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Age as a Susceptibility Factor in the Striatal Dopaminergic Neurotoxicity Observed in the Mouse following Substituted Amphetamine Exposure
Age as a Susceptibility Factor in the Striatal Dopaminergic Neurotoxicity Observed in the Mouse following Substituted Amphetamine Exposure
- Source :
- Annals of the New York Academy of Sciences. 914:194-207
- Publication Year :
- 2000
- Publisher :
- Wiley, 2000.
-
Abstract
- 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.
- Subjects :
- Male
Aging
medicine.medical_specialty
Time Factors
Dose
Dopamine
Models, Biological
General Biochemistry, Genetics and Molecular Biology
Body Temperature
Methamphetamine
Mice
chemistry.chemical_compound
Sex Factors
Substituted amphetamine
History and Philosophy of Science
Internal medicine
medicine
Animals
Dose-Response Relationship, Drug
Tyrosine hydroxylase
Glial fibrillary acidic protein
biology
General Neuroscience
Dopaminergic
Neurotoxicity
Homovanillic Acid
Meth
medicine.disease
Corpus Striatum
Mice, Inbred C57BL
Disease Models, Animal
Endocrinology
nervous system
chemistry
Area Under Curve
Anesthesia
biology.protein
3,4-Dihydroxyphenylacetic Acid
Central Nervous System Stimulants
Female
Neurotoxicity Syndromes
medicine.drug
Subjects
Details
- ISSN :
- 00778923
- Volume :
- 914
- Database :
- OpenAIRE
- Journal :
- Annals of the New York Academy of Sciences
- Accession number :
- edsair.doi.dedup.....9a6eb3848ab66c32761dd90af930faa2
- Full Text :
- https://doi.org/10.1111/j.1749-6632.2000.tb05196.x