Methamphetamine-induced Neuroinflammation and Neurotoxicity:a Role for Interleukin-1β

Abstract

Thesis (Ph.D.)--University of Rochester. School of Medicine & Dentistry. Dept. of Neurobiology and Anatomy, 2012.Methamphetamine (MA) is a potent, addictive psychostimulant abused by millions of people worldwide. MA exposure induces neurotoxicity, particularly in the striatum, where it damages dopaminergic terminals. In parallel with this neurotoxicity, MA also induces neuroinflammation, characterized by activation of striatal microglia and astrocytes, leading to production of pro-inflammatory cytokines and reactive oxygen species. It is unclear whether MA-induced neuroinflammation contributes to MAinduced neurotoxicity. To address this issue, we examined the time course and dose response of MA-induced neurotoxicity and neuroinflammation to search for time- and dose-specific links between the two, using a binge dosing paradigm of four injections given every two hours to mimic human use patterns; we also focused on the specific contributions of the pro-inflammatory cytokine interleukin-1β (IL-1β) and the inflammation-associated oxidative enzyme NADPH oxidase 2 (NOX2). We found that treatment with at least 4 mg/kg MA per injection decreased striatal dopamine, tyrosine hydroxylase, and dopamine transporter levels within one day, and that these decreases persisted for at least one week. Striatal microglia and astrocytes were both activated one day after binge MA treatment of all doses, including those that did not induce measurable neurotoxicity; while astrocyte activation persisted, microglial activation attenuated during the two weeks of the study. Despite this gliosis, we did not find altered mRNA expression of the pro-inflammatory cytokines tumor necrosis factor α, interleukin 6, or chemokine (C-C motif) ligand 2 in the striatum. IL-1β knock-out (KO) mice were resistant to MA-induced neurotoxicity, and local overexpression of IL-1β exacerbated MA-induced neurotoxicity. However, we were unable to find an increase in striatal IL- 1β expression in the hours and days following MA exposure, suggesting that MAinduced IL-1β upregulation and signaling may primarily occur elsewhere, or may be too subtle or rapid for us to detect. Finally, although MA exposure increased NOX2 mRNA expression in the striatum, NOX2 KO mice were not protected against MA-induced neurotoxicity or glial activation. These findings give insight into the complex relationship between MA-induced neuroinflammation and neurotoxicity