Abstract
Methamphetamine (METH), an addictive psycho-stimulant drug exerts euphoric effects on users and abusers. It is also known to cause cognitive impairment and neurotoxicity. Here, we hypothesized that METH exposure impairs the glucose uptake and metabolism in human neurons and astrocytes. Deprivation of glucose is expected to cause neurotoxicity and neuronal degeneration due to depletion of energy. We found that METH exposure inhibited the glucose uptake by neurons and astrocytes, in which neurons were more sensitive to METH than astrocytes in primary culture. Adaptability of these cells to fatty acid oxidation as an alternative source of energy during glucose limitation appeared to regulate this differential sensitivity. Decrease in neuronal glucose uptake by METH was associated with reduction of glucose transporter protein-3 (GLUT3). Surprisingly, METH exposure showed biphasic effects on astrocytic glucose uptake, in which 20 µM increased the uptake while 200 µM inhibited glucose uptake. Dual effects of METH on glucose uptake were paralleled to changes in the expression of astrocytic glucose transporter protein-1 (GLUT1). The adaptive nature of astrocyte to mitochondrial β-oxidation of fatty acid appeared to contribute the survival of astrocytes during METH-induced glucose deprivation. This differential adaptive nature of neurons and astrocytes also governed the differential sensitivity to the toxicity of METH in these brain cells. The effect of acetyl-L-carnitine for enhanced production of ATP from fatty oxidation in glucose-free culture condition validated the adaptive nature of neurons and astrocytes. These findings suggest that deprivation of glucose-derived energy may contribute to neurotoxicity of METH abusers.
Highlights
Methamphetamine (METH) is the second most popular illicit drug widely used in the world
Our findings revealed that human neuronal glucose transporter protein-3 (GLUT3) and astrocytic glucose transporter protein-1 (GLUT1) are affected by METH exposure
Since cytochalasin B exacerbated the effect of METH, these data suggest that the impairment of glucose transporter function may contribute to neuronal loss in chronic METH exposure
Summary
Methamphetamine (METH) is the second most popular illicit drug widely used in the world. It is very prevalent in Western, Southern and Midwestern states of USA [1]. METH abuse is known to promote neurotoxicity by altering dopamine levels [6], as such initial accumulation and long-term depletion of dopamine in the brain causing loss of dopaminergic neurons [7,8]. Initial dopamine accumulation and gradual long-term dopamine depletion associating with neurotoxicity is a typical mechanism of action of METH abuse [13,14]. This is because the ability of METH to release dopamine rapidly and inhibits the reuptake, and/or perhaps blocking the metabolism of dopamine in the reward regions produces the euphoric feeling to METH abusers
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