The Difference of Addictive Behavior of Free-Base Nicotine and Nicotine Salts in Mice Base on an Aerosol Self-Administration Model.

Introduction: The distinctions in the biological impacts of distinct forms of nicotine have become a prominent subject of current research. However, relatively little research has been done on the addictive effects of different forms of nicotine.

Aims and methods: The aerosol self-administration device was briefly characterized by determining aerosol concentration, particle size, and distributional diffusion of the aerosol. And the aerosol self-administration model was constructed at 1, 5, and 10 mg/mL of nicotine to select the appropriate nicotine concentration. Subsequently, the model was used to explore the differences in aerosol self-administration behavior of free-base nicotine and nicotine salts and the behavioral differences after withdrawal.

Results: We successfully constructed mouse aerosol self-administration models at 1, 5, and 10 mg/mL nicotine concentrations. In the study of the difference in addictive behaviors between free-base nicotine and nicotine salts, mice with free-base nicotine and different nicotine salts showed varying degrees of drug-seeking behavior, with nicotine benzoate showing the strongest reinforcement. In post-withdrawal behavioral experiments, nicotine salts mice showed more robust anxiety-like behaviors.

Conclusions: These results confirm the successful development and stability of the nicotine aerosol self-administration model. Furthermore, they demonstrated that nicotine salts enhance drug-seeking behavior to a greater extent than free-base nicotine, with nicotine benzoate exhibiting the most significant effects.

Implications: In this study, an aerosol self-administered model of mice was constructed, which can be used not only for comparing the effects of free-base nicotine and nicotine salts on the behavior but also for other addictive drugs, such as fentanyl and cannabis. In addition, this study shows that nicotine salts may be more addictive compared to free-base nicotine, which is a reference for the future use of nicotine salts in tobacco products such as e-cigarettes.