Low Smoking Exposure, the Adolescent Brain, and the Modulating Role of CHRNA5 Polymorphisms

Abstract

Background: Studying the neural consequences of tobacco smoking during adolescence, including those associated with early light use, may help expose the mechanisms that underlie the transition from initial use to nicotine dependence in adulthood. However, only a few studies in adolescents exist, and they include small samples. In addition, the neural mechanism, if one exists, that links nicotinic receptor genes to smoking behavior in adolescents is still unknown.

Methods: Structural and diffusion tensor magnetic resonance imaging data were acquired from a large sample of 14-year-old adolescents who completed an extensive battery of neuropsychological, clinical, personality, and drug-use assessments. Additional assessments were conducted at 16 years of age.

Results: Exposure to smoking in adolescents, even at low doses, is linked to volume changes in the ventromedial prefrontal cortex and to altered neuronal connectivity in the corpus callosum. The longitudinal analyses strongly suggest that these effects are not preexisting conditions in those who progress to smoking. There was a genetic contribution wherein the volume reduction effects were magnified in smokers who were carriers of the high-risk genotype of the alpha 5 nicotinic receptor subunit gene, rs16969968.

Conclusions: These findings give insight into a mechanism involving genes, brain structure, and connectivity underlying why some adolescents find nicotine especially addictive.

Keywords: Adolescents; Genetics; Gray matter volume; Low smoking exposure; Neuroimaging; fMRI.

Figure 1.

The different participant groups available from the IMAGEN study and used for the neuroimaging regression analyses (A, B) as well as for the genetic analyses (C). Non-smokers are represented with green bars (smoking score = 0). Smokers included in regression and genetic analyses had very low, low and moderate smoking exposure levels (smoking scores 1 to 6). Numbers on bars represent the total number of participants for each smoking score.

Figure 2.

A) Whole brain rendering of the T maps resulting from the brain voxel-wise regression analysis between GMV and smoking score. A significant negative correlation (initial threshold p<0.005; p<0.05 when corrected for multiple comparisons) was observed in the ventromedial prefrontal cortex (vmPFC). No positive correlations between GMV and smoking score were detected. B) The relationship between the vmPFC volume and future smoking at age 16 in 627 adolescents who were smoking naïve at age 14. No significant correlation was observed with r=0.02 and p=0.9. C) The rs16969968 genotype effects on structural GMV in the vmPFC. A 2×3 ANCOVA indicated that smoking status and the smoking-genotype interaction had significant effects on the vmPFC volume (p<0.0005 and p=0.026, respectively), where it was significantly decreased in smokers with the effect being largest in the carriers of the smoking-related high-risk genotype (AA). (*): significant difference with p<0.05.

Figure 3.

Alcohol use and performance IQ association with vmPFC volume in non-smokers. No significant correlations were observed in any of the analyses with R²≤0.0043 and p>0.1, suggesting that alcohol use and performance IQ are not correlated with vmPFC volume. vmPFC: ventromedial prefrontal cortex.

Figure 4.

Smoking status effects on white matter integrity. A) Whole brain rendering of the T map and Pearson’s correlation showing significant negative correlation between FA values in the corpus callosum ROI and smoking occasions, with r =−0.24 and p=5E⁻⁰⁶. B) The regression between the ventromedial prefrontal cortex (vmPFC) volume and future smoking at age 16 in 531 adolescents who were smoking naïve at age 14 revealed no significant correlation relationship with r=0.02 and p=0.8. C) Pearson’s correlation test highlighting the significant positive correlation between FA values in the corpus callosum cluster and the vmPFC volume, with r =0.25 and p=0.00008. (*): significant difference with p<0.05.