Methamphetamine, Neurodegeneration, and Differential Vulnerability of Dopamine Neurons

Abstract

Methamphetamine (meth) is an addictive and neurotoxic psychostimulant. Meth increases monoamine oxidase (MAO)-dependent axonal mitochondrial stress in substantia nigra pars compacta (SNc) dopamine (DA) neurons and chronic meth administration causes MAO-dependent SNc degeneration. Ventral tegmental area (VTA) neurons also express and utilize MAO to metabolize DA. The current study examined whether VTA neurons are vulnerable or resistant to chronic meth-induced degeneration and underlying mechanisms. We found that, similar to findings in SNc axons, meth induced MAO-dependent mitochondrial stress in VTA axons; however, the VTA was resistant to chronic meth-induced degeneration. The differentiating feature between SNc and VTA neurons was that SNc axons also had L-type Ca2+ channel (LCC)-dependent mitochondrial stress whereas VTA neurons did not. Both MAO and LCC inhibition attenuated meth-induced degeneration of SNc neurons as did a mitochondrial antioxidant. Together these data suggest that both MAO- and LCC-dependent mitochondrial stress are necessary for meth-induced degeneration.