Methamphetamine (METH) is a CNS stimulant with high potential for abuse. Moreover, studies of human METH abusers reveal evidence of neurotoxicity as indicated by long-term decreases in the neuronal marker, n-acetylaspartate (Ernst et al, 2000), and in animals, long-term decreases in markers of dopamine (DA) and 5-HT terminals, including decreases in DA and 5HT transporters and content, VMAT2, and tyrosine and tryptophan hydroxylases. Despite these findings, it is unclear if these changes are indicative of actual neuronal damage, although recent evidence indicates that oxidative stress, hyperglutamatergic activity and microglial activation have important roles.

Emerging findings support the contention that METH produces excitotoxicity and oxidative damage. Calcium influx through ionotropic glutamate receptors and the activation of calcium-dependent proteases cause the breakdown of the structural membrane component, spectrin, in an AMPA receptor-dependent manner (Staszewski and Yamamoto, 2006). Although, METH increases free radicals (Giovanni et al, 1995), only recently has there been evidence of actual oxidative damage after METH. Eyerman and Yamamoto (2007) showed that decreases in VMAT2 after METH were likely due to the nitrosylation of VMAT2 as early as 1 h after METH. Furthermore, the nitrosylation and the long-term reduction in VMAT2 and DA transporter protein were attenuated by inhibition of neuronal nitric oxide synthase (nNOS). This indicates that METH causes a rapid glutamate and nNOS-dependent oxidation of VMAT2 that precedes the long-term reductions in DA and 5HT content, thereby linking glutamate and oxidative damage to long-term decreases in markers of monoamine terminals.

Recent evidence shows that METH can affect protein degradation through oxidative damage. Impairment of the ubiquitin–proteasome system (UPS) can result in neurodegeneration such as that observed in Parkinson's disease. Most recently, Moszczynska and Yamamoto (2011) showed that METH causes an oxidative modification to parkin, one of the E3 ubiquitin–protein ligases, which add polyubiquitin chains to proteins destined for degradation. Parkin protein was decreased at 1 to 24 h after METH administration through the conjugation of parkin with 4-hydroxy-2-nonenal, a lipid peroxidation product. Moreover, METH also decreased the activity of the 26S proteasome. Both the oxidative conjugation of parkin protein and the decreased activity of the 26S proteasome were attenuated by pretreatment with antioxidant, vitamin E. Other evidence indicates that METH can oxidatively modify pyruvate kinase isoform M2, a mediator of cellular energetics and proliferation of neural progenitor cells (Venkatesan et al, 2011), thereby producing decrements in cell metabolism and turnover.

Recently, our preliminary data indicate that α-synuclein levels increased by 200% in the striatum and hippocampus of the rat after METH. α-synuclein is a presynaptic protein that is overexpressed in some neurodegenerative conditions. Its accumulation and the eventual degeneration of the dopaminergic neuron have been associated with parkin, although α-synuclein is not traditionally considered a substrate of parkin and E3 ligase activity. This suggests that there could be a different E3 protein ligase that is oxidatively modified by METH. Further studies are warranted that examine how METH can affect the UPS and its subsequent effects on protein accumulation and degradation.