The genetic relationships between ethanol preference, acute ethanol sensitivity, and ethanol tolerance inDrosophila melanogaster

Acute ethanol exposure affects the nervous system as a stimulant at low concentrations and as a depressant at higher concentrations, eventually resulting in motor dysfunction and uncoordination. A recent genetic study of two mouse strains with varying ethanol preference indicated a correlation with a polymorphism (D216N) in the synaptic protein Munc18-1. Munc18-1 functions in exocytosis via a number of discrete interactions with the soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) protein syntaxin-1. We report that the mutation affects binding to syntaxin but not through either a closed conformation mode of interaction or through binding to the syntaxin N terminus. The D216N mutant instead has a specific impairment in binding the assembled SNARE complex. Furthermore, the mutation broadens the duration of single exocytotic events. Expression of the orthologous mutation (D214N) in the Caenorhabditis elegans UNC-18 null background generated transgenic rescues with phenotypically similar locomotion to worms rescued with the wild-type protein. Strikingly, D214N worms were strongly resistant to both stimulatory and sedative effects of acute ethanol. Analysis of an alternative Munc18-1 mutation (I133V) supported the link between reduced SNARE complex binding and ethanol resistance. We conclude that ethanol acts, at least partially, at the level of vesicle fusion and that its acute effects are ameliorated by point mutations in UNC-18.

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Mef2 induction of the immediate early gene Hr38/Nr4a is terminated by Sirt1 to promote ethanol tolerance

10.1101/205666 ◽

2017 ◽

Author(s):

Pratik Adhikari ◽

Donnoban Orozco ◽

Fred W. Wolf

Keyword(s):

Gene Expression ◽

Behavioral Plasticity ◽

Ethanol Tolerance ◽

Early Response ◽

Ethanol Exposure ◽

Early Gene ◽

Immediate Early ◽

Ethanol Preference ◽

Acute Ethanol ◽

Drug Naïve

Drug naïve animals given a single dose of ethanol show changed responses to subsequent doses, including the development of ethanol tolerance and ethanol preference. These simple forms of behavioral plasticity are due in part to changes in gene expression and neuronal properties. Surprisingly little is known about how ethanol initiates changes in gene expression or what the changes do. Here we demonstrate a role in ethanol plasticity for Hr38, the sole Drosophila homolog of the mammalian Nr4a1/2/3 class of immediate early response transcription factors. Acute ethanol exposure induces transient expression of Hr38 and other immediate early neuronal activity genes. Ethanol activates the Mef2 transcriptional activator to induce Hr38, and the Sirt1 histone/protein deacetylase terminates Hr38 induction. Loss of Hr38 decreases ethanol tolerance and causes precocious but short-lasting ethanol preference. Similarly, reduced Mef2 activity in all neurons or specifically in the mushroom body α/β neurons decreases ethanol tolerance; Sirt1 promotes ethanol tolerance in these same neurons. Genetically decreasing Hr38 expression levels in Sirt1 null mutants restores ethanol tolerance, demonstrating that both induction and termination of Hr38 expression are important for behavioral plasticity to proceed. These data demonstrate that Hr38 functions as an immediate early transcription factor that promotes ethanol behavioral plasticity.

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Cannabinoids differentially modulate behavioral and developmental responses to ethanol in Drosophila

10.1101/2021.08.14.456340 ◽

2021 ◽

Author(s):

Jianzheng He ◽

Si Yun Ng ◽

Alice Mei Xien Tan ◽

Wei Lin Yong ◽

Fengwei Yu

Keyword(s):

Ethanol Tolerance ◽

Therapeutic Potential ◽

Model Organism ◽

Well Being ◽

Ethanol Exposure ◽

Developmental Defect ◽

Ethanol Sensitivity ◽

Ethanol Preference ◽

Developmental Abnormalities

Prolonged prenatal or adult exposure to ethanol is detrimental to mental and physical well-being, resulting in developmental abnormalities, progressive addiction and ultimate death. A growing number of studies have shown the therapeutic potential of cannabinoids in ethanol-related behaviors in mammals. However, the potential pharmacological actions of cannabinoids in ethanol responses have not been examined in the model organism Drosophila melanogaster. Here, we systematically investigated the effects of various cannabinoids on ethanol preference, ethanol sensitivity and tolerance, and ethanol-induced developmental defect in Drosophila. We showed that treatment with the phytocannabinoid cannabidiol (CBD) displayed a significant decrease in preference for consuming ethanol in adult flies. Interestingly, cannabinoids exhibited differential roles in short- and long- term ethanol tolerance in flies. Although cannabinoids had no detectable effects on short-term ethanol tolerance, CBD and the endocannabinoid anandamide (AEA) suppressed long-term tolerance to ethanol. Moreover, ethanol exposure delayed larval-to-pupal development and increased larval/pupal size. Unexpectedly, treatment with CBD or endocannabinoids did not attenuate ethanol-induced developmental delay, instead, exacerbated its detrimental effect. Thus, our systematical study reveals, for the first time, a differential role of the cannabinoids in the modulation of ethanol-related responses in Drosophila.

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Presynaptic targets for acute ethanol sensitivity

Biochemical Society Transactions ◽

10.1042/bst0380172 ◽

2010 ◽

Vol 38 (1) ◽

pp. 172-176 ◽

Cited By ~ 9

Author(s):

Jeff W. Barclay ◽

Margaret E. Graham ◽

Mark R. Edwards ◽

James R. Johnson ◽

Alan Morgan ◽

...

Keyword(s):

Nervous System ◽

Caenorhabditis Elegans ◽

Alcohol Abuse ◽

Synaptic Vesicle ◽

Protein Interactions ◽

Model Organism ◽

Acute Exposure ◽

Ethanol Sensitivity ◽

Acute Ethanol ◽

Specific Proteins

Acute exposure to ethanol is known to modulate signalling within the nervous system. Physiologically these effects are both presynaptic and postsynaptic in origin; however, considerably more research has focused primarily on postsynaptic targets. Recent research using the model organism Caenorhabditis elegans has determined a role for specific proteins (Munc18-1 and Rab3) and processes (synaptic vesicle recruitment and fusion) in transducing the presynaptic effects of ethanol. In the present paper, we review these results, identifying the proteins and protein interactions involved in ethanol sensitivity and discuss their links with mammalian studies of alcohol abuse.

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Systems genetics analysis of the LXS recombinant inbred mouse strains:Genetic and molecular insights into acute ethanol tolerance

PLoS ONE ◽

10.1371/journal.pone.0240253 ◽

2020 ◽

Vol 15 (10) ◽

pp. e0240253

Author(s):

Richard A. Radcliffe ◽

Robin Dowell ◽

Aaron T. Odell ◽

Phillip A. Richmond ◽

Beth Bennett ◽

...

Keyword(s):

Recombinant Inbred ◽

Ethanol Tolerance ◽

Inbred Mouse ◽

Systems Genetics ◽

Recombinant Inbred Mouse ◽

Acute Ethanol

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Conservation of the Ethanol-Induced Locomotor Stimulant Response among Arthropods

Brain Behavior and Evolution ◽

10.1159/000370099 ◽

2015 ◽

Vol 85 (1) ◽

pp. 37-46 ◽

Cited By ~ 3

Author(s):

Christopher L. Kliethermes

Keyword(s):

Drosophila Melanogaster ◽

Behavioral Response ◽

Wolf Spider ◽

Fruit Fly ◽

Vertebrate Species ◽

Ethanol Sensitivity ◽

Locomotor Stimulation ◽

Arthropod Species ◽

Acute Ethanol ◽

Reinforcing Effects

Ethanol-induced locomotor stimulation has been variously described as reflective of the disinhibitory, euphoric, or reinforcing effects of ethanol and is commonly used as an index of acute ethanol sensitivity in rodents. The fruit fly Drosophila melanogaster also shows a locomotor stimulant response to ethanol that is believed to occur via conserved, ethanol-sensitive neurobiological mechanisms, but it is currently unknown whether this response is conserved among arthropod species or is idiosyncratic to D. melanogaster. The current experiments surveyed locomotor responses to ethanol in a phylogenetically diverse panel of insects and other arthropod species. A clear ethanol-induced locomotor stimulant response was seen in 9 of 13 Drosophilidae species tested, in 8 of 10 other species of insects, and in an arachnid (wolf spider) and a myriapod (millipede) species. Given the diverse phylogenies of the species that showed the response, these experiments support the hypothesis that locomotor stimulation is a conserved behavioral response to ethanol among arthropod species. Further comparative studies are needed to determine whether the specific neurobiological mechanisms known to underlie the stimulant response in D. melanogaster are conserved among arthropod and vertebrate species.

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