dr. koob connect 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 stimulus-response 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).
Cost and Scope of Addiction• Alcohol
– 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 smoking-Cost 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 ofNonmedical Use and Dependence Among Users
(1990-1992) (NCS)
Tobacco
Alcohol
Illicit Drugs
Cannabis
Cocaine
Stimulants
Anxiolytics
Analgesics
Psychedelics
Heroin
Inhalants
75.6
91.5
51.0
46.3
16.2
15.3
12.7
9.7
10.6
1.5
6.8
Ever Used
24.1
14.1
7.5
4.2
2.7
1.7
1.2
0.7
0.5
0.4
0.3
Prevalence of Dependence
31.9
15.4
14.7
9.1
16.7
11.2
9.2
7.5
4.9
23.1
3.7
Dependence Among Users
From: Anthony JC, Warner LA and Kessler RC, Exp Clin Psychopharmacol, 1994, 2:244-268.
The San Diego Union-TribuneThursday, 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
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.
Theoretical Framework Relating Addiction Cycle to Motivation for Drug Seeking
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)
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
A Primer of Neuropharmacology
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
Dopamine
Opioid peptides
GABA
Glutamate
Serotonin
Positive Hedonic Effects
Withdrawal/Negative Affect Stage
Koob, G. F. and Volkow. N. D. Neurocircuitry of Addiction, Neuropsychopharmacology reviews 35 (2010) 217-238
Motivational Withdrawal- common to all drugs• Anxiety
• Negative emotional state
• Irritability
• Dysphoria
• Everything is gray
Physical Withdrawal- drug specific
• Alcohol- tremor, increased body temperature• Opiates- pain, diarrhea• Nicotine- fatigue, increased appetite• Marijuana- decreased appetite• Psychostimulants- fatigue,?
DRUG WITHDRAWAL
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 Activityin 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
Dopamine … “dysphoria”
Opioid peptides ... pain
Serotonin … “dysphoria”
GABA … anxiety, panic attacks
Dopamine
Opioid peptides
Serotonin
GABA
Positive Hedonic Effects Negative Hedonic Effectsof Withdrawal
CNS Actions ofCorticotropin-Releasing Factor (CRF)
Withdrawal-induced Increases inExtracellular 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 self-administration 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 ofCorticotropin-Releasing Factor (CRF)
Positive
Reinforcement
Negative
Reinforcement
Non-dependentDependent
Negative
Reinforcement
Positive
Reinforcement
Brain Arousal-Stress System Modulationin 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!
!
!
!
!
!
Norepinephrine
Vasopressin
Orexin (hypocretin)
Dynoprhin
"
"
Neuropeptide Y
Nociceptin (orphanin FQ)
Substance P
Medications Development
Treatments for the Light Side of AddictionTreatments 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 AddictionTreatments 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
Disulfiram
Methadone
Naltrexone
Generic name
Trade name
Alcohol addiction
Opiate addiction
Alcohol addiction
Indications
1954
1972
1994
2005
FDA approval
• 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 80-
120 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.
Description
Antabuse
Dolophine
ReVia
Vivitrol
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
Nicotine addiction
Opiate addiction
Indications
1997
2002
FDA approval
• 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.
Description
Zyban
Subutex
Suboxone
Bupropion
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)
Alcohol addiction
Nicotine addiction
Nicotine addiction
Indications
2004
2006
FDA approval
• 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 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.
DescriptionGeneric
nameTrade name
Campral
Chantix
Nicorette
Nicoderm
Commit
Acamprosate
Varenicline
Ncotine gum /
patch /
lozenge
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 AddictionKoob Laboratory
Post-Doctoral Fellows
Cindy Funk
Brendan Walker
Tom Greenwell
Sandy Ghozland
Chitra Mandyam
Dong Ji
Candice Contet
Laura Orio
Kaushik Misra
Nick Gilpin
Sunmee Wee
Scott Edwards
Leandro Vendruscolo
Tim Whitfield
Joel Schossberg
Special thanks to:
Mike Arends
(Senior Research Assistant)
Research
Assistants
Bob Lintz
Richard Schroeder
Elena Crawford
Molly Brennan
Maury Cole
Tess Kimber
Yanabel Grant
Administrative
Assistants
Lisa Maturin
Mellany Santos
Marisa Gallego
Staff ScientistsHeather Richardson
Olivier George
Support from:
National Institute on Alcohol Abuse and Alcoholism
National Institute on Drug Abuse
National Institute of Diabetes and Digestive and Kidney Diseases
Pearson Center for Alcoholism and Addiction Research
Visiting ProfessorsChoon-Gon JangCharles Heyser