Genes and Gene Expression in the Brains of Human Alcoholics

Dodd, Peter R.; Buckley, Sue; Eckert, Allison L.; Foley, P. F.; Innes, David J.

doi:10.1196/annals.1369.010

Cited by 12 publications

(12 citation statements)

References 33 publications

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“…Thus, Dodd and colleagues reported that the GABRB2 gene, which encodes for the β2 subunit, did not influence the β2 subunit expression; rather, expression of β3 subunit was increased in controls with GABRB2-1,2 genotype, but not in alcoholics with the same genotype (Dodd et al 2004). Furthermore, aldehyde dehydrogenase ADH1C, D2 dopamine receptor DRD2B, excitatory amino acid transporter 2 EAAT2, and apolipoprotein E APOE genotypes modulate GABA A receptor β subunit expression in superior frontal cortex toward a less-effective form of the receptor (Dodd et al 2004, 2006). Alleles associated with alcoholism also appear to reduce the β3:β2 ratios in alcoholic’s superior frontal cortex.…”

Section: Human Alcoholicsmentioning

confidence: 99%

The role of GABAA receptors in the acute and chronic effects of ethanol: a decade of progress

et al. 2009

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The past decade has brought many advances in our understanding of GABA A receptor-mediated ethanol action in the central nervous system. We now know that specific GABA A receptor subtypes are sensitive to ethanol at doses attained during social drinking while other subtypes respond to ethanol at doses attained by severe intoxication. Furthermore, ethanol increases GABAergic neurotransmission through indirect effects, including the elevation of endogenous GABAergic neuroactive steroids, presynaptic release of GABA, and dephosphorylation of GABA A receptors promoting increases in GABA sensitivity. Ethanol's effects on intracellular signaling also influence GABAergic transmission in multiple ways that vary across brain regions and cell types. The effects of chronic ethanol administration are influenced by adaptations in GABA A receptor function, expression, trafficking, and subcellular localization that contribute to ethanol tolerance, dependence, and withdrawal hyperexcitability. Adolescents exhibit altered sensitivity to ethanol actions, the tendency for higher drinking and longer lasting GABAergic adaptations to chronic ethanol administration. The elucidation of the mechanisms that underlie adaptations to ethanol exposure are leading to a better understanding of the regulation of inhibitory transmission and new targets for therapies to support recovery from ethanol withdrawal and alcoholism.

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Section: Human Alcoholicsmentioning

confidence: 99%

The role of GABAA receptors in the acute and chronic effects of ethanol: a decade of progress

et al. 2009

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“…It is well known that this system is modulated by both inhibitory and stimulatory inputs, including GABAergic and glutamatergic neurons (Johnson, 2005). Chronic alcohol usage may be associated with alteration in the subunit composition of the GABA receptors in human (Dodd et al, 2006). The GABA A receptor in particular may be pivotal in the sex disparity in response to alcohol intake.…”

Section: Gaba Receptorsmentioning

confidence: 99%

“…The GABA A receptor in particular may be pivotal in the sex disparity in response to alcohol intake. Alcohol is known to alter GABAergic neurotransmission through GABA A receptor, which plays an essential role in acute response to alcohol, alcohol dependence and self-administration (Grobin et al, 1998; Dodd et al, 2006). Activation of the GABA A receptor also mediates behavioral responses including, motor ability, anxiolytic responses, and sedating responses to alcohol (Grobin et al, 1998; Abramov et al, 2006).…”

Section: Gaba Receptorsmentioning

confidence: 99%

“…Chronic alcohol exposure is associated with increased NMDA receptor responsiveness and decreased GABA A receptor activation, which may be due to alterations in the receptor subunit expression for both alcohol target systems (Devaud and Morrow, 1999; Dodd et al, 2006). In glutamatergic system, neuroadaptations in the NMDA receptor system appear to be important in sex dimorphism following alcohol intake (Devaud and Morrow, 1999; Johnson, 2005).…”

Section: Nmda Receptorsmentioning

confidence: 99%

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Sex difference in alcoholism: Who is at a greater risk for development of alcoholic complication?

2010

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Aims-Alcohol abuse and alcoholism are among the major medical problems afflicting both men and women. While men display a higher prevalence for alcoholism, it is women who suffer a much greater risk for alcoholism-associated bodily damage. Although women generally consume less alcohol compared to men, females usually suffer more severe brain and other organ damage following binge or chronic alcohol abuse. Main methods and key findings: Although many biological (i.e., genetic risk and neurological abnormalities) and psychosocial (i.e., impact of positive drinking expectancies, personality characteristics and deviance proneness) factors appear to impact men and women equally. These factors especially social and environmental, physiological, genetic and neurobiological ones have been demonstrated to contribute to the sex difference in response to alcohol intake, as well as the development of alcoholic complications. A number of neurotransmitters and growth factors may be partially involved in these differences between men and women. The mesolimbic dopamine system is implicated in the development of addictive behaviors. Differences in dopamine receptor density are found between sexes where gonadal steroid hormones may play a role. Inhibitory GABAergic and stimulatory glutamatergic systems also act as neuromodulators in the brain and differences in their specific receptors have been identified between men and women (particularly GABA A receptors and NMDA receptors).Significance-Given the variety of factors contributing to the sex difference in response to alcohol intake, alcoholism treatment should take sex dimorphism into consideration. Furthermore, future research needs to be directed towards a better understanding of the mechanism of action of alcohol in both men and women.

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“…The mechanisms by which alcohol achieves its short-and long-term effects on the brain are largely unknown, although ion channels and neurotransmitter receptors have become the targets of intense inquiry (Worst and Vrana, 2005). A number of excellent studies using gene arrays have identified a variety of genes that are upregulated or downregulated by short-or long-term exposure to alcohol in experimental animals and man (Lewohl et al, 2000;Dodd et al, 2006;Mulligan et al, 2006). Despite these investigations, little is known of the molecular mechanisms by which alcohol might alter transcriptional efficiency (Wilke et al, 1994;Hassan et al, 2003).…”

Section: Introductionmentioning

confidence: 99%

Alcohol Regulates Gene Expression in Neurons via Activation of Heat Shock Factor 1

Pignataro

Miller²,

Ma³

et al. 2007

J. Neurosci.

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Drinking alcohol causes widespread alterations in gene expression that can result in long-term physiological changes. Although many alcohol-responsive genes (ARGs) have been identified, the mechanisms by which alcohol alters transcription are not well understood. To elucidate these mechanisms, we investigated Gabra4, a neuron-specific gene that is rapidly and robustly activated by alcohol (10 -60 mM), both in vitro and in vivo. Here we show that alcohol can activate elements of the heat shock pathway in mouse cortical neurons to enhance the expression of Gabra4 and other ARGs. The activation of Gabra4 by alcohol or high temperature is dependent on the binding of heat shock factor 1 (HSF1) to a short downstream DNA sequence, the alcohol response element (ARE). Alcohol and heat stimulate the translocation of HSF1 from the cytoplasm to the nucleus and the induction of HSF1-dependent genes, Hsp70 and Hsp90, in cultured neurons and in the mouse cerebral cortex in vivo. The reduction of HSF1 levels using small interfering RNA prevented the stimulation of Gabra4 and Hsp70 by alcohol and heat shock. Microarray analysis showed that many ARGs contain ARE-like sequences and that some of these genes are also activated by heat shock. We suggest that alcohol activates phylogenetically conserved pathways that involve intermediates in the heat shock cascade and that sequence elements similar to the ARE may mediate some of the changes in gene expression triggered by alcohol intake, which could be important in a variety of pathophysiological responses to alcohol.

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Genes and Gene Expression in the Brains of Human Alcoholics

Cited by 12 publications

References 33 publications

The role of GABAA receptors in the acute and chronic effects of ethanol: a decade of progress

The role of GABAA receptors in the acute and chronic effects of ethanol: a decade of progress

Sex difference in alcoholism: Who is at a greater risk for development of alcoholic complication?

Alcohol Regulates Gene Expression in Neurons via Activation of Heat Shock Factor 1

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