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Dr. koob connect presentation Dr. koob connect presentation Presentation Transcript

  • What is Addiction? What the Science of Addiction Has Taught Us and Will Teach Us George F. Koob, Ph.D. Professor and Chair Committee on the Neurobiology of Addictive Disorders The Scripps Research Institute La Jolla, California Koob, G.F. and Le Moal, M. Addiction and the anti-reward system. Annual Review of Psychology, 59 (2008)29-53 Koob, G. F. and Volkow. N. D. Neurocircuitry of Addiction, Neuropsychopharmacology Reviews 35 (2010) 217-238
  • What is Addiction? Addiction — defined as a chronically relapsing disorder that is characterized by a compulsion to seek and take drug or stimulus, loss of control in limiting intake, and emergence of a negative emotional state (e.g. dysphoria, anxiety, irritability) when access to the drug or stimulus is prevented (here, defined as the “dark side” of addiction)
  • What is Compulsive Use? Compulsive drug seeking-- can be characterized as a maladaptive stimulusresponse habits in which the ultimate goal of the behaviour has been devalued, perhaps through tolerance to the rewarding effects of the drug (Everitt BJ, Belin D, Economidou D, Pelloux Y, Dalley JW, Robbins TW. Philos Trans R Soc Lond B Biol Sci 2008, 363:3125-3135.) Compulsivity — can be defined as perseveration of responding in the face of adverse consequences or perseveration in the face of incorrect responses in choice situations. Compulsive disorders —are characterized by anxiety and stress before committing a compulsive repetitive behavior, and relief from the stress by performing the compulsive behavior (DSM IV American Psychiatric Association).
  • • Alcohol • Cost and Scope of Addiction – 18.6 million Americans are dependent on Alcohol. • 2.2 million - approximately 10%- currently seek treatment • Cost to society estimated at $185 billion/year Smoking --In US, 25.1 million dependent on tobacco 440,000 persons die per year of a cigarette smokingCost to society of 157 million: $75 billion in direct medical costs, and $82 billion in lost productivity/year • Opioids, stimulant, marijuana --In US, 8.2 million dependent on stimulants, opioids or marijuana • 2.1 million stimulants • 1.9 million opioid • 4.2 million marijuana
  • Estimated Prevalence Among 15-54 Year Olds of Nonmedical Use and Dependence Among Users (1990-1992) (NCS) Ever Used Prevalence of Dependence Dependence Among Users Tobacco 75.6 24.1 31.9 Alcohol 91.5 14.1 15.4 Illicit Drugs 51.0 7.5 14.7 Cannabis 46.3 4.2 9.1 Cocaine 16.2 2.7 16.7 Stimulants 15.3 1.7 11.2 Anxiolytics 12.7 1.2 9.2 Analgesics 9.7 0.7 7.5 Psychedelics 10.6 0.5 4.9 Heroin 1.5 0.4 23.1 Inhalants 6.8 0.3 3.7 From: Anthony JC, Warner LA and Kessler RC, Exp Clin Psychopharmacol, 1994, 2:244-268.
  • The San Diego Union-Tribune Thursday, August 30, 2001
  • “When people talk about drugs, they assume people take drugs because they enjoy it,” Williams told the Toronto Star. “But really, it's no different from overeating or watching too much television or drinking too much. You take drugs to make yourself feel better, to fill a hole.” -Ricky Williams -Byline Damien Cox, Toronto Star, May 29, 2006
  • Bottom Lines: Common Elements of Addiction 1. Addiction is a reward deficit disorder 2. Addiction is a stimulus- response perseveration disorder 3. Addiction is a stress surfeit disorder 4. Addiction is an executive function deficit disorder
  • Theoretical Framework Relating Addiction Cycle to Motivation for Drug Seeking From: Koob GF. Theoretical frameworks and mechanistic aspects of alcohol addiction: alcohol addiction as a reward deficit disorder. In: Spanagel R, Sommer W (eds) Behavioral Neurobiology of Alcohol Addiction (series title: Current Topics in Behavioral Neuroscience), Springer, New York, in press.
  • Positive and Negative Reinforcement- Definitions Positive Reinforcement — defined as the process by which presentation of a stimulus (drug) increases the probability of a response (non dependent drug taking paradigms). Negative Reinforcement —defined as a process by which removal of an aversive stimulus (negative emotional state of drug withdrawal) increases the probability of a response (dependence-induced drug taking)
  • A Primer of Neuropharmacology 1. Dopamine is made in cell body 2. Dopamine is shipped down the axon 3. Dopamine is released from the terminal 4. Dopamine stimulates dopamine receptors
  • Neurobiology of Addiction Koob, G. F. and Volkow. N. D. Neurocircuitry of Addiction, Neuropsychopharmacology reviews 35 (2010) 217-238
  • Binge/Intoxication Stage Koob, G. F. and Volkow. N. D. Neurocircuitry of Addiction, Neuropsychopharmacology reviews 35 (2010) 217-238
  • Cocaine Self-Administration From: Caine SB, Lintz R and Koob GF. in Sahgal A (ed) Behavioural Neuroscience: A Practical Approach, vol. 2, IRL Press, Oxford, 1993, pp. 117-143.
  • Converging Acute Actions of Drugs of Abuse on the Ventral Tegmental Area and Nucleus Accumbens From: Nestler EJ, Nat Neurosci, 2005, 8:1445-1449.
  • Reward Transmitters Implicated in the Positive Motivational Effects of Drugs of Abuse Positive Hedonic Effects Dopamine Opioid peptides GABA Glutamate Serotonin
  • Withdrawal/Negative Affect Stage Koob, G. F. and Volkow. N. D. Neurocircuitry of Addiction, Neuropsychopharmacology reviews 35 (2010) 217-238
  • DRUG WITHDRAWAL Physical Withdrawal- drug specific • • • • • Alcohol- tremor, increased body temperature Opiates- pain, diarrhea Nicotine- fatigue, increased appetite Marijuana- decreased appetite Psychostimulants- fatigue,? Motivational Withdrawal- common to all drugs • • • • • Anxiety Negative emotional state Irritability Dysphoria Everything is gray
  • Affective Dynamics Produced by Drug Administration in Non Dependent versus Dependent Subjects From: Solomon RL, American Psychologist, 1980, 35:691-712.
  • Mood Changes Associated with Plasma Levels of Cocaine during Coca Paste Smoking From: Van Dyke C and Byck R, Cocaine, Scientific American, 1982, 246:123-141.
  • Extracellular DA and 5-HT in the Nucleus Accumbens During Cocaine Self-Administration and Withdrawal From: Parsons LH, Koob GF and Weiss F, J Pharmacol Exp Ther, 1995, 274:1182-1191.
  • Decreased Dopamine D2 Receptor Activity in a Cocaine Abuser From: Volkow ND, Fowler JS, Wang GJ, Hitzemann R, Logan J, Schlyer DJ, Dewey S and Wolf AP, Synapse, 1993, 14:169-177.
  • Reward Transmitters Implicated in the Motivational Effects of Drugs of Abuse Positive Hedonic Effects Negative Hedonic Effects of Withdrawal Dopamine Dopamine … “dysphoria” Opioid peptides Opioid peptides ... pain Serotonin Serotonin … “dysphoria” GABA GABA … anxiety, panic attacks
  • CNS Actions of Corticotropin-Releasing Factor (CRF)
  • Withdrawal-induced Increases in Extracellular Levels of CRF
  • Anti-Reward Transmitters Implicated in the Motivational Effects of Drugs of Abuse Dynorphin … “dysphoria” CRF … stress Norepinephrine … stress
  • Preoccupation/Anticipation “Craving” Stage Koob, G. F. and Volkow. N. D. Neurocircuitry of Addiction, Neuropsychopharmacology reviews 35 (2010) 217-238
  • Reward Craving-Type 1 • “Craving”- induced by stimuli that have been paired with drug selfadministration such as environmental cues • An animal model of craving- type 1 is cue induced reinstatement where a cue previously paired with access to drug reinstates responding for a lever that has been extinguished. • Neurobiological substrates include glutamatergic projections from medial prefrontal cortex and basolateral amygdala to nucleus accumbens
  • Role of Glutamate and Dopamine Neurotransmission in Relapse to Drug-Seeking Behavior From: Cornish JL and Kalivas PW, J Addict Dis, 2001, 20:43-54.
  • Relief Craving-Type 2 • State of protracted abstinence in subjects with addiction or alcoholism weeks after acute withdrawal. • Conceptualized as a state change characterized by anxiety and dysphoria or a residual negative emotional state that combines with Craving-Type 1 situations to produce relapse to excessive drug taking • Animal models of Craving-Type 2 include stress-induced reinstatement and increased drug taking in animals during protracted abstinence • Neurobiological substrates include residual activation of brain stress systems including corticotropin releasing factor and norepinephrine in the extended amygdala
  • CNS Actions of Corticotropin-Releasing Factor (CRF)
  • Non-dependent Dependent Positive Reinforcement Negative Reinforcement
  • Brain Arousal-Stress System Modulation in the Extended Amygdala From: Koob, G.F. 2008 Neuron 59:11-34
  • Stress and Anti-stress Neurotransmitters Implicated in the Motivational Effects of Drugs of Abuse ! Corticotropin-releasing factor " Neuropeptide Y ! Norepinephrine " Nociceptin (orphanin FQ) ! Vasopressin ! Orexin (hypocretin) ! Dynoprhin ! Substance P
  • Medications Development
  • Treatments for the Light Side of Addiction Treatments for the Light (binge) side of drug addiction can be conceptualized within the 2 stages of the addiction cycle: – Binge/Intoxication stage – Preoccupation/anticipation (“craving”) stage Treatments for the light side currently exist from the perspective of the binge/intoxication and preoccupation/anticipation (“craving”) stages stage of the addiction cycle: – naltrexone (ReVia, Vivitrol) – buprenorphine (Suboxone, Subutex) – varenicline (Chantix) – nicotine patch, nicotine gum – methadone Novel treatments for the light side can derived from our understanding of the neurobiological basis of drug reward and cue induced craving: – glutamate – dopamine partial agonists – opioid peptide partial agonists – vaccines – orexin (hypocretin)
  • Treatments for the Dark Side of Addiction Treatments for the dark (withdrawal/negative affect) side of drug addiction can be conceptualized within the 2 stages of the addiction cycle: – Withdrawal/negative affect stage – Preoccupation/anticipation (“craving”) stage Treatments for the dark side currently exist from the perspective of the withdrawal/ negative affect and preoccupation/anticipation (“craving”) stages stage of the addiction cycle: – Methadone (Dolophine) – Buprenorphine (Suboxone, Subutex) – Varenicline (Chantix) – Nicotine patch, nicotine gum – Acamprosate (Campral) – Bupropion (Zyban) Novel treatments for the dark side can derived from our understanding of the neurobiological basis of emotional dysregulation during withdrawal and protracted abstinence: – corticotropin releasing factor – dynorphin – Substance P – norepinephrine – vasopressin – Orexin (hypocretin)
  • Medications Currently on the Market for Drug Abuse Treatment Generic name Trade name Indications Disulfiram Antabuse Alcohol addiction 1954 Methadone Dolophine Opiate addiction 1972 Naltrexone ReVia Alcohol addiction 1994 Vivitrol FDA approval Description 2005 • Disulfiram is an acetaldehyde dehydrogenase inhibitor used to prevent relapse in detoxified alcoholics. Disulfiram at average therapeutic doses of 250 mg/day (not to exceed 500 mg/day) blocks acetaldehyde dehydrogenase. • Disulfiram produces an aversive reaction if the subject drinks with adequate blood levels of disulfiram presumably due to increased acetaldehyde in the blood stream which is similar to the intense flush reaction of Asians known to have a deletion of one or two alleles of the ALDH2 gene. • Methadone, a long-acting opioid, was developed as a substitution treatment for opioid addiction because of its properties of being orally active with a long half-life. Methadone also has become the standard medication for opioid detoxification. • Methadone is effective in reducing illicit opioid use at doses of 80120 mg/day. • Naltrexone is a competitive opioid antagonist that has oral bioavailability and binds to the m, d, and k opioid receptors, with a higher affinity for the m than d or k receptors. • Naltrexone decreases heavy drinking in alcoholics and prevents relapses to heavy drinking at doses of 50 mg/day. Naltrexone has more efficacy when combined with associated behavioral treatments, particularly cognitive behavioral therapy. From: Koob GF, Lloyd GK, Mason BJ. Nat Rev Drug Discov, 2009, 8:500-515.
  • Medications Currently on the Market for Drug Abuse Treatment (continued) Generic name Trade name Indications Bupropion Zyban Nicotine addiction 1997 Buprenorphine Subutex Opiate addiction 2002 Suboxone FDA approval Description • Bupropion is an antidepressant with efficacy in smoking cessation that has beneficial effects on protracted abstinence consistent with its antidepressant properties. • Bupropion at doses of 150-300 mg/day effectively doubled abstinence rates after 1 year. • Buprenorphine is an oripavine derivative that is considered a partial agonist at m, k, and nociceptin/orphanin FQ receptors and an antagonist at d receptors. • Multiple controlled studies have shown that maintenance therapy with buprenorphine is an effective treatment for opioid dependence at doses of 16-24 mg/day (maximum 32 mg/day). • Buprenorphine can be prescribed as a sublingual tablet consisting of buprenorphine (Subutex#) or as a sublingual tablet consisting of buprenorphine with naloxone (Suboxone#). The addition of naloxone limits diversion because naloxone is inactive when taken orally, but if the preparation is diverted to intravenous use, the naloxone will block the effects of buprenorphine. From: Koob GF, Lloyd GK, Mason BJ. Nat Rev Drug Discov, 2009, 8:500-515.
  • Medications Currently on the Market for Drug Abuse Treatment (continued) Generic name Trade name Indications Acamprosate Campral Alcohol addiction 2004 • Acamprosate is an indirect partial agonist at the NMDA glutamate receptor and an antagonist at metabotropic glutamate receptors used to prevent relapse in detoxified alcoholics. Doses are typically two 333 mg tablets three times per day. • In a U.S. multicenter double-blind, placebo-controlled trial of acamprosate, treatment efficacy was particularly robust in patients who had a clearly identified goal of achieving abstinence before starting treatment. Varenicline Chantix Nicotine addiction 2006 • Varenicline is a partial $4%2 nicotinic acetylcholine receptor agonist used for detoxification and treatment of nicotine addiction. Doses of 1 mg twice per day doubled abstinence rates in 12-week trials. • Varenicline has been associated with a number of reports of adverse effects related to suicidal ideation. As a result, the use of Chantix# is no longer accepted by the Federal Aviation Administration for aeromedical certification purposes. • Oral slow release nicotine via nicotine chewing gum (2 or 4 mg) or lozenges or percutaneous administration via the nicotine patch are used for detoxification of nicotine addiction. Both the gum and patch facilitate abstinence as an aid to smoking cessation. Ncotine gum / patch / lozenge Nicorette Nicotine addiction Nicoderm Commit FDA approval Description From: Koob GF, Lloyd GK, Mason BJ. Nat Rev Drug Discov, 2009, 8:500-515.
  • Key Findings and Conclusions Acute reinforcing effects of drugs of abuse— depend on neurochemical substrates such as GABA, opioid peptides, serotonin, glutamate and dopamine in the ventral striatum of the basal forebrain. Acute withdrawal from all major drugs of abuse — produces decreases in reward function, increases in stress-like responses and increases in CRF in the amygdala that are of motivational significance Compulsive drug use associated with dependence— is mediated by not only loss of function of reward systems but recruitment of brain stress systems such as corticotropin releasing factor, dynorphin, substance P, norepinephrine, vasopressin, orexin (hypocretin), neuropeptide Y,nociceptinin the extended amygdala Changes in natural reward function (decreases) and stress sensitivity (increases) : are hypothesized to persist in protracted abstinence and contribute to the motivation to relapse and re-escalate compulsive drug use
  • Neurobiology of Drug Addiction Visiting Professors Koob Laboratory Choon-Gon Jang Charles Heyser Research Administrative Post-Doctoral Fellows Assistants Assistants Cindy Funk Bob Lintz Lisa Maturin Brendan Walker Richard Schroeder Mellany Santos Tom Greenwell Elena Crawford Marisa Gallego Sandy Ghozland Molly Brennan Chitra Mandyam Maury Cole Dong Ji Tess Kimber Candice Contet Yanabel Grant Laura Orio Kaushik Misra Support from: Nick Gilpin Sunmee Wee Scott Edwards Staff Scientists Heather Richardson Olivier George Special thanks to: Mike Arends (Senior Research Assistant) National Institute on Alcohol Abuse and Alcoholism National Institute on Drug Abuse Leandro Vendruscolo National Institute of Diabetes and Digestive and Kidney Diseases Tim Whitfield Pearson Center for Alcoholism and Addiction Research Joel Schossberg