Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2024;83(1):28-40.
doi: 10.1159/000535663. Epub 2024 Jan 5.

Methylation of the Oxytocin, Oxytocin Receptor, and Vasopressin Gene Promoters in Tobacco Use Disorder during Cessation

Phileas Johannes Proskynitopoulos  1 , Stefan Bleich  1 , Marc Andre Nicolas Muschler  1 , Vanessa Buchholz  1   2 , Helge Frieling  1   2 , Alexander Glahn  1 , Mathias Rhein  1   2
Affiliations

Methylation of the Oxytocin, Oxytocin Receptor, and Vasopressin Gene Promoters in Tobacco Use Disorder during Cessation

Phileas Johannes Proskynitopoulos et al. Neuropsychobiology. 2024.

Abstract

Introduction: Vasopressin (AVP) and oxytocin (OT) exert sex-specific effects on social pair bonding and stress reactions while also influencing craving in substance use disorders. In this regard, intranasal oxytocin (OT) and AVP antagonists present potential treatments for tobacco use disorder (TUD). Since transcription of both hormones is also regulated by gene methylation, we hypothesized sex-specific changes in methylation levels of the AVP, OT, and OT receptor (OXTR) gene during nicotine withdrawal.

Methods: The study population consisted of 49 smokers (29 males, 20 females) and 51 healthy non-smokers (25 males, 26 females). Blood was drawn at day 1, day 7, and day 14 of smoking cessation. Craving was assessed with the questionnaire on smoking urges (QSU).

Results: Throughout cessation, mean methylation of the OT promoter gene increased in males and decreased in females. OXTR receptor methylation decreased in females, while in males it was significantly lower at day 7. Regarding the AVP promoter, mean methylation increased in males while there were no changes in females. Using mixed linear modeling, CpG position, time point, sex, and the interaction of time point and sex as well as time point, sex, and QSU had a significant fixed effect on OT and AVP gene methylation. The interaction effect suggests that sex, time point, and QSU are interrelated, meaning that, depending on the sex, methylation could be different at different time points and vice versa. There was no significant effect of QSU on mean OXTR methylation.

Discussion: We identified differences at specific CpGs between controls and smokers in OT and AVP and in overall methylation of the AVP gene. Furthermore, we found sex-specific changes in mean methylation levels of the mentioned genes throughout smoking cessation, underlining the relevance of sex in the OT and vasopressin system. This is the first study on epigenetic regulation of the OT promoter in TUD. Our results have implications for research on the utility of the AVP and OT system for treating substance craving. Future studies on both targets need to analyze their effect in the context of sex, social factors, and gene regulation.

Keywords: Epigenetics; Oxytocin; Tobacco use disorder; Vasopressin.

PubMed Disclaimer

Conflict of interest statement

The authors have no conflicts of interest to declare.

Figures

Fig. 1.
Fig. 1.
Mean methylation status of the OT, OT receptor, and vasopressin promoters in male (a) and female (b) smokers at time point 1 compared with healthy controls. Mean values are given in percentages. Numbers (c–e) show the mean methylation status of the oxytocin (c), oxytocin receptor (d), and vasopressin (e) promoters over the cessation period in males and females. Mean values are the estimated marginal means (EMMs) reported by the mixed linear model. The EMMs were then compared in a two-way ANOVA. Each bar represents the mean ± standard error of the mean. Significant differences, as calculated with a t test for independent samples or the two-way ANOVA, are indicated by asterisks. p < 0.05*, p < 0.01**, p < 0.001***, p < 0.0001****. ANP, vasopressin; EMM, estimated marginal means; OT, oxytocin; OXTR, oxytocin receptor.
Fig. 2.
Fig. 2.
Differences in mean methylation (y-axis) of specific CpGs of the oxytocin, oxytocin receptor, and vasopressin promoters in male and female smokers at time point 1 compared with controls (x-axis). All CpGs showed significant differences before correction for multiple testing (Bonferroni’s method). Mean values are given in percentages. Each bar represents the mean ± standard error of the mean. Asterisks indicate significant differences after correction for multiple testing. Oxytocin pcorr < 0.00166*, oxytocin receptor pcorr < 0.00172*, and vasopressin pcorr < 0.005*. ANP, vasopressin; OT, oxytocin; OXTR, oxytocin receptor.
See this image and copyright information in PMC

Similar articles

See all similar articles

References

    1. World Health Organization . WHO report on the global tobacco epidemic, 2021: addressing new and emerging products. Geneva: World Health Organization; 2021.
    1. GBD 2019 Tobacco Collaborators . Spatial, temporal, and demographic patterns in prevalence of smoking tobacco use and attributable disease burden in 204 countries and territories, 1990–2019: a systematic analysis from the Global Burden of Disease Study 2019. Lancet. 2021;397(10292):2337–60. - PMC - PubMed
    1. García-Gómez L, Hernández-Pérez A, Noé-Díaz V, Riesco-Miranda JA, Jiménez-Ruiz C. Smoking cessation treatments: current psychological and pharmacological options. Rev Invest Clin. 2019;71(1):7–16. - PubMed
    1. Muschler M, Rhein M, Ritter A, Hillemacher T, Frieling H, Bleich S, et al. . Epigenetic alterations of the POMC promoter in tobacco dependence. Eur Neuropsychopharmacol. 2018;28(7):875–9. - PubMed
    1. Huang Z, Wu D, Qu X, Li M, Zou J, Tan S. BDNF and nicotine dependence: associations and potential mechanisms. Rev Neurosci. 2020;32(1):79–91. - PubMed

Grants and funding

This study received no funding.