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 mM), the succi-nate 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 re-lease by 30-fold, similar to that seen after systemic administra-tion, but did not increase glutamate or body temperature, and did not deplete neurotransmitter content. Malonate perfusion increased both DA and glutamate overflow, and dose depen-dently 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 dopami-nergic terminals are more vulnerable than 5-HT terminals to damage after metabolic stress. Methamphetamine (MA) is a psychostimulant that induces lasting depletions of striatal dopamine (DA) and serotonin (5-HT) content (Seiden et al., 1975, 1976; Ricaurte et al., 1980). Despite characterization of MA-induced toxicity over the past 25 years, it remains unknown how this drug of abuse damages the brain. There is evidence that MA increases both oxidative and metabolic stress, which may mediate the toxic effects of this drug. Systemic MA increases hydroxyl radical formation and leads to protein modification in the striatu