Age as a Susceptibility Factor in the Striatal Dopaminergic Neurotoxicity Observed in the Mouse Following Substituted Amphetamine Exposure

Details

• Personal Author:
  Ali SF ; Miller DB ; O'Callaghan JP
• Description:
  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 C57BL/6 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. [Description provided by NIOSH]
• Subjects:
  Age Factors Animals Environment Laboratories Nervous System Occupational Health Safety Sex Characteristics
• Keywords:
  Age Factors Animal Studies Environmental Factors Laboratory Animals Neurotoxic Effects Neurotoxicity Neurotoxicology Neurotoxins Sex Factors
• ISBN:
  9781573312806
• ISSN:
  0077-8923
• Document Type:
  Text
• Genre:
  Journal Article
• Place as Subject:
  Arkansas ; OSHA Region 3 ; OSHA Region 6 ; West Virginia
• CIO:
  National Institute for Occupational Safety and Health (NIOSH)
• Division:
  HELD - Health Effects Laboratory Division
• Topic:
  Workplace Safety & Health
• Location:
  North America
• Pages in Document:
  194-207
• Volume:
  914
• NIOSHTIC Number:
  nn:20020755
• Citation:
  Ann NY Acad Sci 2000 Sep; 914:194-207
• Contact Point Address:
  Dr. Diane B. Miller, Toxicology and Molecular Biology Branch, Health Effects Laboratory Division, NIOSH/CDC, 1095 Willowdale Road, Morgantown, WV 26505
• Email:
  dum6@cdc.gov
• Federal Fiscal Year:
  2000
• Peer Reviewed:
  True
• Source Full Name:
  Annals of the New York Academy of Sciences
• Collection(s):
  National Institute for Occupational Safety and Health
• Main Document Checksum:
  urn:sha-512:a695deca2bbef8f12a27535f00f92c8176a36d72ab894ee68ebc9be6ac597570558fddad90fd46aeadeaee749ee1713d53fc3c72de00ed718fb410ca41ee89c4
• Download URL:
  https://stacks.cdc.gov/view/cdc/198425/cdc_198425_DS1.pdf
• File Type:
  [PDF - 8.08 MB ]