Age as a susceptibility factor in the striatal dopaminergic neurotoxicity observed in the mouse following substituted amphetamine exposure.
A number of substituted amphetamines, including methamphetamine (METH) are considered dopaminergic neurotoxicants. METH causes long-term depletions of striatal dopamine (DA) and its metabolites (DOPAC and HVA) that are accompanied by other changes indicative of nerve terminal degeneration. These include argyrophilia as detected by silver degeneration stains and an elevation in glial fibrillary acidic protein (GFAP), a marker of reactive gliosis in response to injury, as well as a long-term decrease in tyrosine hydroxylase (TH) protein levels. The susceptibility to the dopaminergic neurotoxicity of METH and the other amphetamines can be affected by a number of factors including age, gender, stress, and environment. Many of these susceptibility factors have been extensively investigated in the rat but less so in the mouse. As the availability of genetically altered mice continues to expand, this species is increasingly selected for study. Thus, in previous work we determined that stress, gender, and the environment can significantly impact the neurotoxicity of the amphetamines. Here we determined how age affects the striatal DA depletion and GFAP elevation induced by d-METH in C57BL/6 mice. Age was a significant determinant of the ability of a known neurotoxic regimen of d-METH (10 mg/kg x 4) to produce striatal DA depletion with one-month-old C57BL16 mice displaying minimal and nonpersistent depletion of DA or its metabolites while mice 12 months of age displayed large and persistent depletions of DA (87%), DOPAC (71%), and HVA (94%). Large elevations in striatal GFAP were induced in mice 2-23 months of age by d-METH, with lower dosages of d-METH being effective in the older mice. In contrast, the usual neurotoxic regimen of d-METH was minimally effective in inducing GFAP elevations (49% over control) in one-month-old mice, despite elevations in body temperature equivalent to those observed in older mice. Although increasing the dosage of d-METH (20 to 80 mg/kg) did increase the GFAP response (100% over control), it was still well below that usually exhibited at the usual neurotoxic dosage (300-400% over control) in fully mature mice. These data suggest maturity of striatal dopamine systems may be an essential element in the striatal damage induced by the neurotoxic amphetamines.
Miller
D B
DB
Toxicology and Molecular Biology Branch, Health Effects Laboratory Division, NIOSH/CDC, Morgantown, West Virginia 26505, USA. dum6@cdc.gov
O'Callaghan
J P
JP
Ali
S F
SF
D015102:3,4-Dihydroxyphenylacetic Acid / Q000378:metabolism; D000375:Aging / Q000502:physiology*; D000818:Animals; D019540:Area Under Curve; D001831:Body Temperature / Q000187:drug effects; D000697:Central Nervous System Stimulants / Q000008:administration & dosage*; D003342:Corpus Striatum / Q000187:drug effects*; D004195:Disease Models, Animal; D004298:Dopamine / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D005260:Female; D006719:Homovanillic Acid / Q000378:metabolism; D008297:Male; D008694:Methamphetamine / Q000008:administration & dosage*; D051379:Mice; D008810:Mice, Inbred C57BL; D008954:Models, Biological; D020258:Neurotoxicity Syndromes / Q000209:etiology*; D012737:Sex Factors; D013997:Time Factors
D000697:Central Nervous System Stimulants; D015102:3,4-Dihydroxyphenylacetic Acid; D008694:Methamphetamine; D004298:Dopamine; D006719:Homovanillic Acid