Dexamethasone induces limited apoptosis and extensive sublethal damage to specific subregions of the striatum and hippocampus: implications for mood disorders

doi:10.1016/S0306-4522(01)00070-7

Neuroscience

Volume 104, Issue 1, 10 April 2001, Pages 57-69

https://doi.org/10.1016/S0306-4522(01)00070-7 Get rights and content

Abstract

It has been shown previously that the synthetic corticosteroid dexamethasone induces apoptosis of granule cells in the dentate gyrus and striatopallidal neurons in the dorsomedial caudate–putamen. We investigated whether or not dexamethasone can induce damage to other neuronal populations. This issue was addressed using OX42 immunohistochemistry to visualise activated microglia and thereby gauge the extent of dexamethasone-induced neuronal death. A single dose of dexamethasone (20 mg/kg, i.p.) administered to young male Sprague–Dawley rats induced a strong microglial reaction which was restricted to the striatum, the dentate gyrus and all of the CA subfields of the hippocampus. Some OX42-immunoreactive cells were also seen in the lateral septal nucleus. Subsequent quantitative analysis of silver/methenamine-stained sections confirmed that acute administration of dexamethasone induced apoptosis in the striatum and all regions of the hippocampus at doses as low as 0.7 mg/kg. In contrast, dexamethasone failed to induce apoptosis in the lateral septal nucleus at doses up to 20 mg/kg. The levels of dexamethasone-induced striatal and hippocampal apoptosis were attenuated by pretreatment with the corticosteroid receptor antagonist RU38486 (Mifepristone), which implies that the cell death was mediated by a corticosteroid receptor-dependent process. We further determined whether dexamethasone induced sublethal damage to neurons by quantifying reductions in the number of microtubule-associated protein-2-immunoreactive striatal and hippocampal cells following injection of the corticosteroid. Dexamethasone induced dramatic decreases in the striatum, with the dorsomedial caudate–putamen being particularly affected. Similar damage was seen in the hippocampus, with the dentate gyrus and CA1 and CA3 subfields being particularly vulnerable.

Equivalent corticosteroid-induced neuronal damage may occur in mood disorders, where the levels of endogenous corticosteroids are often raised. Corticosteroid-induced damage of striatal and hippocampal neurons may also account for some of the cognitive deficits seen following administration of the drugs to healthy volunteers.

Section snippets

Subjects

All experiments were performed using male Sprague–Dawley rats (250–300 g; Charles River, UK), which were group housed and given free access to food and water. All experiments were conducted in accordance with the Animals (Scientific Procedures) Act, 1986. All efforts were made to minimise the number of animals used and their suffering.

Drug treatments

Each animal typically received a single injection of either dexamethasone (water-soluble form; Sigma, Poole, UK) or vehicle (sterile water), and was returned to

Behaviour of animals following dexamethasone injection

The administration of dexamethasone did not exert a pronounced effect upon the behaviour of the animals. At the highest dose tested (20 mg/kg), the animals showed slight reductions in activity and vasodilation of the skin of the ears.

OX42 immunohistochemistry

Occasional OX42-immunopositive cells were seen in the brains of the vehicle-injected animals. These tended to lie within the major fibre bundles including the corpus collosum and the internal capsule. Some diffuse immunoreactivity was also seen in some of the

Dexamethasone-induced OX42 immunoreactivity

The OX42 immunohistochemical studies enabled the visualisation of activated microglia and thus gave an indication of the extent of dexamethasone-induced neuronal damage. The OX42-immunopositive small, spindle-like cells seen in the corpus callosum of the vehicle-injected animals are in keeping with previous descriptions of resting microglia. These tend to reside in white matter where an elongated morphology is seen.29., 47. The OX42-immunopositive cells seen in the striatum and hippocampus

Conclusion

We have demonstrated that acute administration of dexamethasone induces dose-dependent apoptosis and sublethal injury to specific subpopulations of striatal and hippocampal neurons. The elevated levels of corticosteroids associated with mood disorders may result in selective damage to these neuronal structures. Such damage may contribute to the depressive and psychotic symptoms associated with these psychiatric conditions.

Acknowledgements

This work was supported by the University of Birmingham Interdisciplinary Research Fund and the Medical Research Council. The advice of Drs C. Lendon, N. Craddock and I. Jones is gratefully acknowledged.

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Elevated levels of glucocorticoids have damaging effects on brain function and architecture, especially in the hippocampus, a structure involved in memory formation, mood and behavior. Previous studies on dexamethasone reported dose-dependent apoptosis and sub-lethal damage in the striatum and hippocampal formation of adult rats (Hassan et al., 1996; Mitchell et al., 1998; Haynes et al., 2001). Neurotoxic dexamethasone effects have been attributed mainly to the activation of GR (Miller et al., 1992).
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Dexamethasone induces limited apoptosis and extensive sublethal damage to specific subregions of the striatum and hippocampus: implications for mood disorders

Abstract

Section snippets

Subjects

Drug treatments

Behaviour of animals following dexamethasone injection

OX42 immunohistochemistry

Dexamethasone-induced OX42 immunoreactivity

Conclusion

Acknowledgements

Ann. Allergy Asthma Immun.

Neuropsychopharmacology

Neuroscience

Brain Res.

Expl Neurol.

Cell

J. neurol. Sci.

Brain Res. Rev.

Expl Neurol.

Neuropharmacology

Prog. Neurobiol.

Neuroscience

Prog. Neurobiol.

Neurosci. Lett.

Neurobiol. Dis.

J. chem. Neuroanat.

Brain Res. Bull.

Brain Res.

Pharmac. Biochem. Behav.

Neuroscience

Expl Neurol.

Horm. Behav.

Biol. Psychiat.

Prog. Brain Res.

Neuroscience

Biol. Psychiat.

Brain Res.

Brain Res.

Preferential loss of striato-external pallidal projection neurons in presymptomatic Huntington’s disease

Ann. Neurol.

Elevated CSF corticotropin-releasing factor concentrations in post-traumatic stress disorder

Am. J. Psychiat.

Hippocampal volume reduction in major depression

Am. J. Psychiat.

MRI-based measurement of hippocampal volume in patients with combat-related post-traumatic stress disorder

Am. J. Psychiat.

Motherhood and Mental Health

Energy dependency of glucocorticoid exacerbation of gp120 neurotoxicity

J. Neurochem.

Development of microglia in the postnatal rat hippocampus

Hippocampus

Schizophrenia-like psychoses associated with organic cerebral disorders—a review

Psychiat. Dev.

A molecular and cellular theory of depression

Archs gen. Psychiat.

A receptor for phosphatidylserine-specific clearance of apoptotic cells

Nature