Developmental pathways into adolescent substance abuse: neurophysiologic, genetic and environmental determinants

In this study we want to learn to better understand the interplay of genes, brain function and environmental influences and how they result in the development of adolescent abuse of alcohol, nicotine and cannabis. To this end we will examine 2000 14 year old participants of the IMAGEN sample which have been characterised using functional neuroimaging analysis of behavioural processes like reward dependence, impulsivity and emotional reactivity which are known to be relevant for the development of adolescent substance abuse. In addition, to extensive behavioural and clinical assessments, a genome-wide analysis has been carried out in these children. We now propose to extend the IMAGEN study in order to observe the development of substance use patterns in the context of moderating environmental factors, such as exposure to alcohol, nicotine or drugs as well as psychosocial stress. We aim to identify and to characterise a multidimensional risk profile of genes, brain function and environmental influences which helps us to predict risk for early onset substance abuse, including binge drinking, smoking or cannabis abuse. We will test our model in a second large cohort of 10000 adolescents, the ALSPAC cohort. Our final goal is to contribute to the development of specific early interventions in carriers of the risk profile to reduce the incidence of adolescent substance abuse.

Early onset and progression to adolescent substance abuse is genetically influenced and has been consistently shown to be associated with later risk for substance use disorders. Behavioural constructs, such as impulsivity, sensation seeking and harm avoidance are thought to be involved in mediation of increased genetic risk for substance abuse. However, neurophysiologic processes which mediate genetic risk might not be reflected in behavioural phenotypes due to compensatory factors, but may instead be revealed by functional neuroimaging. Understanding how neurophysiological processes mediate genetic risk but also how moderating environmental factors alter risk or resilience for adolescent substance abuse may identify neurobehavioural determinants which prove crucial for the development of targeted interventions. We propose to identify and to characterize a multidimensional risk profile of determinants for adolescent substance abuse, including abuse of alcohol, nicotine and cannabis based on longitudinal observations of subjects characterized in the IMAGEN study, the first cross sectional, multi-centre functional and structural genetic-neuroimaging study of a cohort of 2000+ 14 year old adolescents which investigates the neurophysiologic and genetic basis of individual differences in behaviours relevant for the development of substance abuse, including reward response, impulsivity and emotional reactivity. To this end we will complement the existing IMAGEN study by adding repeated longitudinal assessments of substance use patterns, behavioural development as well as psychosocial stress and exposure to licit and illicit substances covering adolescence up to the age of 18 years. Longitudinal analysis of the IMAGEN dataset will allow a systematic, genome-wide analysis of gene x environment interactions and their neurobehavioural mediation resulting in adolescent alcohol, nicotine and cannabis abuse. We will replicate our findings in the Avon Longitudinal Study of Parents and Children (ALSPAC), a regional birth cohort of 10.000 individuals. Integrated analysis of the IMAGEN and the ALSPAC study will allow us to better understand the complex interplay of genetic, developmental and environmental factors leading to adolescent substance abuse and relate them to neurobehavioural mechanisms as measured in neuroimaging analyses.