274 Brain Reseatci~ ~13 f i991~I 274-279 lq~c~icr BRES 15351 Dopamine uptake inhibitors block long-term neurotoxic effects of methamphetamine upoo dopaminergic neurons Gerard J. Marek, Georgetta Vosmer and Lewis S. Seiden The University of Chicago, Department of Pharmacological and Physiological Sciences, Chicago, 1L 60637 (U. S. A.) (Accepted 5 September 1989) Key words: Methamphetamine; Amfonelic acid; Mazindol; Neurotoxicity; Dopamine uptake inhibitor A single large dose (100 mg/kg, s.c.) of methamphetamine (MA) is known to exert neurotoxic effects on dopaminergicneurons. The potency at which a series of dopamine (DA) uptake inhibitors blocked MA-induced neostriatal depletions (amfonelic acid (AFA) >> mazindol (MAZ) bupropion (BUP) > benztropine (BENZ)) was similar to their potency at blocking 6-hydroxydopamine(6-OHDA) neurotoxicity in rats. Amfonelic acid was able to block long-term neostriatal DA depletions when given 8 h, but not 16 h, after a single large MA dose. These results suggest that an intact and functional DA uptake site is necessary for the development of MA-induced long-term DA depletions. INTRODUCTION Analogues of amphetamine (AMPH) are known to have neurotoxic effects on brain monoaminergic neurons. A single 10 mg/kg dose of p-chloroamphetamine (PCA) was shown to decrease tryptophan hydroxylase activity and 5-hydroxytryptamine (5-HT) levels for as long as 4 months after the injection in rats z2. Subsequently, neu- rotoxic effects of PCA were demonstrated by decreased tryptophan hydroxylase activity22 and histological evi- dence of neurotoxicity8. Repeated administration of AMPH or methamphetamine (MA) produce long-term depletions of neostriatal dopamine (DA) levels21'24' 27,31,32, reduction in tyrosine hydroxylase activity3'11, and a loss of DA high-affinity uptake sites 21'27'31 in both rodents and primates. Repeated MA administration, in addition to these toxic effects on DA neurons, produces long-term depletions of 5-HT levels, decreases trypto- phan hydroxylase activity and reduces the number of 5-HT high-affinity uptake sites in rats and other species tl' 21,28. Both MA and AMPH produce degenerating axons and terminals in the neostriatum of rodents as revealed by silver impregnation of degenerating nerve fibers 19'2°. Like PCA, (+)-3,4-methylenedioxyamphetamine (MDA), produces long-term decreases in hippocampal 5-HT and 5-hydroxyindole acetic acid (5-HIAA) levels, 5-HT up- take sites along with degenerating axons and terminals in the hippocampus in rats 17. Most recently, (+)-3,4- methylenedioxymethamphetamine (MDMA) has been shown to have neurotoxic effects on 5-HT neurons 1'23. The monoaminergic uptake carrier sites on DA and 5-HT neurons has been shown to be important regarding the mechanism of the amphetamine analogs! neurotoxic effects. The 5-HT uptake inhibitor fluoxetine blocks the neurotoxic action of PCA, MA and MDMA on 5-HT neurons 5'18'23. Similarly, the DA uptake inhibitor amfo- nelic acid blocks the long-term effects of the combined administration of amphetamine and iprindole on DA neurons 6'7"2°'26. In these experiments, iprindole was given to prolong the metabolism of amphetamine by preventing parahydroxylation of amphetamine 4. In the present report, in order to avoid possible pharmacological con- founding variables through the use of iprindole, we have employed a large, single injection of MA (100 mg/kg, s.c.) to study the ability of DA uptake inhibitors 2'34, (amfonelic acid, AFA; mazindol, MAZ; bupropion, BUP; and benztropine, BENZ) to antagonize long-term MA-induced neostriatal DA and hippocampal 5-HT depletions in rats. We have also tested the ability of these DA uptake inhibitors to prevent i.v.t. 6-OHDA,induced neostriatal DA depletions. Finally, we have characterized the time course over which AFA, when given following MA, is able to antagonize MA-induced neurotoxicity. We have found that the ability of DA uptake inhibitors to prevent MA-induced neurotoxicity parallels their ability to antagonize i.v.t. 6-hydroxydopamine (6-OHDA) le- sions. The present results are consistent with the hypothesis 25 that MA induces neurotoxic effects upon Correspondence: L.S. Seiden, The University of Chicago, Department of Pharmacological and PhysiologicalSciences, 947 East 58th Street, Chicago, IL 60637, U.S.A. 0006-8993/90/$03.50 (~) 1990 Elsevier Science Publishers B.V. (Biomedical Division)