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Neurobiology of addiction padova
 

Neurobiology of addiction padova

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Neurobiologia delle Dipendenze

Neurobiologia delle Dipendenze

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    Neurobiology of addiction padova Neurobiology of addiction padova Presentation Transcript

    • Neurobiology of Addiction and Therapeutic Strategies Felice Nava, MD, PhD
    • Why does the Brain Become Addicted?
    • ADDICTION IS A COMPLEX ILLNESSADDICTION IS A COMPLEX ILLNESS
    • NIAAA National Epidemiologic Survey on Alcohol and Related Conditions, 2003 Age Age at tobacco, at alcohol and at cannabis dependence as per DSM IV 0.0% 0.2% 0.4% 0.6% 0.8% 1.0% 1.2% 1.4% 1.6% 1.8% 5 10 15 2125 30 35 40 45 50 55 60 65 %ineachagegroupwhodevelop firsttimedependence THC ALCOHOL TOBACCO Addiction is a Developmental Disease
    • Addiction is a “Normal” Disease
    • The Smokers Body Smokers have a 35-45% reduction in MAO B Flower et al., 2003
    • Effects of Cocaine on Glucose Metabolism in Maternal and Fetal Brain
    • James Old (1922-1976) The Pleasure Centers
    • movement motivation addiction sex & reward Dopamine the Molecule of Life
    • The Brain Reward System
    • Sampling of Interstitial Neurochemicals by in vivo Microdialysis
    • 0 50 100 150 200 0 60 120 180 Time (min) %ofBasalDA Output NAc shell Empty Box Feeding Source: Di Chiara et al. FOOD 100 150 200 DAConcentration(%Baseline) Mounts Intromissions Ejaculations 15 0 5 10 CopulationFrequency Sample Number 1 2 3 4 5 6 7 8 9 1011 1213 1415 1617 Female 1 Female 2 Source: Fiorino and Phillips SEX The Natural Rewards
    • 0 50 100 150 200 250 F latency 8'45"± 30" amount eaten 2± 0.2g Fonzies naive 0 50 100 150 200 250 F latency to eat 15"± 0 amount eaten 4± 0.2g 1 day post Fonzies 0 60 120 180 240 0 50 100 150 200 250 F amount eaten 4.2± 0.2g latency to eat 22"± 0 5 days post Fonzies time (min) %ofbasalDA Time-course of habituation of NAc shell DA responsiveness to one trial Fonzies feeding Bassareo and Di Chiara,J.Neurosci.1999
    • 0 100 200 300 400 500 600 700 800 900 1000 1100 0 1 2 3 4 5 hr Time After Amphetamine %ofBasalRelease DADOPACHVA Accumbens AMPHETAMINE 0 100 200 300 400 0 1 2 3 4 5 hr Time After Cocaine %ofBasalRelease DA DOPAC HVA Accumbens COCAINE 0 100 150 200 250 0 1 2 3 hr Time After Nicotine %ofBasalRelease Accumbens Caudate NICOTINE 100 150 200 250 0 1 2 3 4hr Time After Ethanol %ofBasalRelease 0.25 0.5 1 2.5 Accumbens 0 Dose (g/kg ip) ETHANOLETHANOL Source: Di Chiara and Imperato The Drugs of Abuse and DA Output
    • Tanda, Pontieri & Di Chiara, Science, 1997 Selective increase of DA in the Nac shell after i.v.THC and heroin
    • Fast DA Release is Addictive
    • Reward Circuit in Addiction: The Role of Dopamine
    • Methylphenidate Induced Increase in Striatal DA in Controls and in Alcoholics Subjects
    • Memory/Conditioning: The Role of Dopamine
    • Dopamine and The Incentive Phase
    • [11C] Raclopride Binding In Cocaine Abusers (n =18) Viewing a Neutral and a Cocaine-Cue Video
    • Motivation and Executive Control Circuits: The Role of Dopamine
    • Dopamine D2 Receptors are Lower in Addiction
    • Correlations Between D2 Receptors in Striatum and Brain Glucose Metabolism
    • Actions of Drugs of Abuse on Ventral Tegmental Area and Nucleus Accumbens
    • Stress and Temperament Modulate Drug Intake Response
    • Neurochemical Circuitry in Drug Reward
    • Neurocircuitry of Addiction Derived from: Koob G, Everitt, B and Robbins T, Reward, motivation, and addiction. In: Squire LR, Berg D, Bloom FE, du Lac S, Ghosh A, Spitzer NC (Eds.), Fundamental Neuroscience, 3rd edition, Academic Press, Amsterdam, 2008, pp. 987-1016.
    • Reward Transmitters Implicated in the Motivational Effects of Drugs of Abuse Dopamine … “dysphoria” Opioid peptides ... pain Serotonin … “dysphoria” GABA … anxiety, panic attacks Dopamine Opioid peptides Serotonin GABA Positive Hedonic Effects Negative Hedonic Effects of Withdrawal
    • Extracellular DA and 5-HT in the Nucleus Accumbens During Cocaine Self- Administration and Withdrawal
    • Stress and Anti-stress Neurotransmitters Implicated in the Motivational Effects of Drugs of Abuse Corticotropin-releasing factor Norepinephrine Vasopressin Orexin (hypocretin) Dynoprhin Neuropeptide Y Nociceptin (orphanin FQ)
    • CNS Actions of Corticotropin-Releasing Factor (CRF)
    • Neurochemical Changes Associated with Drug Use, Dependence and Relapse
    • Molecular Targets of Drug Action ??Inhalants Serotonin receptors Serotonin receptors NMDA receptors NMDA receptors Hallucinogens LSD MDMA PCP Ketamine Dopamine transporters Dopamine/NE release Stimulants Cocaine Amphetamines Opioid receptorsOpioids CannabinoidreceptorsMarijuana/THC GABA receptors GABA receptors Depressants Barbiturates Benzodiazepines Nicotinic Ach receptorNicotine Adenosine ReceptorsCaffeine Classes of Drugs Primary Target NMDA receptors (blocked) Kainate receptors (blocked) GABA receptors (stimulated) Glycine receptors (stimulated) Nicotinic Ach receptors (stimulated) Serotonin receptors (stimulated) Calcium channels (blocked) Potassium channels (blocked) Protein Kinase C Protein Kinase A DARPP-32 Phosphatases Neurosteriods Alcohol Targets
    • The Aims of the Pharmacological Treatment of Addiction • The management of the withdrawal syndrome; • The achiment of abstinence and its maintenance • The reduction of harms associated with drug use • The treatment of complications of drug use
    • Principles of Actions of the Drugs for Addiction • Agonists e.g. methadone, buprenorphine • Antagonists e.g. naltrexone • Inhibitory drugs e.g. disulfiram
    • Nava et al., 2010
    • Marie Nyswander & Vincent P. Dole Methadone an Example of Serendipidy
    • Heroin Addiction: Functional State of a Typical Addict "High" "Straight" "Sick" Days AM PM AM PM AM FunctionalState Dole, Nyswander and Kreek, 1966 (overdose) (arrows indicate times of injection)
    • Methadone Maintenance: Functional State of a Former Addict Treated With Methadone Maintenance FunctionalState Dole, Nyswander and Kreek "High" "Straight" "Sick" AM PM AM PM AM Days “Functional state of a patient blockaded with methadone (a single oral dose each morning). The effect of an intravenous injection of heroin in the blocked patient is shown in the second day. The dotted line (---) indicates the course if methadone is omitted.” M M H
    • Wong et al., 2004 GHB The Anti-Alcohol Agent: An Italian Discovery
    • New Therapeutic Strategies Against Addiction • GABAA and GABAB enhancing agents able to contrast alcoholism and other forms of addiction; • Nicotine antagonists able to treat tobacco dependency; • New formulations of opioid-modulating drugs able to favourite the compliance and the efficacy of the heroin treatment; • Dopamine D3 receptor antagonists and dopamine-reuptake inhibitors able to reduce cocaine and psychostimulant • CB1 cannabinoid antagonists able to reduce cannabis or polydrugs intake • Active vaccination against nicotine, cocaine, ect. able to minimize the harmful drug effects and to alleviate the intoxication state
    • New Therapeutic Agents Against Addiction •Learning and ant-learning agents (e.g. the glutamatergic agents); • Agents able to oppose in drug users the switch from a normal to a dependent state (e.g. the GABA and the cannabinoids); • Anti-stress agents (e.g. CRF antagonists); • Molecules able to reduce the sensivity of the reward (e.g. SSRIs, dopamine antagonists); • Agents able to act on new pharmacological targets controlling the drug taking behaviour and relapse (e.g. agonists of the NOP receptors); • Gene-silencing or tur-on (gene therapies) of endogenous compounds (e.g. endorphins, dynorphins or endocannabinoids)
    • Felice Nava, MD, PhD Direttore Comitato Scientifico FeDerSerD www.federserd.it Felice Nava, MD, PhD Responsabile UOS Sanità Penitenziaria Distretto 2 Via Tommaso Temanza, 1 35134 Padova Tel. 049-8214904 Fax 049-8214906 felicealfonso.nava@sanita.padova.it Direttore Comitato Scientifico FeDerSerD www.federserd.it http://felicenava.splinder.com felnava@tin.it