Titrating Tipsy Targets: The Neurobiology of Low-Dose Alcohol

Cui, Changhai; Koob, George F.

doi:10.1016/j.tips.2017.03.002

Cited by 42 publications

(33 citation statements)

References 78 publications

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“…Behavioral, biochemical, and molecular pharmacological evidence indicates that N -methyl- D -aspartate (NMDA) receptors are one of the primary targets of ethanol. Other primary targets include γ-aminobutyric acid A (GABA A ), glycine, serotonin-3, and neuronal nicotinic acetylcholine receptors, as well as L-type calcium channels and G protein-activated inwardly rectifying potassium channels (reviewed in Spanagel, 2009 ; Cui and Koob, 2017 ). Concentrations as low as 1 mM produce alterations in the function of these receptors and ion channels, which initiate a cascade of intracellular events and lead to the acute behavioral effects of ethanol that range from disinhibition to sedation and hypnosis (depending on the dose).…”

Section: Introductionmentioning

confidence: 99%

Binge Ethanol Drinking Produces Sexually Divergent and Distinct Changes in Nucleus Accumbens Signaling Cascades and Pathways in Adult C57BL/6J Mice

Finn¹,

Hashimoto²,

Cozzoli³

et al. 2018

Front. Genet.

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We previously determined that repeated binge ethanol drinking produced sex differences in the regulation of signaling downstream of Group 1 metabotropic glutamate receptors in the nucleus accumbens (NAc) of adult C57BL/6J mice. The purpose of the present study was to characterize RNA expression differences in the NAc of adult male and female C57BL/6J mice following 7 binge ethanol drinking sessions, when compared with controls consuming water. This binge drinking procedure produced high intakes (average >2.2 g/kg/30 min) and blood ethanol concentrations (average >1.3 mg/ml). Mice were euthanized at 24 h after the 7th binge session, and focused qPCR array analysis was employed on NAc tissue to quantify expression levels of 384 genes in a customized Mouse Mood Disorder array, with a focus on glutamatergic signaling (3 arrays/group). We identified significant regulation of 50 genes in male mice and 70 genes in female mice after 7 ethanol binges. Notably, 14 genes were regulated in both males and females, representing common targets to binge ethanol drinking. However, expression of 10 of these 14 genes was strongly dimorphic (e.g., opposite regulation for genes such as Crhr2, Fos, Nos1, and Star), and only 4 of the 14 genes were regulated in the same direction (Drd5, Grm4, Ranbp9, and Reln). Interestingly, the top 30 regulated genes by binge ethanol drinking for each sex differed markedly in the male and female mice, and this divergent neuroadaptive response in the NAc could result in dysregulation of distinct biological pathways between the sexes. Characterization of the expression differences with Ingenuity Pathway Analysis was used to identify Canonical Pathways, Upstream Regulators, and significant Biological Functions. Expression differences suggested that hormone signaling and immune function were altered by binge drinking in female mice, whereas neurotransmitter metabolism was a central target of binge ethanol drinking in male mice. Thus, these results indicate that the transcriptional response to repeated binge ethanol drinking was strongly influenced by sex, and they emphasize the importance of considering sex in the development of potential pharmacotherapeutic targets for the treatment of alcohol use disorder.

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Section: Introductionmentioning

confidence: 99%

Binge Ethanol Drinking Produces Sexually Divergent and Distinct Changes in Nucleus Accumbens Signaling Cascades and Pathways in Adult C57BL/6J Mice

Finn¹,

Hashimoto²,

Cozzoli³

et al. 2018

Front. Genet.

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“…BACs of  100 mM cause strong sedation and can lead to coma or death in alcohol-naïve individuals. Instead, in chronic alcohol consumers BACs of up to 300 mM have been reported (24), and 100 -200 mM typically lead to sedation, anxiolysis and hypnosis (25,26).…”

Section: The Mnh Assay Detects Chronic and Acute Ethanol-induced Neurmentioning

confidence: 99%

Assessment of ethanol-induced toxicity on iPSC-derived human dopaminergic neurons using a novel high-throughput mitochondrial neuronal health (MNH) assay

Zink

Conrad

Telugu

et al. 2020

Preprint

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Excessive ethanol exposure can cause mitochondrial and cellular toxicity. In order to discover potential counteracting interventions, it is essential to develop assays capable of capturing the consequences of ethanol exposure in human dopaminergic (DA) neurons, which are crucial for the development and maintenance of alcohol use disorders (AUD). Here, we developed a novel high-throughput (HT) assay to quantify mitochondrial and neuronal toxicity in human DA neurons from induced pluripotent stem cells (iPSCs). The assay, dubbed mitochondrial neuronal health (MNH) assay, combines live-cell measurement of mitochondrial membrane potential (MMP) with quantification of neuronal branching complexity post-fixation. Using the MNH assay, we demonstrated that chronic ethanol exposure in human iPSC-derived DA neurons decreases MMP and branching complexity in a dose-dependent manner. The toxic effect of ethanol on DA neurons was already detectable after 1 hour of exposure, and occurred similarly in DA neurons derived from healthy individuals and from patients with AUD. We next used the MNH assay to carry out a proof-of-concept compound screening using FDA-approved drugs. We identified potential candidate drugs modulating acute ethanol toxicity in human DA neurons. Among these drugs, flavoxate and disulfiram influenced mitochondrial neuronal health independently from ethanol, leading to amelioration and worsening, respectively. Altogether, we developed an HT assay to probe human mitochondrial neuronal health and used it to assess ethanol neurotoxicity and to identify modulating agents. The MNH assay represents an effective new tool for discovering modulators of mitochondrial neuronal health and toxicity in live human neurons.

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“…Ethanol easily passes through the blood brain barrier and is known to have direct and indirect targets throughout the brain. Unlike other drugs of abuse, even low to intermediate concentrations of ethanol disrupt the normal functioning of neurotransmitter receptors, ion channels, intracellular signaling proteins (Yoshimura et al, 2006;Pany & Das, 2015;Ron & Barak, 2016;Pakri Mohamed et al, 2018), and also perturbs membrane lipids (Cui & Koob, 2017).…”

Section: Reinforcing Properties Of Ethanol and Subsequent Neural Altementioning

confidence: 99%

Nicotine and alcohol: the role of midbrain dopaminergic neurons in drug reinforcement

Morel

Montgomery

Han

2018

Eur J of Neuroscience

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Nicotine and alcohol addiction are leading causes of preventable death worldwide and continue to constitute a huge socio‐economic burden. Both nicotine and alcohol perturb the brain's mesocorticolimbic system. Dopamine (DA) neurons projecting from the ventral tegmental area (VTA) to multiple downstream structures, including the nucleus accumbens, prefrontal cortex, and amygdala, are highly involved in the maintenance of healthy brain function. VTA DA neurons play a crucial role in associative learning and reinforcement. Nicotine and alcohol usurp these functions, promoting reinforcement of drug taking behaviors. In this review, we will first describe how nicotine and alcohol individually affect VTA DA neurons by examining how drug exposure alters the heterogeneous VTA microcircuit and network‐wide projections. We will also examine how coadministration or previous exposure to nicotine or alcohol may augment the reinforcing effects of the other. Additionally, this review briefly summarizes the role of VTA DA neurons in nicotine, alcohol, and their synergistic effects in reinforcement and also addresses the remaining questions related to the circuit‐function specificity of the dopaminergic system in mediating nicotine/alcohol reinforcement and comorbidity.

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Titrating Tipsy Targets: The Neurobiology of Low-Dose Alcohol

Cited by 42 publications

References 78 publications

Binge Ethanol Drinking Produces Sexually Divergent and Distinct Changes in Nucleus Accumbens Signaling Cascades and Pathways in Adult C57BL/6J Mice

Binge Ethanol Drinking Produces Sexually Divergent and Distinct Changes in Nucleus Accumbens Signaling Cascades and Pathways in Adult C57BL/6J Mice

Assessment of ethanol-induced toxicity on iPSC-derived human dopaminergic neurons using a novel high-throughput mitochondrial neuronal health (MNH) assay

Nicotine and alcohol: the role of midbrain dopaminergic neurons in drug reinforcement

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