Transcript The Neurobiology of Alcoholism: Insights from the Dark

Neurobiology of Addiction: Shedding
Light from the Dark Side
George F. Koob, Ph.D.
Professor and Chair
Committee on the Neurobiology of Addictive
Disorders
The Scripps Research Institute
La Jolla, California
Koob GF. The neurobiology of addiction: a neuroadaptational view relevant for diagnosis.
Addiction, 2006, 101(suppl 1):23-30.
Koob GF, Le Moal M. Addiction and the anti-reward system. Annual Review of Psychology,
2008, 59:29-53.
Koob GF. A role for brain stress systems in addiction. Neuron, 2008, 59:11-34.
“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
Key Findings and Conclusions
Addiction — loss of control over drug intake and compulsive drug taking driven by
elements of impulsivity and compulsivity that are mediated by separate but
overlapping neurocircuitry
Acute rewarding effects of drugs of abuse — are mediated by neurochemical
elements such as dopamine and opioid peptides in the nucleus accumbens and
amygdala
Acute withdrawal from all major drugs of abuse — produces increases in
reward thresholds, increases in anxiety-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, norepinephrine and dynorphin in the extended
amygdala
Brain-arousal stress systems in the extended amygdala--- may be key
components of not only for the negative emotional states that drive dependence
on drugs of abuse but also may overlap with the negative emotional components
of other psychopathologies
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.
Key Common Neuroanatomical Structures
in Addiction
Nucleus Accumbens and Central Nucleus of the Amygdala — Forebrain
structures involved in the rewarding effects of drugs of abuse and drives
the binge intoxication stage of addiction. Contains key reward
neurotransmitters: dopamine and opioid peptides
Extended Amygdala — 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. Contains “brain stress” neurotransmitter, corticotropin
releasing factor that controls hormonal, sympathetic, and behavioral
responses to stressors, and is involved in the anti-reward effects of drug
dependence
Medial Prefrontal Cortex — neurobiological substrate for “executive function”
that is compromised in drug dependence and plays a key role in facilitating
relapse. Contains major glutamatergic projection to nucleus accumbens
and amygdala
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.
From: Koob GF, Alcohol Clin Exp Res, 2003, 27:232-243.
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)
Stages of the Addiction Cycle
Animal Models for the Different Stages of the
Addiction Cycle
•
Animal Models for the Binge/Intoxication Stage
1. Oral or intravenous drug self-administration
2. Brain stimulation reward
3. Place preference
•
Animal models for the Withdrawal/Negative Affect Stage
1. Brain stimulation reward
2. Place aversion
•
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
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
From: Koob GF, Clin Neurosci Res, 2005, 5:89-101.
Pieter Bruegel
Protocol for Initiation of Lever Pressing for
Oral Ethanol Self-Administration in the Rat
•
Rats trained to lever press on a FR-1 schedule 0.125% saccharin
• Ethanol added to the saccharin solution
• Access to ethanol and water or ethanol or saccharin and water
Initiation of the free-choice operant task:
ethanol (10%) and water
From: Rassnick S, Pulvirenti L and Koob GF, Alcohol, 1993, 10:127-132.
Effects of Methylnaloxonium on Ethanol SelfAdministration in Non-Dependent Rats
From: Heyser CJ, Roberts AJ, Schulteis G and Koob GF, Alcohol Clin Exp Res, 1999, 23:1468-1476.
Converging Acute Actions of Drugs of Abuse on the
Ventral Tegmental Area and Nucleus Accumbens
From: Nestler EJ, Nat Neurosci, 2005, 8:1445-1449.
Standard Pattern of Affective Dynamics Produced
by Novel and Repeated Unconditioned Stimulus
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.
Protocol for Drug Escalation
1) Initial Training Phase
2) Escalation Phase
All Rats
1-hr SA session
Fixed Ratio 1
0.25 mg cocaine/injection
Short Access
22 x 1-hr SA session
Long Access
22 x 6-hr SA session
Protocol from: Ahmed SH and Koob, Science, 1998, 282:298-300.
3) Testing Phase
Neuropharmacological
probes
Change in Brain Stimulation Reward Thresholds
in Long-Access (Escalation) vs. Short-Access
(Non-Escalation) Rats
From: Ahmed SH, Kenny PJ, Koob GF and Markou A, Nature Neurosci, 2002, 5:625-627.
Progressive-ratio Responding for Cocaine in
Long- and Short-access Rats
From: Wee S, Mandyam CD, Lekic DM and Koob GF, Eur Neuropsychopharmacol, 2008, 18:303-311.
Effect of a-flupenthixol on Cocaine Self-Administration in
Escalated and Non-Escalated Animals
From: Ahmed SH and Koob GF, Psychopharmacology, 2004, 172:450-454.
Escalation of Methamphetamine
Self-administration in Rats
Adapted from: Wee S, Wang Z, Woolverton WL, Pulvirenti L and Koob GF, Neuropsychopharmacology, 2007,
32:2238-2247.
Effects of Aripiprazole on Methamphetamine
Self-administration
(0.05 mg/kg/inf progressive-ratio)
Adapted from:
Wee S, Wang Z, Woolverton WL, Pulvirenti L and Koob GF, Neuropsychopharmacology, 2007,
32:2238-2247.
Sampling of Interstitial Neurochemicals
by in vivo Microdialysis
•
•
•
•
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.
Collaborators: Dr. Friedbert Weiss, Dr. Larry Parsons, Dr. Emilio Merlo-Pich, Dr. Regina Richter
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
Standard Pattern of Affective Dynamics Produced
by Novel and Repeated Unconditioned Stimulus
From: Solomon RL, American Psychologist, 1980, 35:691-712.
Anti-Reward Transmitters Implicated in the
Motivational Effects of Drugs of Abuse
Dynorphin … “dysphoria”
CRF … stress
Norepinephrine … stress
NPY … anti-stress
CNS Actions of
Corticotropin-Releasing Factor (CRF)
Major CRF-Immunoreactive Cell Groups and
Fiber Systems in 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
Sampling of Interstitial Neurochemicals
by in vivo Microdialysis
•
•
•
•
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.
Collaborators: Dr. Friedbert Weiss, Dr. Larry Parsons, Dr. Emilio Merlo-Pich, Dr. Regina Richter
Withdrawal-induced Increases in
Extracellular Levels of CRF
Rodent model of excessive drinking during
withdrawal
(Roberts et al 1996, 2000; O’Dell et al 2004)
Self-administration
training
Dependence
induction
Withdrawal from
alcohol vapors
Negative emotional state:
•Anxiety-like behavior
•Reward threshold deficits
•Increased CRF release in
the extended amygdala
•Excessive drinking:
Sweetened solution fading
used to train animals to lever
press for:
Chronic intermittent
alcohol vapors (4+ wks)
10%w/v EtOH vs Water
Target blood alcohol levels
(BALs): 0.125-.250 g%
• 2-3 fold higher alcohol
intake
•Increased progressive ratio
breakpoints
•Relapse following prolonged
abstinence
Enhanced Ethanol Self-Administration
During Withdrawal in Dependent Animals
***
n = 6/group
*p < 0.001 vs. Nondependent-EtOH
From: Funk C and Koob GF, unpublished results.
***
CRF1 Specific Antagonists
MPZP
From: Richardson HN, Zhao Y, Fekete EM, Funk CK, Wirsching P, Janda KD, Zorrilla EP and
Koob GF, Pharmacol Biochem Behav, 2008, 88:497-510.
Effect of CRF Antagonist D-Phe-CRF12-41
– Central Nucleus of the Amygdala –
From: Funk C, O’Dell LE and Koob GF, J Neurosci, 2006, 26:11324-11332.
1941
Good Housekeeping
Total 23 h Active and Inactive Responding after
Repeated 72 h Nicotine Deprivation Cycles
Followed by 4 Days of Self-administration
From: George O, Ghozland S, Azar MR, Cottone P, Zorrilla EP, Parsons LH, O’Dell LE, Richardson HN and Koob GF,
Proc Natl Acad Sci USA, 2007, 104: 17198-17203.
Effect of CRF1 Antagonism on Nicotine Selfadministration in Rats with Extended Access
From: George O, Ghozland S, Azar MR, Cottone P, Zorrilla EP, Parsons LH, O’Dell LE, Richardson HN and Koob GF,
Proc Natl Acad Sci USA, 2007, 104: 17198-17203.
CRF1 Antagonist has No Effect on Baseline
Responding for Nicotine in Rats with Unlimited
Access
From: George O, Ghozland S, Azar MR, Cottone P, Zorrilla EP, Parsons LH, O’Dell LE, Richardson HN and Koob GF,
Proc Natl Acad Sci USA, 2007, 104: 17198-17203.
Role of Corticotropin-releasing Factor
in Dependence
CRF antagonist
effects on withdrawalinduced anxiety-like
responses
Withdrawalinduced changes
in extracellular
CRF in CeA
CRF antagonist
effects on
dependence-induced
increases in selfadministration
Cocaine
↓
↑
↓
↓
Opioids
↓
↑
↓
↓
Ethanol
↓
↑
↓
↓
Nicotine
↓
↑
↓
↓
9-tetrahydrocannabinol
↓
↑
nt
nt
Drug
*
CRF antagonist
reversal of
stress-induced
reinstatement
* = aversive effects with place conditioning. nt = not tested. CeA = central nucleus of the amygdala.
Non-dependent
Dependent
Positive
Reinforcement
Negative
Reinforcement
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
Brain Arousal-Stress System Modulation
in the Extended Amygdala
Pain, Emotions, and the Amygdala
From: Neugebauer V, Li W, Gird GC and Han JS, The Neuroscientist, 2004, 10:221-234.
Allostatic Change in Mood State associated with
Transition to Drug Addiction
Adapted from: Koob GF and Le Moal M, Neuropsychopharmacology, 2001, 24:97-129.
Key Findings and Conclusions
Addiction — loss of control over drug intake and compulsive drug taking driven by
elements of impulsivity and compulsivity that are mediated by separate but
overlapping neurocircuitry
Acute rewarding effects of drugs of abuse — are mediated by neurochemical
elements such as dopamine and opioid peptides in the nucleus accumbens and
amygdala
Acute withdrawal from all major drugs of abuse — produces increases in
reward thresholds, increases in anxiety-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, norepinephrine and dynorphin in the extended
amygdala
Brain-arousal stress systems in the extended amygdala--- may be key
components of not only for the negative emotional states that drive dependence
on drugs of abuse but also may overlap with the negative emotional components
of other psychopathologies
Neurobiology of Drug Addiction
Koob Laboratory
Postdoctoral Fellows
Research Assistants
Administrative Assistants
Nick Gilpin
Bob Lintz
Lisa Maturin
Sunmee Wee
Richard Schroeder
Mellany Santos
Laura Orio
Elena Crawford
Marisa Gallego
Kaushik Misra
Molly Brennan
Scott Edwards
Maury Cole
Candice Contet
Tess Kimber
Cindy Funk
Yanabel Grant
Brendan Walker
Tom Greenwell
Sandy Ghozland
Chitra Mandyam
Dong Ji
TSRI Chemists
Kim Janda
Tobin Dickerson
Ed Roberts
Staff Scientists
Olivier George
Bob Purdy
Heather Richardson
Special thanks:
Mike Arends
(Senior Research Assistant)
Janet Hightower
(TSRI Biomedical Graphics)
Support from:
Pearson Center for Alcoholism and Addiction Research
National Institute on Alcohol Abuse and Alcoholism
National Institute on Drug Abuse
National Institute of Diabetes and Digestive and Kidney Diseases