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Excitotoxic striatal lesions protect against subsequent methamphetamine- induced dopamine depletions

SJ O'Dell, FB Weihmuller, RJ McPherson and JF Marshall

Department of Psychobiology, University of California, Irvine.

Repeated administration of methamphetamine (m-AMPH) produces a prolonged elevation of extracellular dopamine (DA) levels in rat striatum and subsequent damage to striatal DA terminals. In the present study, a unilateral striatal infusion of quinolinic acid (QA) (15 ug/0.5 microliter) 2 weeks before repeated m-AMPH treatment (four injections of 4 mg/kg, s.c., at 2-hr intervals) protected that striatum from m-AMPH-induced DA terminal injury. One week after m-AMPH treatments, striatal DA contents were substantially below control values in the vehicle-infused striata, whereas the DA contents of the QA-infused striata were equal to those of animals not exposed to m- AMPH. The QA infusions alone injured striatal neurons, as indicated by decreased [3H]SCH 23390 and [3H]spiroperidol binding to D1 and D2 receptors, respectively. However, QA infusions by themselves did not significantly change the DA content or [3H]mazindol binding to the high- affinity DA transporter of the infused striata 3 weeks later. In vivo microdialysis was performed in the previously QA- or vehicle-infused striata during regimens of repeated m-AMPH or saline treatments. QA infusions that were effective in protecting against m-AMPH neurotoxicity did not significantly reduce stimulant-induced DA overflow, compared with the overflow that occurred in the vehicle- infused striata of m-AMPH-treated rats. Thus m-AMPH-induced DA overflow appears to be dissociated from the resulting DA terminal injury in the QA-infused striatum.(ABSTRACT TRUNCATED AT 250 WORDS)

Volume 269, Issue 3, pp. 1319-1325, 06/01/1994
Copyright © 1994 by American Society for Pharmacology and Experimental Therapeutics




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Copyright © 1994 by the American Society for Pharmacology and Experimental Therapeutics.