Substrates of Energy Metabolism Attenuate Methamphetamine‐Induced Neurotoxicity in Striatum

Abstract

High doses of methamphetamine (METH) produce a long-term depletion in striatal tissue dopamine content. The mechanism mediating this toxicity has been associated with increased concentrations of dopamine and glutamate and altered energy metabolism. In vivo microdialysis was used to assess and alter the metabolic environment of the brain during high doses of METH. METH significantly increased extracellular concentrations of lactate in striatum and prefrontal cortex. This increase was significantly greater in striatum and coincided with the greater vulnerability of this brain region to the toxic effects of METH. To examine the effect of supplementing energy metabolism on METH-induced dopamine content depletions, the striatum was perfused directly with decylubiquinone or nicotinamide to enhance the energetic capacity of the tissue during or after a neurotoxic dosing regimen of METH. When decylubiquinone or nicotinamide was perfused into striatum during the administration of METH, there was no significant effect on METH-induced striatal dopamine efflux, glutamate efflux, or the longterm dopamine depletions measured 7 days later. However, a delayed perfusion with decylubiquinone or nicotinamide for 6 h beginning immediately after the last METH injection attenuated the METH-induced striatal dopamine depletions measured 1 week later. These results support the hypothesis that the compromised metabolic state produced by METH administration predisposes dopamine terminals to the neurotoxic effects of glutamate, dopamine, and/or free radicals. Key Words: Methamphetamine -Dopamine-Glutamate -Striatum -Neurotoxicity-Energy metabolism.

Changes in Gene Expression Linked to Methamphetamine-Induced Dopaminergic Neurotoxicity

“…Of the various genes with expression that changed differentially in the setting of METH-induced DA neural injury, we elected to further explore the increase in COX1 because of reports implicating energy metabolism in METH neurotoxicity (Huang et al, 1997;Stephans et al, 1998;Burrows et al, 2000a) and because of reports that the DA neurotoxic effects of 1-methyl-4-phenyltetrahydropyridine (MPTP) and 6-hydroxydopamine (6-OHDA) are also associated with changes in COX activity (see below). To this end, Northern blotting studies were performed, followed by in situ hybridization studies.…”

“…Furthermore, there is evidence that at least part of the effect of temperature on METH neurotoxicity is mediated at the level of the DAT (Xie et al, 2000). More recent studies have also implicated energy metabolism (Huang et al, 1997;Stephans et al, 1998;Burrows et al, 2000a) and possibly ion dysregulation in the METH-induced DA neurotoxic process.…”

“…Furthermore, there is evidence that at least part of the effect of temperature on METH neurotoxicity is mediated at the level of the DAT (Xie et al, 2000). More recent studies have also implicated energy metabolism (Huang et al, 1997;Stephans et al, 1998;Burrows et al, 2000a) and possibly ion dysregulation in the METH-induced DA neurotoxic process.Primarily because of technical barriers, the possibility that gene expression might be involved in METH neurotoxicity has been relatively unexplored. However, with the recent development of microarray technology, it is now possible to rapidly screen large numbers of potentially relevant genes in biological processes.…”

Effect of Glucoprivation on Serotonin Neurotoxicity Induced by Substituted Amphetamines

“…Second, toxic doses of METH have also been reported to decrease levels of striatal ATP (Chan et al, 1994). Third, substituted amphetamine-induced DA neurotoxicity is attenuated by nicotinamide (Huang et al, 1997;Stephans et al, 1998;Wan et al, 1999), which increases neuronal ATP concentrations, and is potentiated by malonate, a metabolic inhibitor (Albers et al, 1996;Nixdorf et al, 2001). Fourth, 2-DG has been found to enhance amphetamine-induced DA neurotoxicity (Chan et al, 1994), although not in all studies (Callahan et al, 1998;Hervias et al, 2000).…”

“…First, increased tissue levels of lactate, suggesting of increased metabolic demand, are observed after repeated doses of METH (Stephans et al, 1998). Second, toxic doses of METH have also been reported to decrease levels of striatal ATP (Chan et al, 1994).…”