Orbitofrontal cortex and drug use during adolescence: role of prenatal exposure to maternal smoking and BDNF genotype

Arch Gen Psychiatry. 2009 Nov;66(11):1244-52. doi: 10.1001/archgenpsychiatry.2009.124.


Context: Prenatal exposure to maternal cigarette smoking (PEMCS) may affect brain development and behavior in adolescent offspring.

Objective: To evaluate the involvement of the orbitofrontal cortex (OFC) in mediating the relationship between PEMCS and substance use.

Design: Cross-sectional analyses from the Saguenay Youth Study aimed at evaluating the effects of PEMCS on brain development and behavior among adolescents. Nonexposed adolescents were matched with adolescents exposed prenatally to cigarette smoking by maternal educational level.

Participants and setting: A French Canadian founder population of the Saguenay-Lac-Saint-Jean region of Quebec, Canada. The behavioral data set included 597 adolescents (275 sibships; 12-18 years of age), half of whom were exposed in utero to maternal cigarette smoking. Analysis of cortical thickness and genotyping were performed using available data from 314 adolescents.

Main outcome measures: The likelihood of substance use was assessed with the Diagnostic Interview Schedule for Children Predictive Scales. The number of different drugs tried by each adolescent was assessed using another questionnaire. Thickness of the OFC was estimated from T1-weighted magnetic resonance images using FreeSurfer software.

Results: Prenatal exposure to maternal cigarette smoking is associated with an increased likelihood of substance use. Among exposed adolescents, the likelihood of drug experimentation correlates with the degree of OFC thinning. In nonexposed adolescents, the thickness of the OFC increases as a function of the number of drugs tried. The latter effect is moderated by a brain-derived neurotrophic factor (BDNF) genotype (Val66Met).

Conclusions: We speculate that PEMCS interferes with the development of the OFC and, in turn, increases the likelihood of drug use among adolescents. In contrast, we suggest that, among nonexposed adolescents, drug experimentation influences the OFC thickness via processes akin to experience-induced plasticity.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adolescent Behavior / psychology*
  • Atrophy / pathology
  • Brain Mapping
  • Brain-Derived Neurotrophic Factor / genetics*
  • Cerebral Cortex / growth & development
  • Cerebral Cortex / pathology*
  • Child
  • Child of Impaired Parents / psychology
  • Child of Impaired Parents / statistics & numerical data
  • Cross-Sectional Studies
  • Female
  • Genotype
  • Health Surveys
  • Humans
  • Magnetic Resonance Imaging
  • Maternal Behavior / psychology
  • Maternal Exposure / adverse effects*
  • Mothers / psychology*
  • Mothers / statistics & numerical data
  • Pregnancy
  • Prenatal Exposure Delayed Effects / genetics*
  • Prenatal Exposure Delayed Effects / pathology
  • Quebec / epidemiology
  • Smoking / adverse effects*
  • Smoking / epidemiology
  • Smoking / genetics
  • Substance-Related Disorders / epidemiology
  • Substance-Related Disorders / genetics*


  • Brain-Derived Neurotrophic Factor