Effects of lubeluzole on the methamphetamine-induced increase in extracellular glutamate and the long-term depletion of striatal dopamine

The administration of a neurotoxic regimen of methamphetamine (MA) produces an acute elevation in the extracellular concentrations of dopamine and glu tamate in the striatum and a long-term depletion of striatal dopamine conte nt in rats. The intent of the present study was to determine whether attenu ation of the MA-induced increase in extracellular glutamate would prevent t he depletion of striatal dopamine. Male rats were treated with MA (10 mg/kg , i.p.) or vehicle every 2 h for four injections and concomitantly perfused intrastriatally with either artificial cerebrospinal fluid or lubeluzole ( 300 muM), a novel neuroprotectant that has been shown to prevent the increa se in extracellular glutamate after the induction of neocortical infarct in rats. Lubeluzole significantly attenuated the MA-induced increase in extra cellular glutamate in the striatum without affecting the MA-induced increas e in extracellular dopamine or the MA-induced hyperthermic response. Nevert heless, lubeluzole did not prevent the long-term depletion of striatal dopa mine produced by a neurotoxic regimen of MA. These results suggest that the MA-induced depletion of striatal dopamine may not be dependent on the incr eased extracellular concentration of striatal glutamate. Synapse 40: 95-101 , 2001. (C) 2001 Wiley-Liss, Inc.