Hippocampal Metabolomics Reveal the Mechanism of α-Conotoxin [S9K]TxID Attenuating Nicotine Addiction

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Abstract
Nicotine is the main substance responsible for the development of tobacco addiction. The α3β4 nicotinic acetylcholine receptors (nAChRs) are a potential key target for mitigating nicotine reward. Preliminary studies in our laboratory suggest that α-conotoxin [S9K]TxID serves as a selective and potent antagonist targeting α3β4 nAChRs, which may be beneficial in addressing nicotine addiction. However, the mechanisms of [S9K]TxID treatment in nicotine addiction are still to be determined. This study aimed to identify the differential metabolic profiles of [S9K]TxID treatment in nicotine addiction using an untargeted metabolomic profiling method. As demonstrated by behavioral experiments, [S9K]TxID effectively attenuated nicotine-induced conditioned place preference (CPP) expression without exerting inhibitory effects on the central nervous system (CNS). The results of untargeted metabolomics revealed that eight metabolites were significantly altered after [S9K]TxID treatment, particularly phenylalanine. [S9K]TxID also attenuated nicotine-induced metabolic disorders by regulating phenylalanine, tyrosine and tryptophan biosynthesis. In conclusion, our findings suggest that [S9K]TxID could be a potential therapeutic compound for nicotine addiction.
Funding Information
  • Major International Joint Research Project of National Natural Science Foundation of China (82320108019)
  • Key Project of Natural Science Foundation of Guangxi (2024GXNSFDA999003)
  • National Natural Science Foundation of China (42376112)
  • National Natural Science Foundation of China (82360698)
  • “Dai Tu Yi Zhi” Project of Key R & D Program of Guangxi (GUIKE AA25069003)
  • Major Intergovernmental Joint Research Project of National Key R & D Program of China (2022YFE0132700)

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