Amphetamine Neurotoxicity: Cause and Consequence of Oxidative Stress

Abstract

Oxidative stress has been demonstrated to occur in response to high doses of substituted amphetamines such as methamphetamine (METH) and 3,4-methlyene-dioxymethamphetamine (MDMA). This term represents a set of complex and multi-faceted precursor events that occur in both a parallel and serial manner, eventually converging to produce oxidative damage. This critical review goes beyond the compilation of previously well-documented evidence demonstrating that oxidative stress mediates METH and MDMA toxicity to dopamine and/or serotonin nerve terminals. The diverse causes, effects, and impact of pro-oxidative processes produced by these drugs are highlighted, integrated, and assembled into a proposed temporal sequence in an effort to explain the long-term neurochemical changes produced by amphetamines. Multiple factors are considered, including dopamine, glutamate, impaired mitochondrial bioenergetics, and inflammatory processes, all of which converge and are necessary but alone may be insufficient to cause damage to dopamine and/or 5-HT terminals. In addition, the processes linking inflammation and oxidative stress are considered and described as a feedforward process. The self-perpetuating cycle of inflammation and oxidative stress that is initiated by dopamine, glutamate, and mitochondrial dysfunction may extend well beyond the acute pharmacodynamic effects of the drugs and could represent an underlying and potentially progressive degenerative process.

Oxidative Stress and Neurotoxicity

“…In addition to oxidative stress, excitotoxicity and mitochondrial dysfunction appear to play a major role in the neurotoxicity (255,256). There is evidence that oxidative stress arises from peroxidative generation of dopamine quinone from dopamine released by METH into the cytoplasm from synaptic vesicles via reverse transport through the dopamine transporter (257,258).…”

Cellular and molecular mechanisms involved in the neurotoxicity of opioid and psychostimulant drugs

“…Amphetamines and oxidative stress. Exposure to amphetamine or amphetamine derivatives has been shown to induce oxidative stress in the nervous system (Table 2), and this was the subject of previous reviews (Yamamoto and Bankson, 2005;Cadet et al, 2007). Methamphetamine and these drugs may be prevented by antioxidants.…”

Revisiting oxidative stress and mitochondrial dysfunction in the pathogenesis of Parkinson disease—resemblance to the effect of amphetamine drugs of abuse

“…Exposure to amphetamine or amphetamine derivatives has been shown to induce oxidative stress in the nervous system [305,306]. Methamphetamine and DͲamphetamine have been shown to increase ROS levels upon in vitro [307,308] or in vivo [309,310] exposure and the toxic effects of these drugs may be prevented by antioxidants.…”