Abstract
Background and Purpose: Alcohol use disorder (AUD) is a serious public health issue and affects the lives of numerous people. Previous studies have shown a link between nicotinic acetylcholine receptors (nAChR) and alcohol addiction. However, the role of α6β2* nAChR in alcohol addiction remains obscure, and whether α6β2* nAChR can be used as a potential drug target for alcohol withdrawal need to be studied. Methods: Zebrafish (Danio rerio) were exposed to 0.2% alcohol for 14 days followed by 7 days of repeated withdrawal and then retro-orbitally injected with α-conotoxin TxIB (a selective α6β2* nAChR antagonist). Open Field Test was applied to characterize zebrafish behavior parameters. The monoamine neurotransmitter amounts and their mRNA expression in the zebrafish brain were identified using ELISA and quantitative real-time PCR (RT-PCR). RNA-sequencing (RNA-seq) and subsequent bioinformatics analysis were employed to explore the potential network regulation of TxIB after alcohol withdrawal. Results: The max speed in the center area of the Open Field Test was significantly higher in the withdrawal group whereas TxIB injection corrected this abnormality. The amount and mRNA expression of monoamine neurotransmitters did not change significantly after alcohol withdrawal and TxIB administration. RNA sequencing of zebrafish brain indicated a total of 657 genes showed aberrant expression and among which 225 were reversed after TxIB injection. These reversed genes were significantly enriched in the calcium ion binding pathway and the gene expression profile was further validated by RT-PCR. Conclusion: Our finding suggests α-conotoxin TxIB improved behavioral abnormality induced by alcohol-withdrawal, and changed gene expression mainly in the calcium signaling pathway. Therefore, α-conotoxin TxIB is expected to become a potential therapeutic agent for alcohol withdrawal.
Highlights
Alcohol abuse poses a great risk to human physical and mental health and a serious economic burden to society
Pang X et al (Pang et al, 2016) reported selectively blocking α6β2 nicotinic acetylcholine receptors (nAChR) in the medial habenula (MHb) alleviated anxiety in mice undergoing nicotine withdrawal, while α6β2 nAChR antagonists had little effect on nicotine naïve mice. These results suggest a role for the α6 nAChR subunit in the withdrawal process
Our lab has previously reported using TxIB as the tool to study its effect on nicotine-induced conditioned place preference (CPP) and found TxIB significantly inhibited the ability of nicotine inducing CPP in mice, we found monoamine neurotransmitters including dopamine, gamma-aminobutyric acid (GABA), and noradrenaline were reduced in nucleus accumbens, hippocampus and prefrontal cortex after TxIB administration (You et al, 2019)
Summary
Alcohol abuse poses a great risk to human physical and mental health and a serious economic burden to society. Alcohol can cause damage to multiple organs, with damage to the cardiovascular system being widely reported, and a study by Whitman IR et al in a California population older than 21 years of age showed that alcohol abuse significantly increased the incidence of atrial fibrillation, myocardial infarction, and congestive heart failure. Alcohol abuse greatly increased the risk of heart disease in people without conventional cardiovascular disease risk factors (Whitman et al, 2017). Four medications are approved by FDA to treat the AUD, which are disulfiram, naltrexone (oral and longacting injectable formulations), and acamprosate. They all have different mechanisms and limitations. Alcohol use disorder (AUD) is a serious public health issue and affects the lives of numerous people. The role of α6β2* nAChR in alcohol addiction remains obscure, and whether α6β2* nAChR can be used as a potential drug target for alcohol withdrawal need to be studied
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