Intrastriatal injection of dopamine results in DNA damage and apoptosis in rats.
Overflow of the neurotransmitter dopamine (DA) in striatum is implicated in the neurodegenerative processes in ischemia, hypoxia and local exposure to high concentrations of excitatory amino acids. However, how DA causes neurotoxicity is not understood. We report that intrastriatal injection of DA (0.5-1 micromol/microl) in Wistar rats produces a robust increase in apoptotic cell death as determined by both a terminal deoxynucleotidyl transferase catalyzed dUTP-biotin nick labeling (TUNEL) and Klenow polymerase catalyzed [32P]dCTP labeled DNA ladder. Cells in which apoptosis was induced by DA are characterized by condensed chromatin, DNA fragmentation, shrinkage and irregular shapes. The apoptotic cell death induced by DA is not due to the effect of hyperosmolar solution since intrastriatal injection of identical concentrations of NaCl on opposite sides of the same rat brains shows little TUNEL-positive labeling. The number of apoptotic cells is proportional to the amount of DA and length of exposure period. With DA concentrations from 0 to 1 micromol/microl, the maximal toxic effect appears at a concentration of 1 micromol/microl after 24 h exposure. Demonstration of DA-induced apoptosis in vivo may provide a potential molecular mechanism for DA neurotoxicity.
Molecular Physiology and Genetics Section, Gerontology Research Center, NIA/NIH, Baltimore, MD 21224-6823, USA.
A
A
Hattori
Y
Y
Luo
H
H
Umegaki
J
J
Munoz
G S
GS
Roth
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D004247:DNA / Q000235:genetics / Q000302:isolation & purification; D004249:DNA Damage / Q000187:drug effects*; D004298:Dopamine / Q000008:administration & dosage / Q000633:toxicity*; D020287:In Situ Nick-End Labeling; D007267:Injections; D008297:Male; D017072:Neostriatum / Q000502:physiology*; D051381:Rats; D017208:Rats, Wistar
D004247:DNA; D004298:Dopamine