Genetic influences on substance use and abuse vulnerability are well documented, however, neural and cognitive mechanisms mediating these genetic influences are little understood. Genetic epidemiological research suggests a common genetic liability to substance use, externalizing psychopathology, and impulsive personality traits. We hypothesize that genetic influences on addiction and comorbid psychopathology vulnerability are mediated by dysfunctional neurocognitive mechanisms of inhibitory self-regulation of behavior. The long-term goal of this study is to test this etiological pathway hypothesis through the implementation of a prospective longitudinal and genetically informative design with a theory-driven choice of experimental paradigms that tap into distinct "component processes" of cognitive control of behavior and have been linked to specific neural substrates in the prefrontal cortex. During the initial funding period, we have ascertained three consecutive birth-year cohorts of 12-year-old twins (n=755) and their parents (n=540). The twins are being followed up longitudinally with biannual comprehensive laboratory assessments including cognitive brain electrophysiology, behavioral tests, and diagnostic measures. During the original funding period, we examined developmental changes of key neurocognitive measures of behavioral regulation, established their heritability, and examined their relationships with behavioral characteristics. This renewal application seeks to extend longitudinal follow-up of the twin cohorts into late adolescence, particularly through the period of highest risk for initiation of substance use and abuse (ages 16-19).
Specific aims will be 1) to examine developmental changes of the neural and cognitive mechanisms of inhibitory control and their genetic/environmental architecture during the transition from early to late adolescence and 2) to examine prospective developmental and genetic associations between neurocognitive predictors and behavioral outcomes, clarify their causal relationships, and evaluate the utility of inhibitory control measures as endophenotypes for addiction vulnerability. The proposed study will contribute to bridging the gap between genetics and complex behaviors and provide important neurocognitive endophenotypes for future genetic studies of drug abuse, as well as increase our understanding of etiological pathways to substance use and abuse in adolescence, which is essential to the development of better prevention and treatment methods.

Public Health Relevance

A better understanding of genetic, developmental, and neurobiological factors increasing the propensity to substance use in adolescence can inform the development of more effective prevention and early intervention methods and thus contribute to reducing the burden of substance use disorders on society. Potential outcomes of this study can inform the development of behavioral and pharmacological treatment methods that are specifically tailored to adolescents and are based on the knowledge about the development of neurocognitive functions underlying impulsivity, risk taking, decision making, as well as individual differences in these processes and their genetic determinants.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
5R01DA018899-09
Application #
8604700
Study Section
Behavioral Genetics and Epidemiology Study Section (BGES)
Program Officer
Gordon, Harold
Project Start
2004-09-30
Project End
2016-01-31
Budget Start
2014-02-01
Budget End
2015-01-31
Support Year
9
Fiscal Year
2014
Total Cost
$529,304
Indirect Cost
$181,078
Name
Washington University
Department
Psychiatry
Type
Schools of Medicine
DUNS #
068552207
City
Saint Louis
State
MO
Country
United States
Zip Code
63130
Golosheykin, Simon; Grant, Julia D; Novak, Olga V et al. (2016) Genetic influences on heart rate variability. Int J Psychophysiol :
Müller, Viktor; Anokhin, Andrey P; Lindenberger, Ulman (2016) Genetic influences on phase synchrony of brain oscillations supporting response inhibition. Int J Psychophysiol :
Anokhin, Andrey P; Golosheykin, Simon (2016) Neural Correlates of Response Inhibition in Adolescents Prospectively Predict Regular Tobacco Smoking. Dev Neuropsychol 41:22-37
Pagliaccio, David; Luking, Katherine R; Anokhin, Andrey P et al. (2016) Revising the BIS/BAS Scale to study development: Measurement invariance and normative effects of age and sex from childhood through adulthood. Psychol Assess 28:429-42
Anokhin, Andrey P; Golosheykin, Simon; Mulligan, Richard C (2015) Long-term test-retest reliability of delayed reward discounting in adolescents. Behav Processes 111:55-9
Anokhin, Andrey P; Grant, Julia D; Mulligan, Richard C et al. (2015) The genetics of impulsivity: evidence for the heritability of delay discounting. Biol Psychiatry 77:887-94
Anokhin, Andrey P; Golosheykin, Simon (2015) Neural correlates of error monitoring in adolescents prospectively predict initiation of tobacco use. Dev Cogn Neurosci 16:166-73
Anokhin, Andrey P (2014) Genetic psychophysiology: advances, problems, and future directions. Int J Psychophysiol 93:173-97
Mulligan, Richard C; Kristjansson, Sean D; Reiersen, Angela M et al. (2014) Neural correlates of inhibitory control and functional genetic variation in the dopamine D4 receptor gene. Neuropsychologia 62:306-18
Anokhin, Andrey P; Golosheykin, Simon; Grant, Julia D et al. (2011) Heritability of delay discounting in adolescence: a longitudinal twin study. Behav Genet 41:175-83

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