Recent studies have shown that the substituted amphetamines promote the dysregulation of the UPS, which may further contribute to neurotoxic and apoptotic events. A decrease in the activity of the UPS can lead to the accumulation of unwanted proteins and has been implicated in the etiology of various neurodegenerative disorders.165 Furthermore, identified mediators of amphetamine neurotoxicity described in the foregoing, such as GLU-induced NOS activity, mitochondrial dysfunction, and oxidative stress, are known to affect or be affected by the UPS. Inhibition of the proteasome can block inducible NOS degradation166 and potentially increase NO production, NO-mediated nitrosative stress, damage to the ubiquitin ligase, parkin,167 and protein misfolding,168 all of which can potentiate the inhibition of the proteasome.60,169,170 Conversely, proteasomal inhibition can produce an impairment of the mitochondria and a release of proapoptotic proteins.171 Therefore, on the basis of the overlap between mediators of amphetamine toxicity and events associated with the UPS, these studies suggest the view that amphetamines can lead to unwanted accumulation of protein through a dysregulation of the UPS.
Administration of high METH or MDMA doses causes formation of intracellular inclusions in the nucleus of medium-sized GABA neurons and cytoplasm of neurons of the substantia nigra pars compacta of mice.117,172–176 The inclusions in GABA neurons stain for ubiquitin and enzymatic components of the UPS (including E3 ligase parkin) but usually not for α-synuclein, whereas inclusions found in substantia nigra neurons stain for α-synuclein, a hallmark of Lewy bodies frequently observed in Parkinson's disease and other degenerative disorders. Occurrence of ubiquitinated inclusions was also reported in the substantia nigra of 37 subjects who abused METH.177 The specific cause of the inclusions is unknown, but neuronal inclusions can occur when the UPS is inhibited pharmacologically.178,179 Moreover, oxidative stress commonly leads to inclusion formation, and the inclusions produced by METH, MDMA, and MPTP180 are ultrastructurally similar to those produced by DA-mediated oxidative stress.117,172,173 In addition, inclusion formation is decreased upon administration of antioxidant/iron-chelating agent, S-apomorphine.175
It is hypothesized that striatal neuronal inclusions are a consequence of amphetamine-mediated increases in DA release followed by overstimulation of DA D1 receptors.117,181 The underlying mechanism is thought to involve β-arrestin that is present together with ubiquitin in inclusions after exposure of PC12 cells to METH.182 Because β-arrestin is involved in the internalization of DA and mGlu5 receptors,183–185 it suggests the possibility that activation of these receptors contributes to the formation of inclusions in striatal GABA neurons. In addition, DA and non–DA-derived ROS might diffuse to GABA neurons and inhibit the function of proteasome.117
α-Synuclein, a presynaptic protein involved in various degenerative disorders including Parkinson's disease, might also contribute to DA-dependent inclusion formation in nigral cells after toxic amphetamine administration. Increases in α-synuclein levels are known to be toxic to DA neurons in vitro186 and in vivo.187 Administration of METH and MDMA increases expression of α-synuclein in DA neurons in the substantia nigra of mice.176 It is possible that covalent modification of α-synuclein by DA-derived quinone188,189 after amphetamine administration promotes the formation of toxic α-synuclein aggregates.190
Misfolded protein aggregates or damaged organelles that accumulate cannot be degraded by the UPS. This function is reserved for the lysosomal system and the process of microautophagy. Autophagic vacuole formation by the lysosomal system will remove oxidized and damaged organelles (such as mitochondria) and misfolded protein aggregates produced by METH. Conversely, inhibition of autophagy is deleterious to cells because of a diminished ability to clear α-synuclein aggregates after METH exposure, eventually resulting in caspase-dependent cell death.191
Now it is unclear whether a dysfunction of the UPS system is a consequence or a cause of the toxicity to the amphetamines. It remains to be determined if the excitotoxic, oxidative, and inflammatory mediators discussed earlier directly target the UPS and thus disrupt the normal, ongoing removal of unwanted proteins to ultimately produce the demise of cell bodies and terminals. A likely scenario, however, is that the damage produced by the amphetamines is ultimately dependent upon the balance of factors that promote toxicity (e.g., excitotoxic glutamatergic events, prooxidant processes, inflammation) and endogenous protective systems (such as the UPS), antioxidants, and growth-promoting molecules (such as neurotrophic factors) that can be targeted by toxic insults.
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in adolescent rats)