Characterization of binge-dosed methamphetamine-induced neurotoxicity and neuroinflammation.
Methamphetamine (MA) is a potent, highly addictive psychostimulant abused by millions of people worldwide. MA induces neurotoxicity, damaging striatal dopaminergic terminals, and neuroinflammation, with striatal glial activation leading to pro-inflammatory cytokine and reactive oxygen species production. It is unclear whether MA-induced neuroinflammation contributes to MA-induced neurotoxicity. In the current study, we examined the linkage between the time course and dose response of MA-induced neurotoxicity and neuroinflammation. Adult male mice underwent a binge dosing regimen of four injections given every 2h with doses of 2, 4, 6, or 8 mg/kg MA per injection, and were sacrificed after 1, 3, 7, or 14 days. Binge MA treatment dose-dependently caused hyperthermia and induced hypoactivity after one day, though activity returned to control levels within one week. Striatal dopamine (DA) was diminished one day after treatment with at least 4 mg/kg MA, while DA turnover rates peaked after seven days. Although striatal tyrosine hydroxylase and DA transporter levels were also decreased one day after treatment with at least 4 mg/kg MA, they trended toward recovery by day 14. All doses of MA activated striatal glia within one day. While astrocyte activation persisted, microglial activation was attenuated over the two weeks of the study. These findings help clarify the relationship between MA-induced neuroinflammation and neurotoxicity, particularly regarding their temporal and dose-specific dynamics.
Department of Neurobiology and Anatomy, University of Rochester School of Medicine and Dentistry, 601 Elmwood Ave, Box 603, Rochester, NY 14642, USA. Electronic address: SEAMcConnell@gmail.com.
Sarah E A
SE
McConnell
Department of Neurobiology and Anatomy, University of Rochester School of Medicine and Dentistry, 601 Elmwood Ave, Box 603, Rochester, NY 14642, USA.
M Kerry
MK
O'Banion
Department of Environmental Medicine, University of Rochester School of Medicine and Dentistry, 601 Elmwood Ave, Box EHSC, Rochester, NY 14642, USA.
Deborah A
DA
Cory-Slechta
Department of Neurobiology and Anatomy, University of Rochester School of Medicine and Dentistry, 601 Elmwood Ave, Box 603, Rochester, NY 14642, USA.
John A
JA
Olschowka
Department of Neurobiology and Anatomy, University of Rochester School of Medicine and Dentistry, 601 Elmwood Ave, Box 603, Rochester, NY 14642, USA; Department of Environmental Medicine, University of Rochester School of Medicine and Dentistry, 601 Elmwood Ave, Box EHSC, Rochester, NY 14642, USA.
Lisa A
LA
Opanashuk
D000818:Animals; D015306:Biogenic Monoamines / Q000378:metabolism; D001831:Body Temperature / Q000187:drug effects; D002135:Calcium-Binding Proteins / Q000378:metabolism*; D000697:Central Nervous System Stimulants / Q000633:toxicity*; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism; D004195:Disease Models, Animal; D050483:Dopamine Plasma Membrane Transport Proteins / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D055664:Electrochemical Techniques; D004660:Encephalitis / Q000139:chemically induced* / Q000503:physiopathology; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D008297:Male; D008694:Methamphetamine / Q000633:toxicity*; D051379:Mice; D008810:Mice, Inbred C57BL; D008840:Microfilament Proteins / Q000378:metabolism*; D009043:Motor Activity / Q000187:drug effects; D020258:Neurotoxicity Syndromes / Q000209:etiology* / Q000503:physiopathology; D013997:Time Factors; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism
C491049:Aif1 protein, mouse; D015306:Biogenic Monoamines; D002135:Calcium-Binding Proteins; D000697:Central Nervous System Stimulants; D050483:Dopamine Plasma Membrane Transport Proteins; D005904:Glial Fibrillary Acidic Protein; D008840:Microfilament Proteins; D008694:Methamphetamine; D014446:Tyrosine 3-Monooxygenase
Astrocytes; Methamphetamine; Microglia; Neuroinflammation; Neurotoxicity; Striatum