doi: 10.3389/fnins.2023.1288102. eCollection 2023.
Pharmacokinetic differences in nicotine and nicotine salts mediate reinforcement-related behavior: an animal model study
Pengfei Han 1 2 3 4 5, Xiaoyuan Jing 6, Shulei Han 2 3 4 5, Xinsheng Wang 1, Qiannan Li 2 3 4 5, Yuan Zhang 2 3 4 5, Pengpeng Yu 2 3 4 5, Xin-An Liu 6, Ping Wu 7, Huan Chen 2 3 4 5, Hongwei Hou 2 3 4 5, Qingyuan Hu 2 3 4 5
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- PMID:38033549
- PMCID: PMC10687399
- DOI: 10.3389/fnins.2023.1288102
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Pharmacokinetic differences in nicotine and nicotine salts mediate reinforcement-related behavior: an animal model study
Pengfei Han et al. Front Neurosci..
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Abstract
Since their introduction in the United States and Europe in 2007, electronic cigarettes (E-Cigs) have become increasingly popular among smokers. Nicotine, a key component in both tobacco and e-cigarettes, can exist in two forms: nicotine-freebase (FBN) and nicotine salts (NS). While nicotine salt is becoming more popular in e-cigarettes, the effect of nicotine salts on reinforcement-related behaviors remains poorly understood. This study aimed to compare the reinforcing effects of nicotine and nicotine salts in animal models of drug self-administration and explore potential mechanisms that may contribute to these differences. The results demonstrated that three nicotine salts (nicotine benzoate, nicotine lactate, and nicotine tartrate) resulted in greater reinforcement-related behaviors in rats compared to nicotine-freebase. Moreover, withdrawal-induced anxiety symptoms were lower in the three nicotine salt groups than in the nicotine-freebase group. The study suggested that differences in the pharmacokinetics of nicotine-freebase and nicotine saltsin vivo may explain the observed behavioral differences. Overall, this study provides valuable insights into the reinforcing effects of nicotine as well as potential differences between nicotine-freebase and nicotine salts.
Keywords: anxiety; dopamine; nicotine salts; pharmacokinetics; self-administration.
Copyright © 2023 Han, Jing, Han, Wang, Li, Zhang, Yu, Liu, Wu, Chen, Hou and Hu.
Conflict of interest statement
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.
Figures
Results of self-administration experiments under a fixed-rate 3 (FR3) schedule.(A) Experimental timeline.(B) Number of infusions for each group: saline (SAL, black circle), nicotine-freebase (FBN, yellow circle), nicotine tartrate (NT, blue circle), nicotine benzoate (NB, green circle), and nicotine lactate (NL, pink circle).(C) Average number of infusions in the last 4 days of rats in each group. Error bars represent the mean ± SEM (n = 8). Bonferroni Student-t test after ANOVAS: *p < 0.05, **p < 0.01, ***p < 0.001, and ****p < 0.0001 versus FBN group;++++p < 0.0001 versus SAL group.
Results of the EPM and OFT tests conducted after 7 days of intraperitoneal injection and 3–4 days of natural withdrawal.(A) Timeline of withdrawal-related behavioral experiments.(B) Time spent in the center.(C) Open arm duration.(D) Total distance traveled.(E) Representative images of each group in the EPM.(F) Representative images of each group in the OFT. Only one representative image is shown for nicotine salt groups, as there were no significant differences in withdrawal-related behaviors between these groups. Bonferroni Student-t test after ANOVAS: *p < 0.05, **p < 0.01, and ***p < 0.001 versus FBN group;++++p < 0.0001 versus SAL group (n = 8).
Pharmacokinetic curves of plasma nicotine levels in rats treated with two different types of nicotine.(A) Timeline of pharmacokinetic experiments.(B) Mean plasma concentration-time plot of nicotine after intraperitoneal administration of nicotine-freebase (0.15 mg/kg nicotine dose) and nicotine tartrate (0.3 mg/kg nicotine dose).(C) Maximum concentration (Cmax) of nicotine after nicotine tartrate and nicotine-freebase administration.(D) Mean plasma concentration-time plot of cotinine (Cot) after intraperitoneal administration of nicotine-freebase (0.15 mg/kg nicotine dose) and nicotine tartrate (0.3 mg/kg nicotine dose).(E) Time to reach maximum concentration (Tmax) after nicotine tartrate and nicotine-freebase administration. Simplet-test: **p < 0.01. All data are presented as Mean ± SEM (n = 7).
The distribution and content of nicotine in rat brain tissue, as well as its impact on the mRNA expression of three nAChR subunits, following intraperitoneal injection of 0.5 mg/kg nicotine or nicotine salt.(A) Timeline of DESI-MSI and RT-qPCR experiments(B,C) Coronal sections containing VTA from the nicotine tartrate group and the nicotine-freebase group, with a spatial resolution of 150 μm. Local scans of the VTA in coronal sections of the two groups, with a spatial resolution of 50 μm.(D,E) The mass spectra of nicotine in the selected region (VTA).(F) Mass spectral response intensities of nicotine in the selected region (VTA) in nicotine-freebase and nicotine tartrate groups, Simple t-test: ns,p > 0.05.(G) RT-qPCR analysis of fold change in mRNA expression of nAChRs (α4, β2, α7) in the VTA. Bonferroni Student-t test after ANOVAS: *p < 0.05, **p < 0.01. All data are presented as Mean ± SEM (n = 3).
(A,B) Timeline of microdialysis experiments(C) Time-course effects of nicotine-freebase and nicotine tartrate on the extracellular level of DA in the nucleus accumbens after a single administration at a dose of 0.5 mg/kg. The release of DA in nicotine tartrate group was significantly higher than that in nicotine-freebase group within 10 min-40 min after injection [Two-way ANOVA,F (14, 225) = 3.188,p = 0.0001; **p < 0.01, ***p < 0.0001, **p < 0.01 and ****p < 0.0001].(D) Time course effects of nicotine-freebase(0.5 mg/kg) and nicotine tartrate(1 mg/kg) on DA extracellular levels in the nucleus accumbens. There was no significant difference in the increases in extracellular dopamine between nicotine tartrate group and nicotine-freebase group at 10–20 min after injection [Two-way ANOVA,F (2, 225) = 29.68]. Percentages relative to baseline were calculated from the three samples preceding the treatment administration. Nicotine-freebase (0.5 mg/kg) and nicotine tartrate (1.0 mg/kg) were injected intraperitoneally after baseline measurement (see arrow). Bonferroni Student-t test after ANOVAS: **p < 0.01, and ***p < 0.001 versus FBN group. All data are presented as Mean ± SEM (n = 6).
The elevated plus maze (EPM) and open field test (OFT) were conducted 3–4 days after the end of self-administration and natural withdrawal.(A) Timeline of withdrawal-related behavioral experiments.(B) Time spent in the center.(C) Open arm duration.(D) Total distance traveled.(E) Representative images of each group in the EPM.(F) Representative images of each group in the OFT. Only nicotine tartrate group of representative images is displayed for the nicotine salt groups, as there were no significant differences in withdrawal-related behaviors among these groups. Bonferroni Student-t test after ANOVAS: *p < 0.05, **p < 0.01, and ***p < 0.001. All data are presented as Mean ± SEM (n = 8).
Correlation analyses of pharmacokinetics of the drug self-administrated and addictive behaviors.(A) Correlation matrix diagram.(B) Correlation clustering heat map. SA: the number of infusions in nicotine self-administration (SA) experiments; OFT: the time spent in the center of rats in the OFT 3–4 days after nicotine withdrawal; EPM: the time in the open arms of rats in the EPM 3–4 days after nicotine withdrawal. Correlation algorithm: spearman. *p < 0.05, and ***p < 0.001 (Correlation significance).
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