Chronic methamphetamine-induced neurodegeneration: Differential vulnerability of ventral tegmental area and substantia nigra pars compacta dopamine neurons

Differential vulnerability of locus coeruleus and dorsal raphe neurons to chronic methamphetamine-induced degeneration

“…Consistent with deleterious effects on the nigrostriatal system, patients with a history of meth abuse have an increased risk for developing Parkinson's disease (Callaghan et al, 2010(Callaghan et al, , 2012Curtin et al, 2015), the most common neurodegenerative movement disorder in which nigrostriatal degeneration is a hallmark. Recent work has linked the pharmacological actions of meth to mitochondrial oxidant stress and nigrostriatal degeneration (Graves et al, 2020Du et al, 2021).…”

“…These electrons enter the mitochondrial intermembrane space, increasing mitochondrial oxidant stress (Graves et al, 2020). Persistently engaging this MAO-dependent mitochondrial stress pathway via chronic 28-day in vivo administration of meth (5 mg/kg) results in overt degeneration of substantia nigra pars compacta (SNc) dopamine neurons whereas inhibiting MAO prevents degeneration (Du et al, 2021;. Administration of meth using an acute binge paradigm also produces SNc degeneration (Sonsalla et al, 1996;Ares-Santos et al, 2014;Mendieta et al, 2016).…”

“…Administration of meth using an acute binge paradigm also produces SNc degeneration (Sonsalla et al, 1996;Ares-Santos et al, 2014;Mendieta et al, 2016). However, neighboring ventral tegmental area (VTA) dopamine neurons are resistant to chronic meth-induced degeneration despite also having meth-induced MAO-dependent mitochondrial stress (Du et al, 2021). A differentiating feature between SNc and VTA dopamine neurons is the presence of L-type Ca 2+ -dependent mitochondrial oxidant stress in SNc but not VTA neurons (Chan et al, 2007;Guzman et al, 2010;Surmeier et al, 2017;Du et al, 2021).…”

“…However, neighboring ventral tegmental area (VTA) dopamine neurons are resistant to chronic meth-induced degeneration despite also having meth-induced MAO-dependent mitochondrial stress (Du et al, 2021). A differentiating feature between SNc and VTA dopamine neurons is the presence of L-type Ca 2+ -dependent mitochondrial oxidant stress in SNc but not VTA neurons (Chan et al, 2007;Guzman et al, 2010;Surmeier et al, 2017;Du et al, 2021). Like MAO inhibition, L-type Ca 2+ channel inhibition similarly prevents chronic meth-induced SNc degeneration, indicating that meth drives degeneration through MAO-dependent mitochondrial stress whereas vulnerability is determined, at least in part, by the presence of L-type Ca 2+ -dependent mitochondrial stress (Du et al, 2021).…”

“…LC norepinephrine neurons, like SNc dopamine neurons, exhibit somatic L-type Ca 2+ channeldependent mitochondrial stress (Sanchez-Padilla et al, 2014). However, meth-induced MAO-dependent mitochondrial stress in dopamine neurons occurs in axonal but not somatic compartments (Graves et al, 2020;Du et al, 2021) and it is unknown whether LC neurons, like SNc neurons (Du et al, 2021), also have L-type Ca 2+ channel-dependent mitochondrial oxidant stress in the axonal compartment. The status of L-type Ca 2+ channel-dependent mitochondrial oxidant stress in serotonergic DR neurons is unknown.…”