1. Gene-Environmental Interactions Across Development Addictions and Brain Reward Systems: Gene-Environmental Interactions Across Development Wilson M. Compton, MD, MPE Deputy Director National Institute on Drug Abuse National Institutes of Health USA

2. Addictions are common, developmental brain diseases expressed as compulsive behavior through continued use of a drug despite negative consequences: Onset depends on many intrinsic and extrinsic factors. Addiction DRUG/ALCOHOL Brain Mechanisms Biology Genes/Development Biology Genes/Development Environment

3. Addictions are brain diseases Key concepts include: Human development Environmental influences Genetic risks Gene-Environment Interactions across development

4. Healthy Heart Diseased Heart Decreased Heart Metabolism in Heart Disease ADDICTION IS A DISEASE OF THE BRAIN as other diseases it affects the tissue function Control Cocaine Abuser Decreased Brain Metabolism in Drug Abuse Sources: From the laboratories of Drs. N. Volkow and H. Schelbert High Low

5. ACG OFC SCC Hipp NAcc VP Amyg REWARD INHIBITORY CONTROL INHIBITORY CONTROL MEMORY/ LEARNING MEMORY/ LEARNING EXECUTIVE FUNCTION EXECUTIVE FUNCTION PFC Becomes severely disrupted in ADDICTION MOTIVATION/ DRIVE MOTIVATION/ DRIVE The fine balance in connections that normally exists between brain areas active in reward, motivation, learning and memory, and inhibitory control

6. Addictions are brain diseases Key concepts include: Human development Environmental influences Genetic risks Gene-Environment Interactions across development

7. Addiction Is Developmental Age of Onset of Drug Abuse and Dependence Source: Compton, et al. Archives of General Psychiatry 2007. NESARC Study.

8. Prefrontal Cortex (cognitive control) Regulates Limbic Activation (emotions and desires) and Impulsivity Ersche et al. Science 335(6068): 601-604 (2012) Reduced frontal-limbic connectivity is associated with impulsivity (self-control)

9. Source: Beauregard, M. et al., Journal of Neuroscience 21 RC165, 2001. Sexual Arousal Condition Attempted Inhibition Condition Attempted Inhibition Condition In Adults, Emotional Self Regulation Normally Implemented By A Neural Circuit Comprising Various Subcortical Limbic Structures… & Prefrontal Regions

10. Children with low self-control had poorer health, more wealth problems, more single-parent child rearing, and more criminal convictions and drug use than those with high self-control A gradient of childhood self-control predicts health, wealth, and public safety (Dunedin Study; 1000+ children) HealthWealthCriminal behavior Moffitt et al., PNAS 2011 Since self-control can be improved by interventions early childhood intervention that enhances self-control is likely to bring a greater return on investment than harm reduction programs targeting adolescents alone.

11. Highly Rewarding Effect of Nicotine/Acetaldehyde During Adolescence Highly Rewarding Effect of Nicotine/Acetaldehyde During Adolescence Belluzzi, et al., Neuropsychopharmacology, 2005 Apr;30(4):705-12.

12. Nicotine administration up-regulates arc, a gene involved in synaptic plasticity in adolescents but not adults T. L. Schochet, A. E. Kelley AND C. F. Landry Neuroscience 135 (2005) 285–297 AdolescentAdult

13. Addictions are brain diseases Key concepts include: Human development Environmental influences Genetic risks Gene-Environment Interactions across development

15. 0 2 4 6 8 10 012345 Odds ratio ACE Score Ever Addicted Adverse Childhood Experiences (ACE) and Illicit Drug Use (n = 8603) SR Dube, et al. PEDIATRICS 111: 564-572, 2003 1.0

16. Children with deprivation (n=17) vs controls (n=15) had decreased connectivity in uncinate fasciculus (connects amygdala with frontal cortex), proportional to time in orphanage. This could facilitate heightened emotional reactivity and impaired cognitive control. Social Neglect During Early Childhood Decreases Brain Connectivity Govindan et al., Cereb Cortex 2009 r = -0.604, p=.01

17. Prevention Programs Should Enhance Protective Factors and Reduce Risk Factors ` Prevention Programs Should Enhance Protective Factors and Reduce Risk Factors ` Reduce these Elevate these

18. Nurse Home Visiting during pregnancy and the first two years of life has an impact on substance use, mental health and academic achievement at 12 years of age Arch Pediatr Adoles Med, 164(5) 412-418, 2010 Percent of Children Who Used Tobacco, Alcohol, or Marijuana (Last 30 Days) Child Age 12 Percent of Children with Internalizing Problems (Borderline or Clinical) Child Age 12 Scores - Reading & Math – Age 12 (Born to Low-Resource Mothers) PIAT Scores - Reading & Math – Age 12 (Born to Low-Resource Mothers) Percent of Mothers with Role Impairment due to Alcohol or Drug Use – Child Age 12

19. Addictions are brain diseases Key concepts include: Human development Environmental influences Genetic risks Gene-Environment Interactions across development

20. Biological Psychiatry Research on nicotine’s reinforcing effects has focused on α4, β2 and α7 and little is known about α5, α3,  4, which have a high concentration in habenula and inter-peduncular nucleus Convergent Results Support CHRNα5/α3/  4 Convergent Results Support CHRN α5/ α3/  4 Gene Cluster Association with Nicotine Dependence CHRNα5 CHRNα3 CHRNβ4

21. Decline in Genetic Influence on Co-Occurrence of Alcohol, Marijuana, and Nicotine Dependence Symptoms From Age 14 to 29: Within and Across Age Correlations Between Substance Use Symptom Count Measures Vrieze et al.., American Journal of Psychiatry 2012

22. Addictions are brain diseases Key concepts include: Human development Environmental influences Genetic risks Gene-Environment Interactions across development

23. GenesGenes ExperienceExperienceDevelopmentDevelopment

24. Genetic and Familial-Environmental Influences on Risk for Drug Abuse Kendler et al., Genetic and Familial-Environmental Influences on Risk for Drug Abuse: A National Swedish Adoption Study, Archives of General Psychiatry 2012;69:690-697

25. Age of Exposure Interacts with Genotype in Predicting Tobacco Dependence: Low Nicotine Dependence (%) as a Function of Haplotypes A and C versus Age of Onset of Daily Smoking Quartiles in the UT-WI-LHS Cohorts. Weiss RB, Baker TB, Cannon DS, von Niederhausern A, et al. (2008) A Candidate Gene Approach Identifies the CHRNA5-A3-B4 Region as a Risk Factor for Age-Dependent Nicotine Addiction. PLoS Genet 4(7): e1000125. doi:10.1371/journal.pgen.1000125 http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1000125

26. Gene Encoding for SERT* Modulate Parenting Impact on Vulnerability to SA Brody et al., J Consulting Clinical Psychol 2009; 77:1-11. * VNTR in promotor region of 5HTT Gene Encoding for SERT* and the Connectivity in Uncinate Fasciculus l-l s-l s-s The low SERT expressing alleles had less connectivity in the UF, which could impair cognitive control No Genetic Risk (l-l allele) Genetic Risk (s-s or s-l allele) Substance Use Rate of Increase Involved-Supportive Parenting LowHigh High supportive parenting decreased SUD risk in those with low SERT expressing alleles (high risk alleles) Pacheco et al., J Neurosci. 2009 29:10461-2.

27. Brody, Chen, Yu, Beach, Kogan, Simons, Windle, Philibert. Development and Psychopathology (2012) 24: 941-951 Growth in participants’ past- month drug use by DRD4 status and life stress. The Impact of Genes on Prevention Outcomes

28. Genetic influences on different stages in the development/remission of addiction are likely to overlap: Specific genetic predictors of smoking quit success also predict addictive substance onset on tobacco, alcohol and cannabis Uhl et al., Molecular Psychiatry 2012 Trajectories of common substances: Green=low/slow; red=escalating; blue=high use v1.0 quit genotype score Scores (range 0-1000) for non- quitters and successful quitters 365 370 375 380 385 390 395 400 NQQ Those with the highest v1.0 scores had greater probability of membership in the low/slow trajectory group (p=0.00036). Those with the lowest v1.0 scores had greater probability of membership in the escalating trajectory group (p=0.00098). Study 1 Study 2

29. Addictions are brain diseases Key concepts include: Human development Environmental influences Genetic risks Gene-Environment Interactions across development

30. “The Next Great American Project” Learning the Language of the Brain