Chronic Methamphetamine Administration Increases Mitochondrial Density and Impairs Mitochondrial Function in the Substantia Nigra Pars Compacta.

Methamphetamine (meth) is an addictive psychostimulant that induces monoamine oxidase (MAO)-dependent mitochondrial oxidative stress and MAO-dependent degeneration of substantia nigra pars compacta (SNc) dopamine neurons in male mice, suggesting that meth-induced mitochondrial oxidative stress is necessary for degeneration. However, the impact of chronic in vivo meth administration on SNc mitochondria is unclear. We therefore examined the impact of chronic meth administration on the expression of mitochondrial fission 1 (FIS1) and Dynamin-related protein 1 (DRP1), proteins involved in mitophagy, as well as mitochondrial density and mitochondrial function in the SNc. Male C57BL/6J mice received saline or meth (5 mg/kg; i.p.) for 28 days; chronic meth administration decreased SNc expression of both DRP1 and FIS1 proteins, suggesting impaired mitophagy. Consistent with this, mitochondrial density in SNc dopamine neurons was also increased. Moreover, this increase in mitochondrial density was MAO-dependent, suggesting that chronic meth-induced SNc degeneration is associated with an increase in mitochondrial density. To determine whether mitochondria were functional, high-resolution respirometry assessments were conducted using SNc tissue from mice treated with either chronic meth or saline. Results indicate that chronic in vivo meth administration decreased mitochondrial complex I as well as complex I + II oxidative phosphorylation capacities and coupling efficiencies in the SNc. Presented data suggest that chronic in vivo meth administration results in an accumulation of functionally compromised mitochondria in the SNc, which is associated with and may potentially contribute to chronic meth-induced neurodegeneration.