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. 2024 Apr;49(5):782-795.
doi: 10.1038/s41386-023-01773-3. Epub 2023 Dec 7.

Factors influencing JUUL e-cigarette nicotine vapour-induced reward, withdrawal, pharmacokinetics and brain connectivity in rats: sex matters

Jude A Frie  1 , Patrick McCunn  2 , Amr Eed  3 , Ahmad Hassan  1 , Karling R Luciani  4 , Chuyun Chen  1 , Rachel F Tyndale  5 , Jibran Y Khokhar  6   7
Affiliations

Factors influencing JUUL e-cigarette nicotine vapour-induced reward, withdrawal, pharmacokinetics and brain connectivity in rats: sex matters

Jude A Frie et al. Neuropsychopharmacology. 2024 Apr.

Abstract

Though vaping likely represents a safer alternative to smoking, it is not without risks, many of which are not well understood, especially for vulnerable populations. Here we evaluate the sex- and age-dependent effects of JUUL nicotine vapour in rats. Following passive nicotine vapour exposures (from 59 mg/ml JUUL nicotine pods), rats were evaluated for reward-like behaviour, locomotion, and precipitated withdrawal. Pharmacokinetics of nicotine and its metabolites in brain and plasma and the long-term impact of nicotine vapour exposure on functional magnetic resonance imaging-based brain connectivity were assessed. Adult female rats acquired conditioned place preference (CPP) at a high dose (600 s of exposure) of nicotine vapour while female adolescents, as well as male adults and adolescents did not. Adult and adolescent male rats displayed nicotine vapour-induced precipitated withdrawal and hyperlocomotion, while both adult and adolescent female rats did not. Adult females showed higher venous and arterial plasma and brain nicotine and nicotine metabolite concentrations compared to adult males and adolescent females. Adolescent females showed higher brain nicotine concentration compared to adolescent males. Both network-based statistics and between-component group connectivity analyses uncovered reduced connectivity in nicotine-exposed rats, with a significant group by sex interaction observed in both analyses. The short- and long-term effects of nicotine vapour are affected by sex and age, with distinct behavioural, pharmacokinetic, and altered network connectivity outcomes dependent on these variables.

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Conflict of interest statement

The authors declare no competing interests.

Figures

Fig. 1
Fig. 1. Sex and age impact the effects of nicotine vapour on reward, withdrawal, locomotion and body weight.
a Female nicotine vapour place conditioning results. Difference score is defined as the difference in time spent in the initially non-preferred chamber pre- to post-conditioning. Adult females acquire CPP at 480 and 600 s doses. Adolescent females do not acquire CPP at any dose tested. b Nicotine vapour place conditioning results for male and female, adult, and adolescent rats at 600 s dose. *p < 0.05 significant shift in preference from zero. c Nicotine (filled circles) and vehicle (empty circles) vapour withdrawal scores. Scores are the sum of all observed somatic withdrawal signs averaged across two blinded scorers. Male adults and adolescents show similar levels of nicotine vapour withdrawal signs compared to control. Females do not show significant levels of nicotine vapour withdrawal though adolescents appear to trend toward significance. *p < 0.05 nicotine vapour versus vehicle vapour. d Nicotine (filled circles) and vehicle (empty circles) vapour effect on locomotion. Locomotion was measured following the second exposure of the day. Adult and adolescent males show significantly higher locomotion following nicotine vapour exposure. Adult and adolescent females do not show any increase in locomotion in response to nicotine vapour exposure. *p < 0.05 nicotine vapour versus vehicle vapour. e Weight change over nicotine vapour treatment period. Adolescent males and adult females have reduced weight gain in response to repeated nicotine vapour exposure. *p < 0.05 significant treatment by day interaction. Data are presented as mean ± SEM.
Fig. 2
Fig. 2. Higher venous plasma nicotine levels in female adults compared to adolescents and male rats.
a comparison of age and sex on venous nicotine plasma level. Adult females display greater nicotine levels compared to adult males or adolescent females. b comparison of age and sex on venous cotinine plasma level. Adult females display greater cotinine levels than all other groups. c Comparison of age and sex on venous nornicotine plasma level. d comparison of age and sex on venous nicotine-n’-oxide plasma level. *p < 0.05 adult versus adolescent or male versus female. N = 7 per group and timepoint. Data are presented as mean ± SEM.
Fig. 3
Fig. 3. Higher arterial plasma nicotine levels in female adults compared to male adult rats.
a–d Comparison of adult to adolescent males. e–h Comparison of adult to adolescent females. i–l Comparison of adult males to adult females. Adult females display greater nicotine, cotinine, and nornicotine compared to adolescent females. m–p Comparison of adolescent males to adolescent females. *p < 0.05 adult versus adolescent or male versus female. N = 7 per group and timepoint. Data are presented as mean ± SEM.
Fig. 4
Fig. 4. Higher brain nicotine levels in female adult and adolescent rats compared to male rats.
a–c Comparison of adult males to adolescent males. d–f Comparison of adult females to adolescent females. g–i Comparison of adult males to adult females. Adult females display greater nicotine, cotinine, and nornicotine concentrations compared to adult males. j–l Comparison of adolescent males to adolescent females. Adolescent females display higher nicotine and cotinine concentrations compared to adolescent males. *p < 0.05 adult versus adolescent or male versus female. N = 7 per group and timepoint. Data are presented as mean ± SEM.
Fig. 5
Fig. 5. Reduced functional connectivity was observed in nicotine vapour-exposed rats, with greater reductions observed in female rats.
a Representative single subject T2 anatomical image (left), diffusion b = 0 image (middle), and the first volume of an fMRI dataset (right). b NBS statistics confirmed reduced functional connectivity in the Nicotine group (n = 34) compared to the Vehicle group (n = 36) when controlling for age and sex (p = 0.013, 12 edges, 13 nodes). Significant edges have anatomical regions labelled. All other regions are labelled with their numerical SIGMA atlas reference. c Average Pearson Correlation Coefficients in edges identified by NBS statistics to have reduced functional connectivity in the Nicotine group when controlling for age and sex (p = 0.013, 12 edges, 13 nodes). Post-hoc analysis confirmed a statistically significant group by sex interaction effect (p < 0.001, 5 edges, 6 nodes). No statistically significant group-by-age interaction effect was confirmed. Abbreviations: L Left, R Right, Hyp Hypothalamus, ParCx Parietal Cortex, PirCx Piriform Cortex, EnPir Endo/piriform Cortex, VisCx Primary and Secondary Visual Cortex, CA1 Cornu Ammonis 1, SomCx Primary Somatosensory Cortex, Ins Insular Cortex, Cing Cingulate Cortex, DDG Dorsal Dentate Gyrus, RetCx Retrosplenial Cortex, Col Colliculus.
Fig. 6
Fig. 6. Nicotine-exposed animals showed decreased between component group connectivity.
a Between-Resting state network average group connectivity. The values were calculated by averaging correlation coefficient within each group between the resting state networks resulting from the ICA. The results are shown as z-scores. b Significant differences in correlation strength were observed between nicotine and vehicle-exposed rats. Non-parametric permutation test was used (10,000 permutations). comparisons are adjusted for sex. A decrease in functional connectivity in animals exposed to nicotine vapour was seen between the hippocampus and the somatosensory cortex (left) components, and between the hippocampus and cingulate cortex (right) components. c Effects of sex on resting state network connectivity strength. Nodes showing significant interaction between sex and connectivity strength (ICA component pair-wise comparisons from left to right): Somatosensory and motor cortex, Hippocampus and somatomotor cortex, Somatosensory and default mode network, Hippocampus and olfactory bulb, Hippocampus and amygdala. FWER-corrected comparisons are presented. *p < 0.05.
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