Rat striatal levels of the antioxidant glutathione are decreased following binge administration of methamphetamine

doi:10.1016/S0304-3940(98)00711-3

Neuroscience Letters

Volume 255, Issue 1, 9 October 1998, Pages 49-52

https://doi.org/10.1016/S0304-3940(98)00711-3 Get rights and content

Abstract

Involvement of the glutathione antioxidant system is a characteristic feature of oxidative stress. We examined the influence of binge (4×20 mg/kg every 5 h) and chronic daily (20 mg/kg per day for 10 days) administration of methamphetamine (MA) on brain levels of total glutathione and major glutathione-related enzymes (glutathione peroxidase and reductase; γ-glutamyltranspeptidase; glucose-6-phosphate dehydrogenase) in the rat. Binge, but not chronic MA administration was associated with a regionally specific reduction (−17%, P<0.05) in striatal levels of glutathione 3 h after the last dose of MA, whereas striatal levels of the glutathione-related enzymes were normal. Although the magnitude of the reduction was only modest, these data are compatible with a more severe glutathione decrease localized to dopamine/serotonin nerve terminal areas. Our observations provide further evidence in support of the oxidative stress hypothesis of MA neurotoxicity and indirectly suggest that drugs designed to increase glutathione might protect against such damage.

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Acknowledgements

This investigation was supported by US NIH NIDA DA07185 to S.J.K. A.M. is a predoctoral fellow of the Ontario Mental Health Foundation.

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Bipolar disorder (BD) is a chronic condition characterized by severe mood swings alternating between episodes of mania and depression. Evidence indicates that protein kinase C (PKC) and oxidative stress are important therapeutic targets for BD. However, what PKC isoforms that are precisely involved in this effect are unknown. Therefore, we evaluated the effects of the intracerebroventricular (ICV) injection of PKC inhibitors (lithium (Li), tamoxifen (TMX), PKCα inhibitor (iPKCα), PKCγ inhibitor (iPKCγ), and PKCε inhibitor (iPKCε)) on the manic-like behaviors and oxidative stress parameters (4-hydroxy-2-nonenal (4-HNE), 8-isoprostane (8-ISO), carbonyl groups, 3-nitrotyrosine (3-NT), glutathione peroxidase (GPx) and glutathione reductase (GR)) in the brains of rats submitted to the model of mania induced by methamphetamine (m-AMPH). Animals received a single ICV infusion of artificial cerebrospinal fluid, Li, TMX, iPKCα, iPKCγ or iPKCε followed by an intraperitoneal injection of saline or m-AMPH before the behavioral analysis (open-field task). Oxidative stress was evaluated in the striatum, frontal cortex, and hippocampus. ICV injection of Li, TMX or iPKCε blocked the m-AMPH-induced increase in the manic-like behaviors – crossings, rearings, visits to the center, sniffing, and grooming. ICV infusion of iPKCα triggered a decrease in these behaviors induced by m-AMPH. Besides, the iPKCε administration significantly prevented the oxidative damage to lipids and proteins, as well as disturbances in the activity of antioxidant enzymes induced by m-AMPH. The findings of the present study suggest that PKCε isoform is strongly implied in the antimanic and antioxidant effects of Li, TMX, and the other PKC inhibitors in the model of mania.
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Although drugs of abuse produce divergent effects in the brain, increased dopaminergic signaling primarily in the mesocortical and mesolimbic pathways, is a common underlying mechanism.47–49 At high concentrations, auto-oxidation of the dopamine catechol ring produces quinone and semiquinone species, which reduces the GSH:GSSG ratio.9,50–52 Alternatively, enzymatic oxidation of dopamine via monoamine oxidases results in the formation of hydrogen peroxide.9
Drug addiction is a chronic relapsing disorder that comes at a high cost to individuals and society. Therefore understanding the mechanisms by which drugs exert their effects is of prime importance. Drugs of abuse increase the production of reactive oxygen and nitrogen species resulting in oxidative stress. This change in redox homeostasis increases the conjugation of glutathione to protein cysteine residues; a process called S-glutathionylation. Although traditionally regarded as a protective mechanism against irreversible protein oxidation, accumulated evidence suggests a more nuanced role for S-glutathionylation, namely as a mediator in redox-sensitive protein signaling. The reversible modification of protein thiols leading to alteration in function under different physiologic/pathologic conditions provides a mechanism whereby change in redox status can be translated into a functional response. As such, S-glutathionylation represents an understudied means of post-translational protein modification that may be important in the mechanisms underlying drug addiction. This review will discuss the evidence for S-glutathionylation as a redox-sensing mechanism and how this may be involved in the response to drug-induced oxidative stress. The function of S-glutathionylated proteins involved in neurotransmission, dendritic spine structure, and drug-induced behavioral outputs will be reviewed with specific reference to alcohol, cocaine, and heroin.

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Rat striatal levels of the antioxidant glutathione are decreased following binge administration of methamphetamine

Abstract

Section snippets

Acknowledgements

Methods Enzymol.

Brain Res.

Neurochem. Int.

Biochim. Biophys. Acta

Pharmacology

Exp. Neurol.

Mol. Brain Res.

Methods Enzymol.

Biochem. Biophys. Res. Commun.

J. Nutr. Biochem.

Anal. Biochem.