Central administration of methamphetamine synergizes with metabolic inhibition to deplete striatal monoamines.

These studies examined, in vivo, the effect of local intrastriatal perfusion of methamphetamine (MA) on dopamine (DA) and glutamate release in relation to changes in striatal DA and serotonin (5-HT) content measured 1 week after treatment. Interactions between the inhibition of energy metabolism and the direct perfusion of MA on long-term decreases in DA and 5-HT content also were investigated. MA (100 microM), the succinate dehydrogenase inhibitor malonate, or the combination of MA and malonate was reverse-dialyzed into the striatum for 8 h. The continuous local perfusion of MA alone increased DA release by 30-fold, similar to that seen after systemic administration, but did not increase glutamate or body temperature, and did not deplete neurotransmitter content. Malonate perfusion increased both DA and glutamate overflow, and dose dependently decreased DA content. 5-HT content was not as affected by malonate perfusions (200 mM malonate depleted DA by 66% and 5-HT by 40%). When MA was coperfused with 200 mM malonate, DA content was reduced by 80% and to a greater extent compared with malonate alone. Coperfusion of MA and 200 mM malonate did not enhance 5-HT loss. Overall, the present findings provide evidence that energy metabolism plays an important role in MA toxicity and that striatal dopaminergic terminals are more vulnerable than 5-HT terminals to damage after metabolic stress.