these receptors, particularly in the hippocampus, may underlie the hyperactivity observed. Various antidepressant drugs increase hippocampal mineralocorticoid and glucocorticoid receptor levels in vivo. These effects are thought to be mediated via alterations in monoaminergic neurotransmission. We examined whether serotonin (5HT) and noradrenaline (NA) have direct effects on glucocorticoid receptor and mineralocorticoid receptor expression in primary hippocampal neurones, and whether antidepressants also exert direct effects on target neurones. Exposure of hippocampal cells to 5HT for 4 days increased both glucocorticoid and mineralocorticoid receptor mRNA and protein expression. The induction of mineralocorticoid receptor mRNA was completely blocked by the 5HT₇ receptor antagonist SB 269970. In contrast glucocorticoid receptor induction was insensitive to the 5HT₇ receptor, whilst studies with the 5HT_1A receptor agonist 8-hydroxy-2-(di-n-proplamino) tetralin hydrochloride and the 5HT_1A receptor antagonist N-[2-[4-2-[O-methoxyphenyl)-1-piperazinyl]ethyl]-N-(2-pyridinyl) cyclohexane carboxamide trihydrochloride (WAY 100635) suggest a partial role for 5HT_1A receptors in hippocampal glucocorticoid receptor regulation. Treatment with NA for 4 days also increased glucocorticoid receptor expression but had no effect on mineralocorticoid receptor expression. This was blocked by propanolol suggesting action via β-adrenergic receptors. Similarly to NA, fluoxetine and amitriptyline also selectively increased glucocorticoid receptor mRNA and protein levels over this time course. However, glucocorticoid receptor induction by fluoxetine or amitriptyline was not blocked by WAY 100635 or propanolol.
These results show that 5HT, NA and antidepressants act directly but via distinct mechanisms on hippocampal neurones to regulate mineralocorticoid and glucocorticoid receptor expression. Thusly manipulation of neurotransmitter or antidepressant levels in the brain may aid in reversing hypothalamic–pituitary–adrenal axis hyperactivity by restoring hippocampal corticosteroid receptor balance.
Antenatal glucocorticoids and the developing brain: Mechanisms of action
2001, Seminars in Neonatology
Glucocorticoids are critical for normal brain development. There is no doubt that prenatal treatment with synthetic glucocorticoid affords great benefit to the preterm infant. However, animal studies, now carried out in many species, indicate that there may be some long-term physiological costs of early exposure to excess glucocorticoid, and that these appear sex-dependant. Further, the effects may not become apparent until later life. Given the dynamics of corticosteroid receptor systems in late gestation, it is likely that there are critical windows of development when specific regions of the brain are more sensitive to the influence of synthetic glucocorticoid. Once such windows have been identified it will be possible to target prenatal treatments, so as to maximize benefit and reduce risk of long-term effects. Notwithstanding, the data reviewed below indicate that caution should be exercised in the use of multiple course glucocorticoid therapy during pregnancy.
Chronic lithium chloride injection increases glucocorticoid receptor but not mineralocorticoid receptor mRNA expression in rat brain
2000, Neuroscience Research
Lithium has been used clinically for the treatment of bipolar disorders. However, the brain mechanisms, by which lithium acts, are still unclear. An impaired hypothalamic–pituitary–adrenal (HPA) axis has been implicated in the pathogenesis of mood disorders. In this study, we investigated the effects of chronic lithium on the corticosteroid receptors in the brain. Male Wistar rats were injected with LiCl (1.5 mEq/kg) or saline intraperitoneally (i.p.) once a day for 14 days. Twenty-four hours after the last injection, the expressions of mRNA for glucocorticoid receptor (GR) and mineralocorticoid receptor (MR) in the brain were determined by non-radioactive in situ hybridization. Chronic administration of LiCl increased the expression of GR mRNA in the hippocampus and paraventricular nucleus of the hypothalamus (PVN). However, no significant changes were observed in the expression of either MR mRNA in the hippocampus or GR mRNA in the locus ceruleus. Since the hippocampus and PVN mediate negative feedback regulation of the HPA axis, an increased expression of GR mRNA in these regions may normalize HPA axis activity in mood disorders. Thus, the effect of chronic lithium on GR function may be involved in its antimanic and/or prophylactic activity in bipolar disorders.
Twenty-four hour cortisol release profiles in patients with Alzheimer's and Parkinson's disease compared to normal controls: Ultradian secretory pulsatility and diurnal variation
1997, Neurobiology of Aging
Endocrine abnormalities of the hypothalamic-pituitary-adrenal (HPA) system in patients with Alzheimer’s disease (AD) and Parkinson’s disease (PD) have been described repeatedly. However, no data are available on the diurnal cortisol secretory pattern in these major neurodegenerative disorders. Therefore, we studied 24-h pulsatile cortisol secretion in 12 patients with AD and 12 patients with PD compared to 10 normal community- and age-matched volunteers (NV). Twenty-four hour blood sampling was performed from 1800 h to 1800 h at 15-min intervals. Cortisol half-life, number of cortisol secretory bursts/24-h, interpulse interval, mass of cortisol secreted per burst, amplitude of cortisol secretory bursts, pulsatile cortisol production rate, 24-h mean, and integral cortisol concentrations were calculated by applying deconvolution analysis. Furthermore, the relative diurnal variation and the quiescent period were determined. Patients with AD and PD were found to have significantly higher total plasma cortisol concentrations (24-h pulsatile cortisol production rate: AD + 56%; PD + 52%/24-h integrated cortisol: AD + 37%; PD + 29%) compared to NV. This sustained hypercortisolism is due to a higher mass of cortisol secreted per burst (AD + 62%; PD + 79%), but not to increased cortisol half-life or secretory pulse frequency or amplitude. Despite these similarities between AD and PD patients, relative diurnal variation of cortisol secretion was significantly decreased in patients with PD (−22%), whereas the pattern of secretory curves was not different between NV and AD patients. This observation was indirectly supported by a reduction of the quiescent period in patients with PD (−74 min) compared to the NV and AD group. Based on these results and recently published animal data, we hypothesize that decreased expression of hippocampal mineralocorticoid receptors (MR) may account for the flattened diurnal cortisol secretory curve observed in PD patients, whereas the intact diurnal profile in AD patients may be due to a relative increase in MR compensating for the hippocampal neuronal loss commonly occurring in this disorder.
Hippocampal type I and type II corticosteroid receptors are differentially regulated by chronic prazosin treatment
1996, Neuroscience
Two types of hippocampal corticosteroid receptors play an important role in regulating the secretion of corticosterone: type I receptors are thought to regulate both the basal and stress induced release of corticosterone whereas type II receptors seem to be involved only in the stress response. Although these receptors are known to be regulated by circulating levels of corticosterone, there is also evidence for a direct neural control independent of hormonal influences. Furthermore, several studies suggest differential regulation of type I and type II corticosteroid receptors, with greater hormonal control of type II and greater neural control of type I. In order to investigate this theory of differential regulation of type I and type II corticosteroid receptors, we studied the effect of chronic treatment with either vehicle or the α₁ noradrenergic antagonist prazosin (0.5 mg/kg, i.p), on hippocampal corticosteroid receptors. Rats in one group had intact adrenal glands, whereas rats in a second group were adrenalectomized, their plasma corticosterone levels being maintained in the physiological range by implantation of corticosterone pellets. Thus, in the first group, the effects of drug-induced changes in both noradrenergic transmission and corticosterone secretion on corticosteroid receptors were investigated, whereas in the second group, the influence of altered noradrenergic transmission was effectively isolated. The results of this experiment show that, in comparison to the vehicle treatment, chronic treatment with the a, receptor antagonist prazosin decreased the number of type I corticosteroid receptors in adrenalectomized animals with corticosterone substitutive therapy. This effect on type I was not evident in adrenal-intact animals. In contrast, the prazosin treatment reduced the number of type II corticosteroid receptors in adrenal-intact animals, but not in adrenalectomized animals with corticosterone substitutive therapy. It has also been demonstrated here that, in the adrenal-intact animals, chronic prazosin induces hypersecretion of corticosterone after stress, which may account for the reduction of type II corticosteroid receptors noted in this group.
Taken together, these results support the theory that type I and type II are differentially regulated: type I receptors can be regulated by noradrenaline independently of corticosterone, whereas type II receptors seem to be adjusted by circulating levels of corticosterone. These results may also suggest possible pharmacotherapies of hypothalamo-pituitary-adrenal axis dysregulation, such as that occurring during depression, Alzheimer's disease and Cushing syndrome, by targeting type I corticosteroid receptors.

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Central 6-hydroxydopamine lesions decrease mineralocorticoid, but not glucocorticoid receptor gene expression in the rat hippocampus

Abstract

Neuron

Psychoneuroen-docrinology

Exp. Neurol.

Exp. Neurol.

Mol. Cell Endocrinol.

Brain Res.

Neuroscience

Serotoninergic innervation and glucocorticoid binding in the hippocampus: relevance to depression

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

Science

Interactions between hippocampal serotonin and the pituitary-adrenal axis in the septal driving of hippocampal theta-rhythm

Neuroendocrinology

Adrenal steroids and behavioural adaptation: relationship to brain corticosteroid receptors

The steroid and thyroid hormone receptor superfamily

Science

Neurotransmitter involved in ACTH secretion: catecholamines: ACTH and related peptides: structure and action

Ann. NY Acad. Sci.

Localization and regulation of glucocorticoid and mineralocorticoid receptor messenger RNAs in the hippocampal formation of the rat

Mol. Endocrinol.

Effects of glucocorticoid and norepinephrine on the excitability in the hippocampus

Science

Mineralocorticoid hormones suppress serotonin-induced hyperpolarization of rat hippocampal CA1 neurons

J. Neurosci.