Long-term effects of amphetamine neurotoxicity on tyrosine hydroxylase mRNA and protein in aged rats.
Four injections (intraperitoneal) of 3 mg/kg amphetamine (2 hr apart) produced pronounced hyperthermia and sustained decreases in dopamine levels and tyrosine hydroxylase (TH) protein levels in the striatum of 15-month-old male rats. A partial recovery of striatal dopamine levels was observed at 4 months after amphetamine. In contrast, TH mRNA and TH protein levels in the midbrain were unaffected at all time points tested up to 4 months after amphetamine treatment. The number of TH-immunopositive cells in the midbrain was also unchanged at 4 months after amphetamine, even though the number of TH-positive axons in the striatum remained dramatically decreased at this time point. Interestingly, TH-immunopositive cell bodies were observed 4 months after amphetamine in the lateral caudate/putamen, defined anteriorly by the genu of the corpus collosum and posteriorly by the junction of the anterior commissures; these striatal TH-positive cells were not observed in saline- or amphetamine-treated rats that did not become hyperthermic. In addition, low levels (orders of magnitude lower than that present in the midbrain) of TH mRNA were detected using reverse transcription-polymerase chain reaction in the striatum of these amphetamine-treated rats. Our results suggest that even though there is a partial recovery of striatal dopamine levels, which occurs within 4 months after amphetamine treatment, this recovery is not associated with increased TH gene expression in the midbrain. Furthermore, new TH-positive cells are generated in the striatum at this 4-month time point.
Division of Neurotoxicology, National Center for Toxicological Research, Jefferson, Arkansas 72079-9502, USA.
J F
JF
Bowyer
L T
LT
Frame
P
P
Clausing
K
K
Nagamoto-Combs
C A
CA
Osterhout
C R
CR
Sterling
A W
AW
Tank
D000375:Aging / Q000378:metabolism*; D000661:Amphetamine / Q000633:toxicity*; D000818:Animals; D015153:Blotting, Western; D004298:Dopamine / Q000378:metabolism; D018765:Dopamine Uptake Inhibitors / Q000633:toxicity*; D005987:Glyceraldehyde-3-Phosphate Dehydrogenases / Q000378:metabolism; D007150:Immunohistochemistry; D008297:Male; D008636:Mesencephalon / Q000187:drug effects / Q000201:enzymology; D017072:Neostriatum / Q000187:drug effects / Q000378:metabolism; D009410:Nerve Degeneration / Q000139:chemically induced / Q000201:enzymology* / Q000473:pathology; D016133:Polymerase Chain Reaction; D012333:RNA, Messenger / Q000096:biosynthesis*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013378:Substantia Nigra / Q000187:drug effects / Q000201:enzymology; D014446:Tyrosine 3-Monooxygenase / Q000096:biosynthesis*; D015854:Up-Regulation / Q000187:drug effects
D018765:Dopamine Uptake Inhibitors; D012333:RNA, Messenger; D000661:Amphetamine; D014446:Tyrosine 3-Monooxygenase; D005987:Glyceraldehyde-3-Phosphate Dehydrogenases; D004298:Dopamine