title: Neurotoxicity of d-amphetamine in the C57BL/6J and CD-1 mouse. Interactions with stress and the adrenal system.
abstract: Substantial evidence suggests that stress can alter the general toxicological properties of the substituted amphetamines (AMPs) as well as their psychostimulant properties. Research concerning the interactions between stress and the neurotoxicity associated with the AMPs is, however, limited. Our previous work demonstrated that a variety of AMPs, including d-METH, d-MDA, d-MDMA but not d-FEN are able to damage dopaminergic elements of the striatum as shown by decreases in dopamine and tyrosine hydroxylase. The neurotoxic capabilities of these AMPs appear linked to their hyperpyrexic actions as diverse manipulations able to block AMP-induced hyperthermia are also neuroprotective. Surprising, since stress usually potentiates the actions of the AMPs, it is our finding that restraint, a commonly used stressor, is protective against the injurious actions of all neurotoxic AMPs evaluated to date. In the mouse restraint acts to elevate blood levels of corticosterone (CORT) by activating the hypothalamic-pituitary-adrenal (HPA) axis as well as inducing a profound hypothermia. The role CORT may play in the neuroprotective actions of restraint, if any, is unknown. Here, data is presented showing the impact of several HPA axis manipulations, including restraint, supplementation with CORT in the drinking water and removal of CORT by adrenalectomy (ADX) on the striatal dopaminergic neurotoxicity of d-AMP. As strain is known to be a powerful determinant of the actions of stress an essential element of these experiments was the evaluation of both an inbred, C57BL/6J and outbred, CD-1, mouse strain. Exposure to d-AMP caused hyperthermia and substantial striatal dopaminergic neurotoxicity in both strains suggesting that an elevation in body temperature is as important a component of the neurotoxicity of d-AMP, as it is of the other neurotoxic AMPs. Restraint was equally effective in both strains and completely blocked the hyperthermia and striatal neurotoxicity induced by d-AMP. CORT supplementation, evaluated in only the C57BL/6J mouse at dosages not capable of involuting either the thymus or the spleen, did not alter d-AMP-induced neurotoxicity. Although the immune system organs of the two strains responded differentially to the removal of CORT, ADX provided equivalent partial protection against the loss of dopaminergic elements in striatum for both strains. Adrenal status clearly affects d-AMP neurotoxicity but the interaction is complex. Future work should examine the roles of the cortical and medullary components of the adrenal gland in the neuroprotective actions of ADX. A precise assessment of the role of circulating CORT In the neurotoxicity of the AMPs will require additional work in which a wider range of CORT dosages, including those capable of involuting thymus and spleen, are evaluated.
authors.affiliation: Neurotoxicology Division, National Health and Environmental Effects Research Laboratory, Research Triangle Park, NC 27711, USA.
authors.forename: D B
authors.initials: DB
authors.lastname: Miller
authors.forename: J P
authors.initials: JP
authors.lastname: O'Callaghan
mesh_terms: D000305:Adrenal Cortex Hormones / Q000494:pharmacology; D000311:Adrenal Glands / Q000187:drug effects* / Q000502:physiology; D000315:Adrenalectomy; D000818:Animals; D001831:Body Temperature / Q000187:drug effects; D003342:Corpus Striatum / Q000187:drug effects* / Q000378:metabolism; D003913:Dextroamphetamine / Q000633:toxicity*; D004298:Dopamine / Q000378:metabolism; D005260:Female; D007103:Immobilization; D051379:Mice; D008810:Mice, Inbred C57BL; D009929:Organ Size; D013045:Species Specificity; D013154:Spleen / Q000187:drug effects / Q000473:pathology; D013312:Stress, Physiological / Q000378:metabolism*; D013950:Thymus Gland / Q000187:drug effects / Q000473:pathology; D013963:Thyroid Hormones / Q000378:metabolism
chemical_list: D000305:Adrenal Cortex Hormones; D013963:Thyroid Hormones; D003913:Dextroamphetamine; D004298:Dopamine