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Vol. 286, Issue 2, 1074-1085, August 1998

Long-term Effects of Amphetamine Neurotoxicity on Tyrosine Hydroxylase mRNA and Protein in Aged Rats1

John F. Bowyer, Lynn T. Frame, Peter Clausing, Kumi Nagamoto-Combs, Cheryl A. Osterhout, Carol R. Sterling and A. William Tank

Division of Neurotoxicology, National Center for Toxicological Research, Jefferson, Arkansas (J.F.B., P.C.); Department of Surgery, University of Arkansas Medical Center, Little Rock, Arkansas (L.T.F.); and Department of Pharmacology and Physiology and the Neurosciences Program, University of Rochester Medical Center, Rochester, New York (K.N.C., C.A.O., C.R.S., A.W.T.)

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.

0022-3565/98/2862-1074$03.00/0
THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
Copyright © 1998 by The American Society for Pharmacology and Experimental Therapeutics


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