title: Chronic treatment with supraphysiological levels of corticosterone enhances D-MDMA-induced dopaminergic neurotoxicity in the C57BL/6J female mouse.
abstract: Chronic stress and extended periods of elevated circulating glucocorticoids have been reported to exacerbate excitotoxicity-induced hippocampal neuronal injury in rat. Despite continued interest in the effects of protracted exposure to stress or glucocorticoids, there has been little examination of how other types of neurotoxicity may be exacerbated or blocked, by stress. Here we examined the effects of chronic supraphysiologic levels of corticosterone on D-3,4-methylenedioxymethamphetamine (D-MDMA)-induced striatal dopaminergic neurotoxicity in the female C57BL/6J mouse. Corticosterone (5 mg, 15 mg or placebo) pellets were implanted to continuously elevate circulating glucocorticoids and create a model of the ultimate effect of chronic activation of the hypothalamic-pituitary-adrenal axis. After 7 days, a neurotoxic regimen of D-MDMA was administered (20 mg/kg s.c. every 2 hx4); thymus, spleen, striatum and hippocampus were collected 72 h later. Significant involution of thymus and spleen confirmed the bioavailability of the corticosterone at both dosages. D-MDMA increased the striatal levels of the astrocyte-localized protein glial fibrillary acidic protein (GFAP, a marker of gliosis); both dosages of corticosterone exacerbated this increase but only the 15 mg pellet exacerbated the decrease in tyrosine hydroxylase protein. Corticosterone alone or in combination with D-MDMA produced no neural injury in hippocampus, as measured by GFAP. Our work indicates corticosterone was able to increase the vulnerability of the striatum, but not the hippocampus to D-MDMA. An examination of other mouse strains and models of neurotoxic injury would be useful in determining the general validity of the glucocorticoid neuroendangerment hypothesis.
authors.affiliation: Chronic Stress and Molecular Neurotoxicology Laboratories, Toxicology and Molecular Biology Branch, National Institute for Occupational Safety and Health/Centers for Disease Control, 1095 Willowdale Road, Morgantown, WV 26505, USA. edj2@cdc.gov
authors.forename: Elizabeth Anne
authors.initials: EA
authors.lastname: Johnson
authors.forename: James P
authors.initials: JP
authors.lastname: O'Callaghan
authors.forename: Diane B
authors.initials: DB
authors.lastname: Miller
mesh_terms: D018759:Adrenergic Uptake Inhibitors / Q000633:toxicity*; D000818:Animals; D001831:Body Temperature / Q000187:drug effects / Q000502:physiology; D003345:Corticosterone / Q000378:metabolism* / Q000494:pharmacology; D004298:Dopamine / Q000096:biosynthesis*; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation / Q000187:drug effects / Q000502:physiology; D004334:Drug Administration Schedule; D004347:Drug Interactions / Q000502:physiology; D005260:Female; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D006897:Hydroxyindoleacetic Acid / Q000378:metabolism; D007030:Hypothalamo-Hypophyseal System / Q000378:metabolism / Q000503:physiopathology*; D007107:Immune System / Q000187:drug effects / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D018817:N-Methyl-3,4-methylenedioxyamphetamine / Q000633:toxicity*; D017072:Neostriatum / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D009498:Neurotoxins / Q000633:toxicity*; D009929:Organ Size / Q000187:drug effects / Q000502:physiology; D012701:Serotonin / Q000096:biosynthesis; D013312:Stress, Physiological / Q000378:metabolism* / Q000503:physiopathology; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism
chemical_list: D018759:Adrenergic Uptake Inhibitors; D005904:Glial Fibrillary Acidic Protein; D009498:Neurotoxins; D012701:Serotonin; D006897:Hydroxyindoleacetic Acid; D014446:Tyrosine 3-Monooxygenase; D018817:N-Methyl-3,4-methylenedioxyamphetamine; D004298:Dopamine; D003345:Corticosterone