Behavioral Deficits Following Withdrawal from Chronic Ethanol Are Influenced by SLO Channel Function in <i>Caenorhabditis elegans</i>

Scott, Luisa L.; Davis, Scott J.; Yen, Rachel C.; Ordemann, Gregory J.; Nordquist, Sarah K.; Bannai, Deepthi; Pierce, Jonathan T.

doi:10.1534/genetics.116.193102

Cited by 24 publications

(51 citation statements)

References 71 publications

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“…However, the recently isolated slo1 mutant and mutants with impaired serotonin signaling fail to show EtOH‐induced impairments in learning. The slo1 gene is not only involved in the regulation of EtOH actions, as described above, but together with serotonin signaling, also regulates the effect of EtOH on learning and influences behavioral impairment during withdrawal (Scott et al., ; Wang et al., ). After chronic exposure and withdrawal of EtOH, the effects of withdrawal as analyzed in spontaneous deep body bends can be weakened by EtOH administration (Davies et al., ).…”

Section: Decision Making Reward and Learning: Dissecting Relationshmentioning

confidence: 99%

Unraveling the Mechanisms of Behaviors Associated With AUDs Using Flies and Worms

Scholz

2019

Alcoholism Clin & Exp Res

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Alcohol use disorders (AUDs) are very common worldwide and negatively affect both individuals and societies. To understand how normal behavior turns into uncontrollable use of alcohol, several approaches have been utilized in the last decades. However, we still do not completely understand how AUDs evolve or how they are maintained in the brains of affected individuals. In addition, efficient and effective treatment is still in need of development. This review focuses on alternative approaches developed over the last 20 years using Drosophila melanogaster (Drosophila) and Caenorhabditis elegans (C. elegans) as genetic model systems to determine the mechanisms underlying the action of ethanol (EtOH) and behaviors associated with AUDs. All the results and insights of studies over the last 20 years cannot be comprehensively summarized. Thus, a few prominent examples are provided highlighting the principles of the genes and mechanisms that have been uncovered and are involved in the action of EtOH at the cellular level. In addition, examples are provided of the genes and mechanisms that regulate behaviors relevant to acquiring and maintaining excessive alcohol intake, such as decision making, reward and withdrawal, and/or relapse regulation. How the insight gained from the results of Drosophila and C. elegans models can be translated to higher organisms, such as rodents and/or humans, is discussed, as well as whether these insights have any relevance or impact on our understanding of the mechanisms underlying AUDs in humans. Finally, future directions are presented that might facilitate the identification of drugs to treat AUDs.

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Section: Decision Making Reward and Learning: Dissecting Relationshmentioning

confidence: 99%

Unraveling the Mechanisms of Behaviors Associated With AUDs Using Flies and Worms

Scholz

2019

Alcoholism Clin & Exp Res

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“…After the plates were cooled down to room temperature, OP50 E. coli were seeded at a center area of the plate and were allowed to grow overnight. Next day, a desired amount of ethanol (300 mM), which gives an internal ethanol concentration of approximately 30 mM (15,53), was applied to the NGM plates without direct contact with bacteria. The plates were then sealed with parafilm and left at room temperature for equilibration at least for an hour.…”

Section: Methodsmentioning

confidence: 99%

Alcohol induces mitochondrial fragmentation and stress responses to maintain normal muscle function in Caenorhabditis elegans

Hong-kyun

2019

Preprint

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AbstractsChronic excessive ethanol consumption produces distinct toxic and adverse effects on different tissues. In skeletal muscle ethanol causes alcoholic myopathy characterized by myofiber atrophy and loss of muscle strength. Alcoholic myopathy is more prevalent than all inherited muscle diseases combined. Current evidence indicates that ethanol directly impairs muscle organization and function. However, the underlying mechanism by which ethanol causes its toxicity to muscle is poorly understood. Here, we show that the nematode C. elegans recapitulates key aspects of alcoholic myopathy when exposed to ethanol. As in mammals, ethanol exposure impairs muscle strength and organization and induces the expression of protective genes, including oxidative stress response. In addition, ethanol exposure causes a fragmentation of mitochondrial networks aligned with myofibril lattices. This ethanol-induced mitochondrial fragmentation is dependent on mitochondrial fission factor DRP-1 (dynamin-like protein 1), and its receptor proteins on the mitochondrial outer membrane. Our data indicate that this fragmentation contributes to activation of mitochondrial unfolded protein response (UPR). We also found that robust perpetual mitochondrial UPR activation effectively counters muscle weakness caused by ethanol exposure. Our results strongly suggest that modulation of mitochondrial stress responses provides a mechanism to ameliorate alcohol toxicity and damage to muscle.SignificanceChronic alcohol abuse causes the damage and toxicity to peripheral tissues, including muscle. Alcohol perturbs the structure and function of striated skeletal and cardiac muscles. These toxic effects of alcohol on striated muscles negatively impact morbidity and mortality to alcohol misusers. Here, we demonstrate that the nematode C. elegans also exhibits key features of alcoholic myopathy when exposed to ethanol. Ethanol exposure impairs muscle organization and strength, and induces the expression of genes that cope with alcohol toxicity. Particularly, we find that ethanol toxicity is centered on mitochondria, the power plants of the cell. As an adaptive protective response to mitochondrial dysfunction, ethanol-exposed cells induce global transcriptional reprogramming to restore normal mitochondrial function. Upregulation of this transcriptional reprogramming in C. elegans effectively blocks ethanol-induced muscle weakness, a key feature of alcoholic myopathy. Thus, the modulation of mitochondrial stress responses is a potentially promising therapeutic strategy to ameliorate alcohol toxicity to muscle.

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“…C. elegans ethanol exposure paradigm and compound screen The ethanol withdrawal paradigm was modified from Mitchell et al (2010) as described previously [28]. Briefly, L4-stage worms raised on the same plates were divided between ethanol-infused (+ethanol) and standard control (−ethanol) seeded plates.…”

Section: Methodsmentioning

confidence: 99%

“…Ethanol plates (400 mM) were prepared by adding 280 µL of 200-proof ethanol (Sigma Aldrich) beneath the agar of the standard seeded plates and allowing the ethanol to soak into the agar. The plates were sealed with Parafilm and worms were exposed for~24 h. C. elegans only absorbs a fraction of the high external concentration of ethanol when treated on standard plates [28,29]. The internal concentration achieved by these methods,~50 mM [28], is physiologically relevant to alcohol dependence in humans [30][31][32][33].…”

Section: Methodsmentioning

confidence: 99%

“…In order to identify novel compounds that affect alcohol-related behaviors, we screened a small collection of analogs of 1 and 2 that are potent and selective σ2R/Tmem97 binding ligands [19,20,22]) in a model of alcohol withdrawal in the nematode Caenorhabditis elegans [27,28]. The subtype-selective σ2R/ Tmem97 ligands 3 and JVW-1034 improved behavioral impairments in worms withdrawn from chronic exposure to ethanol.…”

Section: Introductionmentioning

confidence: 99%

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Small molecule modulators of σ2R/Tmem97 reduce alcohol withdrawal-induced behaviors

Scott

Sahn

Ferragud

et al. 2018

Neuropsychopharmacol

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Repeated cycles of intoxication and withdrawal enhance the negative reinforcing properties of alcohol and lead to neuroadaptations that underlie withdrawal symptoms driving alcohol dependence. Pharmacotherapies that target these neuroadaptations may help break the cycle of dependence. The sigma-1 receptor (σ1R) subtype has attracted interest as a possible modulator of the rewarding and reinforcing effects of alcohol. However, whether the sigma-2 receptor, recently cloned and identified as transmembrane protein 97 (σ2R/TMEM97), plays a role in alcohol-related behaviors is currently unknown. Using a Caenorhabditis elegans model, we identified two novel, selective σ2R/Tmem97 modulators that reduce alcohol withdrawal behavior via an ortholog of σ2R/TMEM97. We then show that one of these compounds blunted withdrawal-induced excessive alcohol drinking in a well-established rodent model of alcohol dependence. These discoveries provide the first evidence that σ2R/TMEM97 is involved in alcohol withdrawal behaviors and that this receptor is a potential new target for treating alcohol use disorder.

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Behavioral Deficits Following Withdrawal from Chronic Ethanol Are Influenced by SLO Channel Function in Caenorhabditis elegans

Cited by 24 publications

References 71 publications

Unraveling the Mechanisms of Behaviors Associated With AUDs Using Flies and Worms

Unraveling the Mechanisms of Behaviors Associated With AUDs Using Flies and Worms

Alcohol induces mitochondrial fragmentation and stress responses to maintain normal muscle function in Caenorhabditis elegans

Small molecule modulators of σ2R/Tmem97 reduce alcohol withdrawal-induced behaviors

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