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

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 bring 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. (C) 2001 IBRO. Published by Elsevier Science Ltd. All rights reserved.