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A Brain Developmental Disorder

DRUG ADDICTION:. A Brain Developmental Disorder. Nora D. Volkow, M.D. Director National Institute on Drug Abuse. ADDICTION IS A DEVELOPMENTAL DISEASE starts in adolescence and childhood. 1.8%. TOBACCO. THC. 1.6%. ALCOHOL. 1.4%. 1.2%. % in each age group who develop. time dependence.

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A Brain Developmental Disorder

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  1. DRUG ADDICTION: A Brain Developmental Disorder Nora D. Volkow, M.D. Director National Institute on Drug Abuse

  2. ADDICTION IS A DEVELOPMENTAL DISEASE starts in adolescence and childhood 1.8% TOBACCO THC 1.6% ALCOHOL 1.4% 1.2% % in each age group who develop time dependence 1.0% 0.8% 0.6% first 0.4% 0.2% 0.0% 5 10 15 21 25 30 35 40 45 50 55 60 65 Age Age attobacco, atalcohol and at cannabisdependence as per DSM IV NIAAA National Epidemiologic Survey on Alcohol and Related Conditions, 2003.

  3. 1100 AMPHETAMINE 1000 900 800 700 % of Basal Release 600 500 400 300 200 100 0 0 1 2 3 4 5 hr Time After Amphetamine FOOD 200 150 % of Basal Release 100 Empty 50 Box Feeding 0 0 60 120 180 Time (min) Di Chiara et al. Dopamine Neurotransmission frontal cortex nucleus accumbens VTA/SN

  4. Self-Reports (0-10) 10 8 6 Change in Dopamine Bmax/kd (Placebo - MP) 4 2 0 -2 -10 0 10 20 30 40 DA and Drug Reinforcement “High” T Y R O S I N E T Y R O S I N E D O P A D O P A D A D A DA D A DA D A D A D A D A D A raclopride D A m e t h y l p h e n i d a D A D A D A raclopride D A R D A D A R R D A R R R t e DA initiates and maintains responses to salient stimuli such as drugs

  5. [11C]Raclopride 6.0 r = 0.69, p < 0.0001 5.5 (n = 25) 5.0 4.5 DV(BG) / DV (CB) 4.0 24 year old 3.5 3.0 2.5 2.0 10 20 30 40 50 60 70 80 Age 86 year old DOPAMINE D2 RECEPTORS Decrease with Age in the Human Brain

  6. 2.00 2.00 1.50 1.50 1.00 1.00 0.50 0.50 0.00 0.00 -0.50 -0.50 20 25 30 35 40 45 50 20 25 30 35 40 45 50 Methylphenidate Induced DA Increases Response to stimulants decrease with Age Intravenous MPH Oral MPH (Bsl - MP) Changes in Bmax/Kd Age

  7. Although Adolescents are in their Prime Physically, Morbidity and Mortality Doubles As A Result of Behavioral Changes that Occur During the Transition from Childhood to Adolescence What Makes This Time One of Increased Risk?

  8. 80 70 60 50 40 30 20 10 0 Percent of Initiates Child <12 Teen 12-17 Young Adult 18-25 Adult >25 Age at Which Marijuana Use Is First Initiated Source: Gfroerer, JC et al., SMA 02-3711, OA, SAMHSA – Data from National Survey of Drug Use and Health.

  9. Recent Studies Have Shown that Maturation of the Brain’s Gray Matter Moves from Back to Front Brain areas where volumes are smaller in adolescents than young adults Source: Sowell, E.R. et al., Nature Neuroscience, 2(10), pp. 859-861, 1999

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

  11. Amygdalo-cortical Sprouting Continues Into Early Adulthood During Adolescence the COGNITION-EMOTION Connection is Still Undergoing Development Low-power light photomicrographs of immunoperoxidase-labeled, biocytin-containing amygdalofugal varicose fibers within the mPFC of animals at 6 stages of development Source: Cunningham, M et al., J Comp Neurol 453, pp 116-130, 2002.

  12. Different Drugs, Same Ultimate Effect Source: Nestler, EJ and Malenka, RC, Scientific American, pp. 78-85, March 2004.

  13. Exposure to Drugs of Abuse During Adolescence Could Have Profound Effects on Brain Plasticity

  14. Molecular Targets for Drugs of Abuse Appear Early in Gestation and Are Involved in Fetal Brain Development CANNABINOID RECEPTORS NICOTINIC RECEPTORS Postnatal 7 Postnatal 7 ADULT ADULT GENSAT Drug Stimulation of these Receptors is Likely to Affect Development

  15. 125 100 75 50 Percent baseline firing rate vehicle pretreated CB adolescent vehicle pretreated CB adolescent CB adult 250 225 200 175 150 125 100 .1 1 10 Cocaine (mg/kg) 125 100 75 50 vehicle pretreated CB adolescent Percent baseline firing rate Percent baseline firing rate 1 10 Morphine (mg/kg) .1 1 Amphetamine (mg/kg) Adolescent Exposure to Cannabinoids Alters the Response of VTA Dopamine Neurons to Drugs of Abuse Source: Pistis, M. et al., Biol Psychiatry, 56: 86-94, 2004.

  16. Exposure to Marijuana May Increase Later Drug Problems Drug Use Outcomes in Twin Pairs Discordant for Cannabis Use Before Age 17 7 6 Sedatives 5 Opiates ODDS Ratio 4 Cocaine/ Stimulants 3 2 Cannabis 1 Drug Abuse/Dependence Source: Lynskey, MT et al., JAMA, 289, pp. 427-433, 2003.

  17. Mental Disorder Addictive Disorder Addictive Disorders Often Co-Exist With Mental Disorders Comorbid Disorders

  18. Age of Onset of Brain Disorders Drug Abuse and Addiction 10 – 13 Years Eating Disorders Obsessive-Compulsive Disorders Developed from Time Magazine, January 20, 2003, p. 82

  19. The Use of Alcohol, Nicotine and Other Commonly Abused Drugs Generally Begins in Adolescence… Substance Abuse Disorder Mental Health Disorder Disorder in Late 20s Major Depressive Disorder Alcohol Dependence Substance Use Disorders Tobacco Use Childhood Adolescent Early 20s 1.461 1.422 0.920 1.589 1.484 2.085 1.565 1.438 1.175 1.482 1.160 2.154 Alcohol Use Childhood Adolescent Early 20s Marijuana Use Childhood Adolescent Early 20s Other Illicit Drug Use Childhood Adolescent Early 20s And…Increases the Odds of Later Depressive And Substance Use Disorders Source: Brook, DW et al., Arch Gen Psychiatry, 59, November 2002.

  20. COMORBIDITY Smoking and Mental Illness • 44% of all cigarettes consumed in the US • are by individuals with a current • psychiatric disorder • 75% of patients in addiction and mental • health treatment programs smoke cigarettes

  21. Comorbidity with Mental Illness 1.6 1.4 1.2 1.0 0.8 0.6 0.4 0.2 0.0 α7/β-actin Controls Medicated Non-medicated i.e > 80% Schizophrenics Smoke Schizophrenics have Fewer 7 AChR in Hippocampus mRNA Levels of 7 AChR are Lower in Schizophrenics control subjects schizophrenic patients Perl, O et al., FASEB J, 17, pp. 1948-1950, 2003. nicotine normalizes a sensory gating abnormality defect, found in most schizophrenics Freedman et al, Biol Psychiat 38, 22-33, 1995

  22. # of Cigarettes Smoked at Age 18 and Risk for Schizophrenia During 4–16-Year Follow-Up in 14,248 Males • Smokers were at greater risk • to develop schizophrenia; • the adjusted relative risk • was 1.94 (CI 1.05-3.58) • Numbers of cigarettes • smoked was significantly • associated with schizophrenia • When compared with non • smokers the increased risk • for hospitalization for • schizophrenia on those who • smoked 1-9 cigarettes was • 1.38 and on those who • smoked > 10 cigarettes it • was 2.28 greater Weiser et al., Am J Psychiatry 161:1219-1223 2004.

  23. Understanding Drug Abuse & Addiction from A Developmental Perspective Has Important Implications for Its Prevention & Treatment

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