Methamphetamine enhances the cleavage of the cytoskeletal protein tau in the rat brain.
The view that methamphetamine is neurotoxic to dopaminergic and serotonergic axon terminals has been based largely on biochemical and histological studies. In the present study, methamphetamine-induced structural damage to axons was quantified using a sensitive sandwich enzyme-linked immunosorbent assay developed for the detection of the cleaved form of the cytoskeletal protein tau. The administration of a monoamine-depleting regimen of methamphetamine (4 x 10 mg/kg, i.p. every 2 hours for a total of four injections) produced a time-dependent increase in the concentration of cleaved tau in the striatum. Maximal concentrations of cleaved tau were detected 3 days following methamphetamine administration. Cleaved tau concentrations also were significantly elevated in the dorsal hippocampus and, to a lesser extent, in the prefrontal cortex of methamphetamine-treated rats. Maintenance of rats in a cold (4 degrees C) environment not only prevented the methamphetamine-induced depletion of striatal dopamine and serotonin but also prevented the methamphetamine-induced increase in striatal cleaved tau concentrations. The novel findings from this study are supportive of the view that methamphetamine produces acute structural damage to neurons that may lead to the long-term neurotoxic effects of repeated, high-dose administration of the drug and that cleaved tau reliably quantifies the time-dependent neurotoxic effects of methamphetamine.
Wallace
T L
TL
Neuroscience Graduate Program, University of Cincinnati, Cincinnati OH 45267, USA.
Vorhees
C V
CV
Zemlan
F P
FP
Gudelsky
G A
GA
D000818:Animals; D001921:Brain / Q000378:metabolism*; D001923:Brain Chemistry / Q000187:drug effects*; D003598:Cytoskeletal Proteins / Q000378:metabolism; D006801:Humans; D008297:Male; D008694:Methamphetamine / Q000633:toxicity*; D051381:Rats; D017207:Rats, Sprague-Dawley; D016875:tau Proteins / Q000378:metabolism*
D003598:Cytoskeletal Proteins; D016875:tau Proteins; D008694:Methamphetamine