In Vivo Effects of Chronic Methamphetamine Exposure: A Study of Elemental and Inflammatory Responses and Potential Mechanisms for Zinc Accumulation in the Midbrain

Abstract

There is a well-established association between methamphetamine intoxication and neurodegeneration. Excessive buildup of zinc in the brain is implicated in many neurodegenerative diseases. The pathology of these diseases parallels the damage that occurs following methamphetamine exposure, exerting the maximum effect in dopaminergic brain regions. Therefore, we hypothesize that accumulation of zinc in the brain is involved in the exacerbated neurodegeneration following methamphetamine treatment. Adult C57BL/6J mice were injected intraperitoneally with either saline or 5 mg/kg methamphetamine for ten days to model addictive behavior. On Day 10, dopaminergic brain regions were isolated and sonicated. Elemental levels in brain homogenates were determined by Total Reflection X-Ray Fluorescence. Zinc concentration was significantly increased in the midbrain of methamphetamine treated mice compared to saline treated mice (p0.05) or expression of the brain-specific zinc transporter, metallothionein 3 (mRNA expression p>0.05), as measured by an activity assay and real-time PCR analysis, respectively. Histological analysis of Evans Blue permeation of the blood brain barrier is currently underway, and will determine whether our METH dose is sufficient to cause blood brain barrier breakdown, allowing metal accumulation. Notably, mRNA expression of interleukin 1-beta is significantly decreased (p