5/4/2016. Neurobiology of Addiction. Financial Disclaimers. Learning Objectives. Question 2. Question 1

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1 Neurobiology of Addiction Daniel Hall-Flavin, MD University of Wisconsin La Crosses Families and Addiction Conference 4 May, MFMER slide-1 Financial Disclaimers Dr. Hall-Flavin has no financial interests to disclose Dr. Hall-Flavin will address off-label use of some medications to treat addictive illness. Learning Objectives To cite the three major developmental stages of addiction. To understand the basic neurobiological hierarchy of phenotypic expression in these stages To understand To understand the targets of treatment To understand how the environment impacts the biological underpinnings of addiction 2016 MFMER slide MFMER slide-4 Question 1 Emotional regulatory structures include: a) Amygdala b) Anterior cingulate cortex c) Prefrontal cortex d) B and C e) All of the above Question 2 Allostasis in the context of substance use disorders: a) Occurs in binge drinking cycle before the onset of negative reinforcement. b) Occurs once addiction is established. c) Is characterized by overactivity of GABA and serotonin. d) Occurs with activation of the insula. e) B and D 2016 MFMER slide MFMER slide-6 1

2 Question 3 True or false: Activation of the emotions processing areas (amygdala and insula) are not consistently observed. Question 4 The concept of neuroplasticity includes all of the following, except: a) Dendritic sprouting b) Long term potentiation c) An increase in metabotropic glutamate receptors post-synaptically d) B and C e) Decreased responsivity to glutamate in the presence of drug cues MFMER slide MFMER slide-8 Substance Use Disorder DSM 5 Recurrent use of alcohol and/or other psychoactive substance that causes clinically and functionally significant impairment in health, disability, and failure to meet major responsibilities at work, school, or home. Classified as mild, moderate, or severe. The latter is considered to be synonymous with addiction (substantial evidence of impaired control over use). 11 criteria that may be summarized by evidence of impaired control, continued use despite adverse consequence, preoccupation, and evidence of physiologic dependence. Epidemiology 8-10 % of people 12 years of age or older (20 to 22 million people) are addicted to alcohol and other drugs. Economic cost 700 billion dollars annually. Mental Health Parity and Addiction Equity Act of MFMER slide MFMER slide-10 Development of Addiction Behavior Neuronal networks Environment Synapses Environment Risk Factors Molecules (receptors) Genes Substance intake Pharmacokinetics 2016 MFMER slide-12 2

3 What factors determine if a person will become addicted? EXAMPLES OF RISK AND PROTECTIVE FACTORS Risk Factors Domain Protective Factors Early Aggressive Behavior Poor Social Skills Lack of Parental Supervision Substance Abuse Drug Availability Poverty Individual Individual Family Peer School Community Self-Control Positive Relationships Parental Monitoring and Support Academic Competence Anti-Drug Use Policies Strong Neighborhood Attachment NIDA NIDA The brain continues to develop into adulthood and undergoes dramatic changes during adolescence. The Addiction Cycle NIDA 2016 MFMER slide-16 Development of Addiction Withdrawal Stress Negative reinforcement Intoxication Reward Positive reinforcement Compulsion to seek alcohol and drugs Loss of control in limiting intake The Addiction Cycle Source: Volkow, NEJM, 2016 Koob and Volkow. Neurocircuitry of Addiction, Neuropsychopharmacology reviews 35 (2010)

4 Development of Addiction Withdrawal Stress Negative reinforcement Compulsion to seek alcohol and drugs The Addiction Cycle The Addiction Cycle Intoxication Reward Positive reinforcement Loss of control in limiting intake Source: Volkow, NEJM, 2016 Koob and Volkow. Neurocircuitry of Addiction, Neuropsychopharmacology reviews 35 (2010) The Antireward System Development of Addiction Withdrawal Stress Negative reinforcement Intoxication Reward Positive reinforcement Compulsion to seek alcohol and drugs Loss of control in limiting intake Murphy A et al: Front Integ Neurosci, 2012 Koob and Volkow. Neurocircuitry of Addiction, Neuropsychopharmacology reviews 35 (2010) Some of the neural substrates implicated in motivation to use during withdrawal and protracted abstinence The Addiction Cycle salience Negative reinforcement Source: Volkow, NEJM, 2016 Down-regulation of Reward System Disruption of natural rewards Dopamine Serotonin Opioid peptides GABA Recruitment of Extra-Hypothalamic Stress System Negative emotional state Corticotropin-releasing factor (CRF) Norepinephrine Dynorphin Neurokinin (Substance P) Neuropeptide Y (NPY) Koob GF

5 Emotional Regulation and Behavior Emotional Regulation Affective Intensity/Reactivity of Affect (magnitude and degree of changeability) Affective Modulation Cognitive Modulation Behavioral Control 2016 MFMER slide MFMER slide-26 Impaired Emotional Regulation Functional Categories and Regions Impaired Emotional Regulation Connectivity Wilcox C, American Journal of Psychiatry, 173(4), 2016 Wilcox C, American Journal of Psychiatry, 173(4), 2016 Impaired Emotional Regulation Controls vs. SUD Individuals Impaired Emotional Regulation Novel Treatment Targets I Augment Activity PFC Improve WM/resting state Conductivity CBT Change default network activation Wilcox C, American Journal of Psychiatry, 173(4), 2016 Wilcox C, American Journal of Psychiatry, 173(4),

6 Cellular Connections Circuits to Cells MFMER slide-31 Cells and their Receptors Neuroplasticity. Matthew S, et al: Neuropsychopharm 2008M. Neuroplasticity in Brain Circuits associated with the Development of Addiction Cortical Spheroids Compulsivity Loss of Control Dorsal Striatum Nucleus Accumbens Prefrontal Cortex Extended Amygdala Mesolimbic DA Neuroplasticity with Increasing Use Koob, G. F. and Volkow. N. D. Neurocircuitry of Addiction, Neuropsychopharmacology reviews 35 (2010) Pasca S: Personalized Human Cortical Spheroids, Am J Pscyhiatry, 2016;173 (4):

7 Lower Dopamine D2 Receptor Neurons Opioid Dependent Individuals Receptors to Genes Sheng Y, et al: Am J Psychiatry 2016; 173(4): MFMER slide-38 Targets for Drugs of Abuse are Known and Can be Investigated Possible Families of Risk Factors Alcohol Metabolizing Enzymes Level of Response (LR) Impulsivity Psychiatric Disorders Karpyak et al: Current Psych 7, (2): 57, Alcohol Metabolism Alcohol ADH Acetaldehyde ALDH CO 2 + H 2 O Association Studies Candidates GABRA6 COMT 5HTT GABRG2 DRD2/ANKK1 ADORA GABRA5 DRD4 NPY GABRA1 KCNMA1 DGKZ ADHIB GNAS ADH1C PK CYP2E A 7

8 BDNF and Alcohol Use Disorderse Gene Expression Biological Psychiatry 2016; 79: MFMER slide-44 Epigenetics and Drugs of Abuse Epigenetics and Drugs of Abuse Robison E, et al: Nature Reviews Neuroscience, Trivedi M et al: Front Neurosci, 2015 The brain continues to develop into adulthood and undergoes dramatic changes during adolescence. Neurobiology and Treatment NIDA 2016 MFMER slide-48 8

9 These images of the dopamine transporter show the brain's remarkable potential to recover, at least partially, after a long abstinence from drugs - in this case, methamphetamine. Source: The Journal of Neuroscience, 21(23): NIDA R ev e r s e g e n e ti c s Antidipsotropic Medications & Their Targets Conceptual Framework Novel Drugs II Behavioral (clinical) phenotypes Intermediate phenotypes (endophenotypes) Brain function (circuits) Cellular function (pathways) Gene expression & protein modification Epigenetic effects Gene variations (genotypes) Endophenotypes Alcoholism- Specific Endophenotypes Examples Pertinent to Pharmacogenomics Clinical Phenotypes Summary F o r w a r d g e n e ti c s Antidipsotropic Medications Currently on the Market Year of release Drug Addiction Varenicline Nicotine 2006 Cocaine Vaccine Naltrexone extended* Alcohol 2005 Acamprosate Alcohol 2004 Buprenorphine Opiate 2002 Bupropion Nicotine 1997 Naltrexone* Alcohol 1994 Methadone Opiate 1972 Disulfiram Alcohol 1954 Nicotine replace Tx Nicotine Based on Koob et al: Nature Reviews/Drug Discovery, June 2009 Source: DEA Varenicline How Does it Work? Comorbidity: Targets and Treatment Varenicline binding leads to competitive blocking and partial activation of receptor-mediated release of dopamine in the reward center and competitive inhibition of receptor binding by nicotine delivered from cigarettes Varenicline suppresses the symptoms of nicotine withdrawal and reduces the pharmacologic reward from cigarette smoking Hays and Ebbert: NEJM 359:2018,

10 Questions/Responses Question 1 Emotional regulatory structures include: a) Amygdala b) Anterior cingulate cortex c) Prefrontal cortex d) B and C e) All of the above 2016 MFMER slide MFMER slide-56 Question 1 Emotional regulatory structures include: a) Amygdala b) Anterior cingulate cortex c) Prefrontal cortex d) B and C e) All of the above Question 2 Allostasis in the context of substance use disorders: a) Occurs in binge drinking cycle before the onset of negative reinforcement. b) Occurs once addiction is established. c) Is characterized by overactivity of GABA and serotonin. d) Occurs with activation of the insula. e) B and D 2016 MFMER slide MFMER slide-58 Question 2 Allostasis in the context of substance use disorders: a) Occurs in binge drinking cycle before the onset of negative reinforcement. b) Occurs once addiction is established. c) Is characterized by overactivity of GABA and serotonin. d) Occurs with activation of the insula. e) B and D Question 3 True or false: Activation of the emotions processing areas (amygdala and insula) is not consistently observed in those with established substance use disrorders MFMER slide MFMER slide-60 10

11 Question 3 True or false: Activation of the emotions processing areas (amygdala and insula) is not consistently observed in those with established substance use disrorders. Question 4 The concept of neuroplasticity includes all of the following, except: a) Dendritic sprouting b) Long term potentiation c) An increase in metabotropic glutamate receptors post-synaptically d) B and C e) Decreased responsivity to glutamate in the presence of drug cues MFMER slide MFMER slide-62 Question 4 The concept of neuroplasticity includes all of the following, except: a) Dendritic sprouting b) Long term potentiation c) An increase in metabotropic glutamate receptors post-synaptically d) B and C e) Decreased responsivity to glutamate in the presence of drug cues. Bibliography Addiction Comorbidity Hägele C, Schlangenhauf F, Rapp M, et al: Dimensional psychiatry: reward dysfunction and depressive mood across psychiatric disorders. Psychopharmacology (Berl) 2015;232: Addiction Neurobiology General Volkow N, Koob G, McLellan AT: Neurobiological advances from the brain disease model of addiction. N Engl J Med 2016;374(4): Volkow N, Morales M: The brain on drugs: from reward to addiction. Cell 2015; 162: Addiction Neurobiology Molecular, Cellular, and Circuitry Britt JP, Bonei A: Optogenetic interrogations of the neural circuits underlying addiction. Curr Opin Neurobiol 2013;23: Goldstein R, Volkow N: Dysfunction of the prefrontal cortex in addiction: neuroimaging findings and clinical implications. Nat Rev Neurosci 2011:12: Jennings J, Sparta D, Stamatakis A, et al: Distinct extended amygdala circuits for divergent motivational states. Nature 2013;496: Kaufling J, Aston-Jones G: Persistent adaptions in afferents to ventral tegmental dopamine neurons after opiate withdrawal. J Neurosci 2015;35: Koob G, LeMoal M: Plasticity of reward neurocircuitry and the dark side of drug addiction. Nat Neurosci 2005;8: Kourrich S, Calu D, Bonci A: Intrinsic plasticity: an emerging player in addiction. Nat Rev Neurosci 2015 ;16: Pasca S: Personalized human cortical spheroids. Am J Psychiatry 2016;173(4): Trifilieff P, Feng B, Urizar, et al: Increasing dopamine D2receptor expression in the adult nucleus accumbens enhances motivation. Mol Psychiatry 2013;18: Saddoris MP, Cacciapaglia F, Wightman R, et al: Differential dopamine release dynamics in the nucleus accumbens core and shell reveal complementary signals for error prediction and incentive motivation. J Neurosci 2015;35: MFMER slide MFMER slide-64 Bibliography Sheng Y, et al: Lower dopamine D2 receptor expression levels in human dopaminergic neurons derived from opioid-dependent ipcs. Am J Psychiatry 2016;173(4): Volkow N, Tomasi D, Wang G, et al: Stimulant-induced dopamine increases are markedly blunted in active cocaine abusers. Mol Psychiatry 2014;19: Wilcox C, et al: Neural circuitry of impaired emotional regulation in substance use disorders. Am J Psychiatry (4): Addiction Treatment Bell J: Pharmacological maintenance treatments of opiate addiction. Br J Clin Pharmacol 2014;77: Kiluk B, Carrol K: New developments in behavioral treatments for substance use disorders. Curr Psychiatry Rep 2013;15: 420. Litten R, Ryan M, Falk D, et al: Heterogeneity of alcohol use disorder: understanding mechanisms to advance personalized treatment. Alcohol Clin Exp Res 2015;39: Muller C, Geisel O, Banas R, et al: Current pharmacological treatment approaches for alcohol dependence. Expert Opin Pharmacother 2014;15: Bibliography Behavioral Addiction Potenza M: Perspective: behavioral addictions matter. Nature 2015;522: S62. Epidemiology Warner L, Kessler R, Hughes M, et al: Prevalence and correlates of drug use and dependence in the United States: results from the National Comorbidity Survey. Arch Gen Psych 1995;52: Sandler I, Wolchick S, Cruden G, et al: Overview of meta-analyses of the prevention of mental health, substance use, and conduct problems. Annu Rev Clin Psychol 2014; 10: Genetics Demers C, Bogdan R, Agrawal A: The genetics, neurogenetics and pharmacogenetics of addiction. Curr Behav Neurosci Repr 2014;1: Volkow N, Muenke M: The genetics of addiction. Hum Genet 2012;131: Adolescence Durlack J, Weissberg R, Dymnicki A, et al: The impact of enhancing students social and emotional learning: a meta-analysis school-based universal interventions. Child Dev 2011;82: Greenberg M, Lippold M: Promoting healthy outcomes among youth with multiple risks: innovative approaches. Annu Rev Public Health 2013;34: Quinn P, Harden K: Differential changes in impulsivity and sensation seeking and the escalation of substance use from adolescence to early adulthood. Dev Psychopathol 2013;25: Stanis J, Andersen S: Reducing substance use during adolescence: A translational framework for prevention. Psychopharmacology (Berl) 2014; 231: Brain Disease Model Volkow N, Koob G: Brain disease model of addiction: why is it so controversial? Lancet Psychiatry 2015; 2: MFMER slide MFMER slide-66 11

12 Thank You, and Enjoy the Conference! 2016 MFMER slide-67 12