Methamphetamine-induced degeneration of dopaminergic neurons involves autophagy and upregulation of dopamine synthesis.
Methamphetamine (METH) selectively injures the neurites of dopamine (DA) neurons, generally without inducing cell death. It has been proposed that METH-induced redistribution of DA from the vesicular storage pool to the cytoplasm, where DA can oxidize to produce quinones and additional reactive oxygen species, may account for this selective neurotoxicity. To test this hypothesis, we used mice heterozygous (+/-) or homozygous (-/-) for the brain vesicular monoamine uptake transporter VMAT2, which mediates the accumulation of cytosolic DA into synaptic vesicles. In postnatal ventral midbrain neuronal cultures derived from these mice, METH-induced degeneration of DA neurites and accumulation of oxyradicals, including metabolites of oxidized DA, varied inversely with VMAT2 expression. METH administration also promoted the synthesis of DA via upregulation of tyrosine hydroxylase activity, resulting in an elevation of cytosolic DA even in the absence of vesicular sequestration. Electron microscopy and fluorescent labeling confirmed that METH promoted the formation of autophagic granules, particularly in neuronal varicosities and, ultimately, within cell bodies of dopaminergic neurons. Therefore, we propose that METH neurotoxicity results from the induction of a specific cellular pathway that is activated when DA cannot be effectively sequestered in synaptic vesicles, thereby producing oxyradical stress, autophagy, and neurite degeneration.
Larsen
Kristin E
KE
Department of Neurology, Columbia University, and New York Psychiatric Institute, New York, New York 10032, USA.
Fon
Edward A
EA
Hastings
Teresa G
TG
Edwards
Robert H
RH
Sulzer
David
D
D000818:Animals; D001343:Autophagy / Q000187:drug effects*; D002452:Cell Count; D016923:Cell Death / Q000187:drug effects; D002478:Cells, Cultured; D002851:Chromatography, High Pressure Liquid; D004298:Dopamine / Q000032:analysis / Q000378:metabolism*; D050483:Dopamine Plasma Membrane Transport Proteins; D008562:Membrane Glycoproteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D026901:Membrane Transport Proteins / Q000378:metabolism; D008636:Mesencephalon / Q000166:cytology; D008694:Methamphetamine / Q000633:toxicity*; D051379:Mice; D018345:Mice, Knockout; D008817:Mice, Mutant Strains; D009419:Nerve Tissue Proteins; D016501:Neurites / Q000187:drug effects; D009474:Neurons / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D009479:Neuropeptides; D018384:Oxidative Stress / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects; D013572:Synaptic Vesicles / Q000187:drug effects / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects*; D050492:Vesicular Biogenic Amine Transport Proteins; D050493:Vesicular Monoamine Transport Proteins
D050483:Dopamine Plasma Membrane Transport Proteins; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D009419:Nerve Tissue Proteins; D009479:Neuropeptides; C493453:Slc18a2 protein, mouse; D050492:Vesicular Biogenic Amine Transport Proteins; D050493:Vesicular Monoamine Transport Proteins; D008694:Methamphetamine; D004298:Dopamine