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 inform the mechanisms that underlie the transition from initial use to nicotine dependence in adulthood. However, only a few studies in adolescents have appeared and those available 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 age 16.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 pre-existing 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 reinforcing.

Genetic susceptibility to nicotine addiction: Advances and shortcomings in our understanding of the CHRNA5/A3/B4 gene cluster contribution

“…This discrepancy might reflect the existence of spurious associations due to the small sample sizes. Finally, the IMAGEN consortium has recently reported that both smoking tobacco and being homozygote for rs16969968 high-risk genotype were associated with a reduction in cortical thickness of the ventromedial prefrontal cortex (PFC), with additive smoking + genotype effects (Chaarani et al, 2019).…”

Age-Dependent and Pathway-Specific Bimodal Action of Nicotine on Synaptic Plasticity in the Hippocampus of Mice Lacking the miR-132/212 Genes

“…The hippocampus of humans and rodents share a large variety of genetic, structural, functional, and pharmacological commonalities and also overlap in key events in maturation during adolescence and adulthood [ 14 , 15 , 20 ]. While the time scale of the central nervous system developmental phases is considerably different between human and murine species, rodents, however, also exhibit a remarkable vulnerability to nicotine addiction at to human corresponding age stages (e.g., adolescence) and also share numerous features when addiction-related physiological and behavioral changes are examined [ 14 , 15 , 103 , 104 , 105 , 106 , 107 , 108 , 109 , 110 ]. The signaling elements that become altered and consolidated in the young brain upon nicotine exposure remain, however, poorly understood.…”

Adolescent Substance Use and the Brain: Behavioral, Cognitive and Neuroimaging Correlates

“…Many studies have shown morphological and functional differences between smoking and non-smoking adolescents in the prefrontal cortex (PFC), inferior parietal cortex, and anterior insula that in part comprise the selective and divided attention neural circuits (Elsey et al, 2016 ). Gray matter loss in the cortex may be exacerbated by smoking; smokers reportedly have lower amounts of gray matter in the frontal cortex (Li et al, 2015 ; Akkermans et al, 2017 ; Chaarani et al, 2019 ), inferior parietal lobe (Li et al, 2015 ; Akkermans et al, 2017 ), and insula (Li et al, 2015 ) than non-smoking controls, and gray matter in the dorsolateral PFC (DLPFC) was negatively correlated with smoking dependency (Li et al, 2015 ). A recent fMRI study of adolescent smokers found that resting-state functional connectivity (RSFC) was lower between the anterior insula and the DLPFC, amygdala, and striatum of smokers compared to non-smokers (Bi et al, 2017 ).…”

“…Cortical gray matter reductions undergo steeper declines in those with schizophrenia than healthy individuals, suggesting a link between synapse refinement and development of the disease (Selemon and Zecevic, 2015 ). Since cortical thickness and GMV is lower in smoking adolescents (Li et al, 2015 ; Akkermans et al, 2017 ; Chaarani et al, 2019 ) and the rate of cortical thinning, though non-significant, is greater in novel smokers compared to non-smokers (Akkermans et al, 2017 ), it is possible that smoking may exacerbate gray matter declines in youth with a genetic predisposition to develop schizophrenia. Longitudinal MRI studies of adolescent smokers and non-smokers with schizophrenia risk (genetic or environmental) would help to elucidate the potential for additive effects of these factors on gray matter development.…”

“…Adolescent smokers show increased FA in the corpus callosum, internal capsule, and inferior longitudinal fasciculus (Jacobsen et al, 2007b ; Yu et al, 2016 ), as well as the corona radiata (Yu et al, 2016 ) and forceps minor (Jacobsen et al, 2007b ) relative to non-smokers. However, the exact relationship between smoking and FA in the corpus callosum remains unclear considering FA in this region has been negatively, rather than positively, correlated with the extent of youth smoking history (Chaarani et al, 2019 ). These overlapping regional differences in white matter integrity between young smokers and those with ADHD could suggest that the ADHD brain is differentially sensitive to tobacco’s potential effects on white matter compared to those without ADHD.…”