Sex Differences in the Relationship Between Nucleus Accumbens Volume and Youth Tobacco or Marijuana Use Following Stressful Life Events

Abstract

Background: Exposure to stressful life events (SLEs) can upset balance and affect the healthy brain development of children and youths. These events may influence substance use by altering brain reward systems, especially the nucleus accumbens (NAc), which plays a key role in motivated behaviors and reward processing. The interaction between sensitization to SLEs, depression, and substance use might vary between male and female youths, potentially due to differences in how each sex responds to SLEs. Aims: This study aims to examine the effect of sex on the relationship between SLEs, Nucleus Accumbens activity, and substance use in a nationwide sample of young individuals. Methods: We utilized data from the Adolescent Brain Cognitive Development study (ABCD), a longitudinal study of pre-adolescents aged 9–10 years, comprising 11,795 participants tracked over 36 months. Structured interviews measuring SLEs were conducted using the Kiddie Schedule for Affective Disorders and Schizophrenia (K-SADS). Initial linear regression analyses explored if SLEs could predict volumes of the right and left NAc. Subsequently, Cox regression models were used to investigate how SLEs and NAc volume might predict the initiation of tobacco and marijuana use, with the analysis stratified by sex to address potential sex differences. Results: Our findings reveal that SLEs significantly predicted marijuana use in males but not in females, and tobacco use was influenced by SLEs in both sexes. A higher number of SLEs was linked with decreased left NAc volume in males, a trend not seen in females. The right NAc volume did not predict substance use in either sex. However, volumes of both the right and left NAc were significant predictors of future tobacco use, with varying relationships across sexes. In females, an inverse relationship was observed between both NAc volumes and the risk of tobacco use. In contrast, a positive correlation existed between the left NAc volume and tobacco and marijuana use in males, with no such relationship for females. Conclusion: This study underscores that the associations between SLEs, NAc volume, and subsequent substance use are influenced by a nuanced interplay of sex, brain hemisphere, and substance type.