Transcript Neurobiology of Drug Addiction: A Dysregulated

The Neuroscience of Addiction
George F. Koob, Ph.D.
Professor and Chairman
Committee on the Neurobiology of Addictive
Disorders
The Scripps Research Institute
La Jolla, California
Cost and Scope of Addiction
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Alcohol
– 18 million Americans abuse or are dependent on Alcohol.
• 2.2 million - approximately 10% currently seek treatment
• Cost to society estimated at $185B/year
Smoking
--In US, approximately 440,000 persons die per year of a cigarette smokingattributable illness
• This is approx. $75 billion in direct medical costs, and $82 billion
in lost productivity/year
Opioid Dependency
– Dependency has been growing rapidly:
• From 1990 to 2001, the number of people who used prescription
painkillers recreationally for the first time grew by 335% to include
almost 2.5 million people.
• Over an 8-year period (1994-2002):
• Admissions involving oxycodone rose 450%
• Admissions involving hydrocodone rose 170%
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
Key Definitions
Drug Addiction — Chronically relapsing disorder that is characterized by a
compulsion to seek and take drug, loss of control in limiting intake, and
emergence of a negative emotional state (e.g. dysphoria, anxiety, irritability)
when access to the drug is prevented (here, defined as the “dark side” of
addiction)
Nucleus Accumbens and Extended Amygdala — Forebrain structures
involved in the rewarding effects of drugs of abuse. Composed of central
nucleus of the amygdala, bed nucleus of the stria terminalis, and a
transition zone in the medial part of the nucleus accumbens
Corticotropin-Releasing Factor — “brain stress” neurotransmitter, 41 amino
acid polypeptide that controls hormonal, sympathetic, and behavioral
responses to stressors
Transcription Factors — brain chemicals involved in the longterm
neuroadaptive changes within neurocircuits associated with chronic
administration of drugs of abuse. Transcription factors can gene expression
“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
From: Koob GF, Alcohol Clin Exp Res, 2003, 27:232-243.
Stages of the Addiction Cycle
Animal Models for the Different Stages of the
Addiction Cycle
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Animal Models for the Binge/Intoxication Stage
1. Oral or intravenous drug self-administration
2. Brain stimulation reward
3. Place preference
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Animal models for the Withdrawal/Negative Affect Stage
1. Brain stimulation reward
2. Place aversion
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Animal Models for the Transition to Addiction
1. Dependence-induced drug taking
2. Escalation in drug self-administration with prolonged access
3. Drug taking despite aversive consequences
•
Animal Models for the Preoccupation/Anticipation (“Craving”) Stage
1. Drug- induced reinstatement
2. Cue- induced reinstatement
3. Alcohol Deprivation Effect
4. Stress- induced reinstatement
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.
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.
Neurochemical Circuitry in Drug Reward
Neurobiological Substrates for the Acute
Reinforcing Effects of Drugs of Abuse
Neurotransmitter
Site
Dopamine
Ventral tegmental area, nucleus accumbens
Opioid Peptides
Nucleus accumbens, amygdala, ventral
tegmental area
GABA
Amygdala, bed nucleus of stria terminalis
Glutamate
Nucleus accumbens
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
From: Solomon RL and Corbit JD, Psychol Rev, 1974, 81:119-145.
Sampling of Interstitial Neurochemicals
by in vivo Microdialysis
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•
•
•
Allows sampling of neurochemicals in
conscious animals (correlate brain
chemistry with behavior).
Implanted so that semi-permeable
probe tip is in specific brain region of
interest.
Substances below the membrane MW
cutoff diffuse across membrane based
on concentration gradient.
Both neurochemical sampling and
localized drug delivery are possible.
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.
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
Potential Substrates in the Extended Amygdala
for the Motivational Effects of Drug Dependence
Modified from: Heimer L and Alheid G, Piecing together the puzzle of basal forebrain anatomy. In: Napier TC, Kalivas
PW and Hanin I (Eds), The Basal Forebrain: Anatomy to Function (series title: Advances in Experimental
Medicine and Biology, Vol. 295), Plenum Press, New York, 1991, pp. 1-42.
Pieter Bruegel
CNS Actions of Corticotropin Releasing Factor
(CRF)
Major CRF-IR Cell Groups and Fiber Systems
Illustrated Schematically in a
Sagittal View of the Rat Brain
From: Swanson LW, Sawchenko PE, Rivier J and Vale W, Neuroendocrinology, 1983, 36:165-186.
CRF Produces Arousal, Stress-like Responses,
and a Dysphoric, Aversive State
Paradigm
CRF Agonist
CRF Antagonist
Acoustic startle
Facilitates startle
Blocks fear-potentiated startle
Elevated plus maze
Suppresses exploration
Reverses suppression of exploration
Defensive burying
Enhances burying
Reduces burying
Fear conditioning
Induces conditioned fear
Blocks acquisition of conditioned
fear
Cued electric shock
Enhances freezing
Attenuates freezing
Taste / Place Conditioning
Produces place aversion
Weakens drug-induced place
aversion
Protocol for Initiation of Lever Pressing for
Oral Ethanol Self-Administration in the Rat
Training
Saccharin
(w/v)
EtOH (w/v)
Ethanol added to the saccharin
solution
Days
1-3
0.2%
0% *
Days
4-9
0.2%
5% *
Day
10
-
5% *
Days
11-12
Day
0.2%
5%
13
-
5%
Day
14
0.2%
8%
Days
15-16
-
8%
Day
17
0.2%
10%
Day
18+
-
Rats trained to lever press on a
FR-1 schedule
Access to ethanol and water or
ethanol + saccharin and water
10% *
Initiation of the free-choice
operant task: ethanol (10%) and
water
Ethanol Dependence Induction
From: Rogers J, Wiener SG and Bloom FE,
Behav Neural Biol, 1979, 27:466-486.
From: Rassnick S, Heinrichs SC, Britton KT and Koob GF,
Brain Res, 1993, 605:25-32.
The AWOL System
(Alcohol WithOut Liquid)
• Patented by Spirit Partners, Inc.
• Available as 1, 2, or 4 user machines (cost $299 to $2845).
• Legal in U.S.
• Consists of oxygen generator and hand-held vaporizer.
• 80-proof alcohol (40% alcohol by volume) is poured into
vaporizer, and vapor is inhaled.
Extracellular CRF Levels in the Central
Amygdala During Ethanol Withdrawal
Effect of CRF Antagonist D-Phe-CRF12-41
– Central Nucleus of the Amygdala –
From: Funk C, O’Dell LE and Koob GF, Journal of Neuroscience, 2006, 44:11324-11332
Neurotransmitters Implicated in the Motivational
Effects of Withdrawal from Drug of Abuse
Dopamine … “dysphoria”
Dynorphin … “dysphoria”
Serotonin … “dysphoria”
CRF … stress
GABA … anxiety, panic attacks
Norepinephrine … stress
NPY … anti-stress
Glutamate….hyperexcitability
Neurochemical Changes Associated with the
Transition from Drug Use to Dependence
From: Roberts AJ and Koob GF, Alcohol: ethanol antagonists/amethystic agents. in Adelman G and Smith BH (Eds.),
Encyclopedia of Neuroscience, 3rd edn, Elsevier, New York, 2003 [http://203.200.24.140:8080/Neuroscience].
Craving-Type 1
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“Craving”- induced by stimuli that have been paired with
ethanol self-administration such as environmental cues
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Termed conditioned positive reinforcement in experimental
psychology
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An animal model of craving- type 1 is cue induced
reinstatement where a cue previously paired with access to
ethanol reinstates responding for a lever that has been
extinguished.
Craving-Type 2
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State of protracted abstinence in alcoholics weeks after acute
withdrawal
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Conceptualized as a state change characterized by anxiety
and dysphoria or a residual negative affective state that
combines with Craving-Type 1 situations to produce relapse
to excessive drinking
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Animal models of Craving-Type 2 include stress-induced
reinstatement, or increased drinking in animals after a
prolonged deprivation (Alcohol Deprivation Effect)
Neurobiological Effects of Exposure to
Drug-Associated Contextual Stimuli
Reinstatement
Daily Sessions of Self-Administration
SA
EXT
S-
S+
Effects of D-Phe-CRF12-41 and Naltrexone on
Stress- and Cue-Induced Reinstatement of Ethanol-Seeking
Liu & Weiss (2002) J Neurosci
Neurochemical Changes Associated with the Drug
Use, Dependence and Relapse
Common Molecular Changes
Associated with Dependence
• Dopamine D-2 receptor binding- decreased in human
imaging studies in dependent subjects
•
CREB ( cyclic adenosine monophosphate response
element binding protein) transcription factor- decreased
in nucleus accumbens and extended amygdala during
the development of dependence
• Delta-FosB transcription factor-changed during
protracted abstinence to drugs of abuse
Key Common Neurocircuitry Elements in Drug
Seeking Behavior of Addiction
Summary- Neurocircuitry of
Addiction
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Reward Circuit- nucleus accumbens and
extended amygdala (bed nucleus of the stria
terminalis and central nucleus of the amygdala)
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“Craving” Circuit- dorsal prefrontal cortex,
basolateral amygdala
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“Compulsivity” Circuit- ventral striatum, ventral
pallidum,medial thalamic- orbitofrontal cortical
loop
Medications for Alcohol Dependence
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Disulfiram (Antabuse)
- FDA approved 1954
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Naltrexone (ReVia)
- FDA approved 1994
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Acamprosate
- FDA approved 2004
Effects of Drugs on Animal Models of
Different Components of the Addiction Cycle
Relevant for Medications Development
CRF
Antagonist
NMDA/
GABA
Allosteric
Modulator
Orphanin FQ /
Nociceptin
Agonist
mGluR
Group II
Agonist
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Naltrexone
Acamprosate
Baseline
Drinking
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—
DependenceInduced drinking
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Cue-Induced
Reinstatement
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Stress-Induced
Reinstatement
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ADE / Protracted
Abstinence
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Medications Development
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