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Chrna3 modulates alcohol response in zebrafish

ABSTRACT: Alcohol use disorders (AUDs) are complex phenomena governed by genetics, neurophysiology, environment, and societal structures. New methods to understand the underlying neurogenetics are valuable for designing personalised interventional strategies. Here, we used a novel, two-choice self-administration zebrafish assay (SAZA) to isolate the function of nicotinic acetylcholine receptor (nAChR) subunit alpha3 (chrna3) in alcohol response. Juvenile zebrafish exhibited a biphasic response when self-administering alcohol that transitioned from attraction to aversion within minutes, suggesting they can regulate exposure to alcohol. This inverted U-shaped self-administration mirrored the effect alcohol has on shoaling behaviour. Exposure to low concentration of alcohol reduced anxiety-like behaviours, while sedative effects became prominent at higher concentrations resulting in reduced locomotion and uncoordinated swimming. In contrast, these responses are blunted in chrna3 mutants. They exhibit prolonged alcohol self-administration, and increased gregariousness. Transcriptomic analyses suggest that glutamatergic and GABAergic neurotransmission alongside cholinergic signalling is impacted in the mutant brains. Our results thus suggest that chrna3 dysfunction has a systemic change with an increase in alcohol tolerance being one effect. These findings also highlight the use of non-rodent alternatives to understand the neurogenetics of development of AUD.

ORGANISM(S): Danio rerio

PROVIDER: GSE280965 | GEO | 2025/11/01

REPOSITORIES: GEO

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Project description:Sustained or repeated exposure to sedating drugs such as alcohol triggers homeostatic adaptations in the brain that lead to the development of drug tolerance and dependence. These adaptations involve long-term changes in the transcription of drug-responsive genes as well as an epigenetic restructuring of chromosomal regions that is thought to signal and maintain the altered transcriptional state. Drug-induced epigenetic changes have been shown to be important in the long-term adaptation that leads to alcohol tolerance and dependence endophenotypes. A major constraint impeding progress is that alcohol produces a surfeit of changes in gene expression, most that may not make any meaningful contribution to the ethanol response under study. Here we used a novel genomic epigenetic approach to find genes relevant for functional alcohol tolerance by exploiting the commonalities of two chemically distinct drugs. In Drosophila melanogaster, ethanol and benzyl alcohol induce mutual cross-tolerance, indicating that they share a common mechanism for producing tolerance. We surveyed the genome-wide changes in histone acetylation that occur in response to these drugs. Each drug induces modifications in a large number of genes. The genes that respond similarly to either treatment, however, represent a subgroup enriched for genes important for the common tolerance response. Genes were functionally tested for behavioral tolerance to the sedative effects of ethanol and benzyl alcohol using mutant and inducible RNAi stocks. We identified a network of genes that are essential for the development of tolerance to sedation by alcohol. A total of six samples. Two H4Ac ChIP-chip biological replicates from heads of Drosophila (untreated, IP/input), two H4Ac ChIP-chip biological replicates from heads of Drosophila sedated with benzyl alcohol (IP_treated/IP_control), and two H4Ac ChIP-chip biological replicates from heads of Drosophila sedated with ethanol (IP_treated/IP_control) are included.

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Chrna3 modulates alcohol response in zebrafish

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