LONG-TERM EFFECTS OF AMPHETAMINE NEUROTOXICITY ON TYROSINE-HYDROXYLASE MESSENGER-RNA AND PROTEIN IN AGED RATS

Four injections (intraperitoneal) of 3 mg/kg amphetamine (2 hr apart) produced pronounced hyperthermia and sustained decreases in dopamine l evels 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 t ested up to 4 months after amphetamine treatment. The number of TH-imm unopositive cells in the midbrain was also unchanged at 4 months after amphetamine, even though the number of TH-positive axons in the stria tum remained dramatically decreased at this time point. Interestingly, TH-immunopositive cell bodies were observed 4 months after amphetamin e in the lateral caudate/putamen, defined anteriorly by the genu of th e corpus collosum and posteriorly by the junction of the anterior comm issures; these striatal TH-positive cells were not observed in saline- or amphetamine-treated rats that did not become hyperthermic. In addi tion, low levels (orders of magnitude lower than that present in the m idbrain) of TH mRNA were detected using reverse transcription-polymera se chain reaction in the striatum of these amphetamine-treated rats. O ur results suggest that even though there is a partial recovery of str iatal dopamine levels, which occurs within 4 months after amphetamine treatment, this recovery is not associated with increased TH gene expr ession in the midbrain. Furthermore, new TH-positive cells are generat ed in the striatum at this 4-month time point.