Putative oxidative metabolites of 1-methyl-6-hydroxy-1,2,3,4-tetrahydro-β-carboline of potential relevance to the addictive and neurodegenerative consequences of ethanol abuse

Wrona, Monika Z.; Waśkiewicz, Jolanta; Qing-ping, Han; Han, Jilin; Li, Hong; Dryhurst, Glenn

doi:10.1016/s0741-8329(96)00144-9

Cited by 16 publications

(13 citation statements)

References 78 publications

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“…Chronic alcohol is well known to produce reactive oxygen species which plays a major role in neurodegeneration. Neurodegeneration is mediated in part by a reduction in cysteine containing GSH in human alcoholic brain and in binge drinking mice (Marballi et al, 2016; Wrona et al, 1997). In addition, increased glutamatergic excitatory signaling within corticostriatal pathways is associated with craving in humans and is necessary for reinstatement in rodents.…”

Section: Genome-wide Association Studies Of Alcohol Dependencementioning

confidence: 99%

Genetic studies of alcohol dependence in the context of the addiction cycle

et al. 2017

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Family, twin and adoption studies demonstrate clearly that alcohol dependence and alcohol use disorders are phenotypically complex and heritable. The heritability of alcohol use disorders is estimated at approximately 50–60% of the total phenotypic variability. Vulnerability to alcohol use disorders can be due to multiple genetic or environmental factors or their interaction which gives rise to extensive and daunting heterogeneity. This heterogeneity makes it a significant challenge in mapping and identifying the specific genes that influence alcohol use disorders. Genetic linkage and (candidate gene) association studies have been used now for decades to map and characterize genomic loci and genes that underlie the genetic vulnerability to alcohol use disorders. These approaches have been moderately successful in identifying several genes that contribute to the complexity of alcohol use disorders. Recently, genome-wide association studies have become one of the major tools for identifying genes for alcohol use disorders by examining correlations between millions of common single-nucleotide polymorphisms with diagnosis status. Genome-wide association studies are just beginning to uncover novel biology; however, the functional significance of results remains a matter of extensive debate and uncertainty. In this review, we present a select group of genome-wide association studies of alcohol dependence, as one example of a way to generate functional hypotheses, within the addiction cycle framework. This analysis may provide novel directions for validating the functional significance of alcohol dependence candidate genes. This article is part of the Special Issue entitled “Alcoholism”.

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Section: Genome-wide Association Studies Of Alcohol Dependencementioning

confidence: 99%

Genetic studies of alcohol dependence in the context of the addiction cycle

et al. 2017

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“…118 The effects of alcohol on the brain are complex and varied with ethanol consumption affecting norepinephrine, serotonin, dopamine, opioid, and GABA signaling. 119,120 The primary effects of ethanol are exerted via GABAA and NMDARs to enhance GABA and inhibit glutamate signaling, which when combined produces an overall depressive effect. 45,121 However, with increasing use, NMDAR function is increased and this is further exacerbated in withdrawal to produce cognitive effects such as delirium.…”

Section: S-glutathionylation In Alcohol Addictionmentioning

confidence: 99%

“…139 Acetaldehyde reacts with 5-hydroxytryptamine in serotonergic neurons to produce 1-methyl-6-hydroxy-1,2,3,4-tetrahydro-β-carboline. 120 The oxidation of this product by hydroxyl radicals produces greater flux in ROS with the potential to cause oxidative damage. 120 The resultant damage to serotonergic neurons and concomitant decrease in 5-hydroxytryptamine is believed to contribute to increased alcohol preference and ultimately addiction.…”

Section: S-glutathionylation In Alcohol Addictionmentioning

confidence: 99%

“…120 The oxidation of this product by hydroxyl radicals produces greater flux in ROS with the potential to cause oxidative damage. 120 The resultant damage to serotonergic neurons and concomitant decrease in 5-hydroxytryptamine is believed to contribute to increased alcohol preference and ultimately addiction. 120 In addition, the GSH conjugates of 1-methyl-6-hydroxy-1,2,3,4-tetrahydro-β-carboline are oxidized to form 8-S-glutathionyl-1-methyl-1,2,3,4-tetrahydro-β-carboline-5,6-dione, which binds to GABA B receptors, stimulation of which results in increased ethanol-addictive-type behaviors such as locomotor stimulation and increased risk of relapse.…”

Section: S-glutathionylation In Alcohol Addictionmentioning

confidence: 99%

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S-Glutathionylation and Redox Protein Signaling in Drug Addiction

Womersley

Uys

2016

Progress in Molecular Biology and Translational Science

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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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“…Acetaldehyde is a very reactive compound. It forms adducts with brain DNA (Steinberg et al, 1997) and biogenic amines (Cohen and Collins, 1970;Davis and Walsh, 1970;Wrona et al, 1997). Ethanol-derived acetaldehyde inhibited growth of rat astroglial (Holownia et al, 1996) and astrocyte cells (Holownia et al, 1999); it also altered the cell cycle, increased cellular calcium, and brought about DNA fragmentation in these cells.…”

mentioning

confidence: 99%