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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 α 6 β 2* nAChR in alcohol addiction remains obscure, and whether α 6 β 2* 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 α 6 β 2* 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., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Mao, Li, Chen, Dong, Zhangsun, Zhu and Luo.)

Morphine, the main component of opium, is a commonly used analgesic in clinical practice, but its abuse potential limits its clinical application. Nicotinic acetylcholine receptors (nAChRs) in the mesolimbic circuitry play an important role in the rewarding effects of abused drugs. Previous studies have showed that α6β2* (* designated other subunits) nAChRs are mainly distributed in dopaminergic neurons in the midbrain area, which regulates the release of dopamine. So α6β2* nAChRs are regarded as a new target to treat drug abuse. α-Conotoxin TxIB was discovered in our lab, which is the most selective ligand to inhibit α6β2* nAChRs only. Antagonists of α6β2* nAChRs decreased nicotine, cocaine, and ethanol rewarding effects previously. However, their role in morphine addiction has not been reported so far. Thus, it is worth evaluating the effect of α-conotoxin TxIB on the morphine-induced conditioned place preference (CPP) and its behavioral changes in mice. Our results showed that TxIB inhibited expression and acquisition of morphine-induced CPP and did not produce a rewarding effect by itself. Moreover, repeated injections of TxIB have no effect on learning, memory, locomotor activity, and anxiety-like behavior. Therefore, blocking α6/α3β2β3 nAChRs inhibits the development of morphine-induced CPP. α-Conotoxin TxIB may be a potentially useful compound to mitigate the acquisition and/or retention of drug-context associations., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Li, Xiong, Zhang, Zhangsun and Luo.)