Abstract
Methamphetamine (Meth) abuse has been shown to induce alterations in mitochondrial function in the brain as well as to induce hyperthermia, which contributes to neurotoxicity and Meth-associated mortality. Brown adipose tissue (BAT), a thermogenic site known to be important in neonates, has recently regained importance since being identified in significant amounts and in correlation with metabolic balance in human adults. Given the high mitochondrial content of BAT and its role in thermogenesis, we aimed to investigate whether BAT plays any role in the development of Meth-induced hyperthermia. By ablating or denervating BAT, we identified a partial contribution of this organ to Meth-induced hyperthermia. BAT ablation decreased temperature by 0.5°C and reduced the length of hyperthermia by 1 h, compared to sham-operated controls. BAT denervation also affected the development of hyperthermia in correlation with decreased the expression of electron transport chain molecules, and increase on PCG1a levels, but without affecting Meth-induced uncoupling protein 1 upregulation. Furthermore, in isolated BAT cells in culture, Meth, but not Norepinephrine, induced H2O2 upregulation. In addition, we found that in vivo Reactive Oxygen Species (ROS) play a role in Meth hyperthermia. Thus, sympathetically mediated mitochondrial activation in the BAT and Meth-induced ROS are key components to the development of hyperthermia in Meth abuse.
Highlights
INTRODUCTION dMethamphetamine HCl Methamphetamine (Meth) is a powerful stimulant with potent addictive and neurotoxic properties
The Respiratory exchange ratio (RER) was calculated from ventilated CO2 (VCO2) divided by ventilated Oxygen (VO2) during the same period, and Heat production was derived from VO2 measurements normalized with body mass, as described in Section “Materials and Methods.”
All animals showed a transient peak in temperature and motor activity (MA) immediately after the injection, which was caused by the stress of manipulation, but there was no significant difference between groups
Summary
Methamphetamine HCl Methamphetamine (Meth) is a powerful stimulant with potent addictive and neurotoxic properties. It is illegally used for various reasons, including weight loss, alertness, and enhancement of sexual pleasure, and is popular due to its price, availability, and effects. Meth is a substrate for the Dopamine (DA) transporter, which allows the drug access to DAergic neurons, where it inhibits the vesicular monoamine transporter, increasing DA in the synaptic cleft. This can result in nerve terminal damage and neurotoxicity through mechanisms that are not yet fully understood. How the mechanisms by which Reactive Oxygen species (ROS) are generated in Meth abuse, in addition to how ROS generated in peripheral sites such as brown adipose tissue (BAT) contribute to the hyperthermia phenomenon, have not been extensively explored
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