EXCITOTOXIC STRIATAL LESIONS PROTECT AGAINST SUBSEQUENT METHAMPHETAMINE-INDUCED DOPAMINE DEPLETIONS

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 mu l) 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 [H-3]SCH 23390 and [H-3]spiroperidol binding to D1 and D2 receptors, respectively. However, QA infusions by themselves did not significantly change the DA content or [H-3]mazindot 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. Several mechanisms for the protective influence of the QA infusion are discussed, including (1) removal of neurons that are part of a circuit necessary for m-AMPH-induced neurotoxicity, (2) glial response to QA infusion and (3) alterations within the surviving dopaminergic afferent fibers that render them resistant to m-AMPH-induced toxicity.