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Download Slide Presentation Addiction: Science Drives New & Novel Treatments Yasmin Hurd Director, Addiction Institute of Mount Sinai Icahn School of Medicine at Mount Sinai Depts Psychiatry, Neuroscience and Pharmacological Sciences ADDICTION AND AMERICA >> 30 40 million million OVERDOSE STIGMA DEATHS HEALTHCARE STIMULANTS Economic + Intangible OPIOIDS SYSTEM Costs (USD in Billions) UNDER SEIGE CANNABIS synthetics ECONOMIC $>1000 BURDEN tobacco $749 Alcohol Total (Drug & Alcohol) + Intangible Costs (Quality of Life Lost) Lifespan 2 COVID: stress, social isolation and drug use National increase in urine drug test positivity rates during COVID-19 fentanyl 67% heroin 33% methamphetamine 23% ~85,000 drug overdose cocaine 19% 0% 20% 40% 60% 80% Wainwright et al., JAMA. 2020;324(16):1674-1677. Morphine maintenance clinics Treatments for Substance Use Disorders created (1919-1924) Alcoholics Anonymous formed (1935) Model of rehab created (1948-1950) Disulfiram (1948-1950) Methadone introduced for addiction (1964) Drug toxicology (1971) Narcan (1971) Naltrexone (1994) FDA approves buprenorphine for clinical use (2002) Acamprosate (2004) Varenicline (Chantix) (2006) 1919 2006 2020 Medications Used To Treat Substance Use Disorder Only ~17 percent of people who need SUD treatment receive it Barriers: Stigma Governmental regulation Science-based novel treatments Behavioral Therapies Cognitive Behavioral Therapy Contingency Management Motivational Enhancement Therapy Group/ Family Therapy Neurodevelopment Environmental Genetics factors (e.g., stress, impoverished conditions, early drug exposure) Drug use Inhibitory control Behavioral traits/ Impulsivity Reward Psychiatric sensitivity comorbidity Anxiety/ Depression Neurobiology of Addiction DS PFC NAc (ventral striatum; Nucleus accumbens): reward VTA expectation; goal-directed behavior OFC DS (Dorsal striatum): habit formation NAc AMG PFC (Prefrontal cortex): cognitive control OFC (orbitofronal cortex): goal-directed behavior, motivational drive; cognitive flexibility AMG (amygdala): emotional regulation; drug- seeking behavior HIPP (hippocampus): memory VTA (ventral tegmental area): reward, cognition, emotional regulation Impaired Cortical Function in Drug-Addicted Subjects and Individuals With Orbitofrontal Cortical Lesions • Poor decision • Poor impulse control • Emotional lability • Rapid temporal discounting of rewards Ventral Striatum (nucleus accumbens and reward) COCAINE Dorsolateral Striatum = CaudateNAc and SLEA responsible for the stimulus– signal changes response (S–R) associations; correlate strongly habitual responding with rush measures. Associative striatum (caudate nucleus) = Crucial for the learning and expression of goal- By contrastPutamen, directed actions; involved in the amygdala signal selection of actions that lead to NAc changes correlate more strongly with reward craving measures, Ventral striatum (NAc) = Reinforcement Breiter and Rosen, 1999 Reut Avinun et al. J. Neurosci. 2017;37:9724-9729 Amygdala Craving Cue reactivity Emotional regulation Wiers et al., Am J Psychiatry, 2015 Neurobiology of Addiction Drug USE EUPHORIA SYNAPTIC (DA) Drug URGES DYSPHORIA Dopamine Glutamate GABA Nucleus accumbens Opioid Endocannabinoid Treatment Development Human molecular studies Neurobiological Clinical Studies targets Preclinical Animal Models ResearchS Molecular Insights: Human Brain Transcriptional Profile of Heroin Abusers Control Heroin Dysregulation of Glutamatergic Genes and Epigenetic Remodelers in the Striatum of Human Heroin Abusers Glutamatergic system Glutamatergic-related genes Epigenetic Ac Synaptic plasticity PFC: Glutamate Whole genome co-expression network analysis Striatum EpiGenetics Addiction — Complex Disorder Environment -control gene activity Describes the study of mechanisms by which genes are turned on or off without altering their genetic code or DNA sequences. Epigenetics Cellular and physiological trait Decondensed chromatin Condensed chromatin variations that are not caused by changes in Histone deacetylases the DNA sequence; the (HDACs) study of changes in Histone acetyltransferases organisms caused by (HATs) modification of gene expression rather than methyltransferases alteration of the genetic code itself demethylation Histone methyltransferases Histone demethylation Transcriptional Transcriptional activation repression Sawan et al, 2008 Dysregulation of Epigenetic Remodelers in the Striatum of Human Heroin Abusers Predict Increased Acetylation and Transcription More accessible state of DNA = enhanced transcription DNA HAT Increased histone H3 acetylation HDAC - elevated histone acetyl transferase (HAT) levels (e.g., Ncoa1, Ncoa3) decreased histone deaceylase (HDAC) (e.g., HDAC5) Egervari et al., Biological Psychiatry, 2016 Epigenetic Marks Related to Transcriptional Activation Correlate to Glutamatergic Impairments Control Heroin Abusers Epigenetic marks Epigenetic Glutamate receptor gene expression Ac Years of heroin use Egervari et al., Biological Psychiatry, 2016 Translational: Consistent Hyperacetylation in the Rat Heroin Self-administration Model HumanHuman RatRat Model GRIA1 Gria1 AcH3 Control Heroin Control H3K27ac GRIA1 - Neurons Heroin ATAC-seq: Assay for Transposase-Accessible Chromatin with high throughput sequencing TSS, transcription start site Egervari et al., Biological Psychiatry, 2016 Bromodomain and Extraterminal (BET) Inhibitors - Potential Drug Abuse Treatment? Reader Bromodomain Ac ‘readers’: Bind Bromodomain complex binds acetylated histones Acetylated Lysine BET domain proteins reads acetylated lysine residues Residues Modified from Taverna and Cole, 2010 Bromodomain and Extraterminal (BET) Inhibitors - Potential Drug Abuse Treatment Ac Heroin self-administration behavior can be reduced Specific Epigeneticby specific Inhibitors epigenetic reduce rewarding inhibitors effects of heroin Heroin self-administration Vehicle Intra-dorsal striatal infusion BET inhibitor vehicle BET inhib Systemic administration Egervari et al., Biological Psychiatry, 2016 Treatment Development - Part II Human molecular studies Neurobiological Clinical Studies targets Preclinical Animal Models ResearchS Epigenetics Epigenome sequencing Neuron Glia Molecular Neurobiology of Opioid Abuse Epigenome Most significant epigenomic change in neurons relate to the FYN gene Nygaard et al., Alzheimer's Research & Therapy, 2014 FYN – (tyrosine kinase) is a component of the Increased phosphorylated-Tau in synaptic machinery that regulates the the brains of heroin users phosphorylation of Tau; hyperphosphorylated Tau is a pathological feature of neurodegenerative disorders (tauopathies) Kovacs et al.,. Neurobiol Aging, 2015 Phosphorylated Tau-Y18 Vehicle Opioid Activated Fyn hyperphosphorylated Tau pTau Synaptic dysfunction Neurodegeneration Stable Microtubule microtubule destabilization Egervari et al., Nature Communications, 2020 Inhibiting FYN (that reduces pTau) reduces heroin self-administration in animal models ** Epigenetic and synaptic regulation Clinical Trials target drugs Fyn Expression Regulates Heroin Seeking Behavior Knockdown of Fyn Reduces Cue-Induced Reinstatement Behavior Active Lever presses Inactive Lever presses Egervari et al., Nat Communication, 2020 Fyn Medication Development Saracatinib (AZD0530) ** AZD0530Compound X Specific epigenetic and synaptic dysregulation associated with Epigenetic and Food selfheroin-administration abuse linked to glutamatergic pathology may provide synaptic regulation Clinical Trials targetstarget drugs for treatment development Egervari et al., Nature Commun. 2020 AZD0530 Reduces Alcohol Self‐ Administration and Seeking Behavior Morisot et al., Addict Biol, 1227-1234, 2019 Treatment Development - Part III Human molecular studies Neurobiological Clinical Studies targets Preclinical Animal Models ResearchS Developmental THC Exposure Increases Heroin Self-Administration in Adulthood 120 Latency to 1st drug 140 lever press 100 ** vehicle 120 THC presses 80 ** - 100 60 80 60 40 Time (sec) Time * 40 20 20 Number of lever 0 0 0 7.5 15 30 60 100 Vehicle THC heroin dose (ug/kg/inf) 70 60 Vehicle active 50 lever presses Vehicle - 40 inactive lever 30 20 10 Number of lever 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 Session Epigenetic Mechanisms me m Prenatal and Adolescent THC exposures induce e protracted alteration of epigenetic modifications K4 Environment -control gene activity Synaptic Plasticity D9-THC CBD 9- D tetrahydrocannabinol Cannabidiol Cannabis contains over 500 chemicals including >140 cannabinoids which have a greater or lesser degree of psycho-pharmaco-activity THC and CBD: Cannabinoids with Different Actions CBD Reward THC CBD THC Intoxication CBD Anxiety THC Low dose High dose Diarrhea, dry mouth, CBD drowsiness (high dose) Side effects short-term memory deficit, impaired judgement, impaired motor coordination, THC tachycardia, sedation, withdrawal symptoms CBD Reduces Cue-induced Reinstatement of Heroin-Seeking Behavior Cannabidiol 24hr prior to heroin reinstatement session Vehicle *** Vehicle 30 CBD5 * CBD 5 mg/kg CBDCBD20 20 mg/kg 20 10 Number of lever press lever Numberof 0 Active Lever Inactive Lever CBD Ren et al, Journal Neuroscience, 2009 Initial training Maintenance Abstinence Drug seeking D9-THC CBD Decrease heroin seeking Enhance heroin self-adminstration 25 Vehicle 70 Vehicle active lever 20 3xCBD 60 THC active lever 50 15 40 pressing 10 30- 20 5 10 presses lever of Number 0 0 Number of lever 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 Active Lever Inactive Lever Session Heroin Abuse is Characterized by Impairments
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