Transcript The Neurobiology of Alcoholism: Insights from the Dark Side of

Neurocircuitry of Addiction: View
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, 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
“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
Addiction is a Reward Deficit Disorder
Reward neurotransmission is compromised. Brain reward
systems are hypoactive during acute withdrawal, remain
hypoactive with repeated withdrawal and during protracted
abstinence.
Anti-reward neurotransmission is recruited- Brain stress
systems are activated during acute withdrawal, sensitize with
repeated withdrawal and remain activated during protracted
abstinence.
Progression of Drug Dependence
From:Heilig M and Koob GF, Trends Neurosci, 2007, 30:399-406.
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
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.
Effects of 6-OHDA Lesions of the Nucleus
Accumbens on Cocaine Self-administration
in Rats
From: Roberts DCS, Koob GF, Klonoff P and Fibiger HC, Pharmacol Biochem
Behav, 1980, 12:781-787.
Converging Acute Actions of Drugs of Abuse on the
Ventral Tegmental Area and Nucleus Accumbens
From: Nestler EJ, Nat Neurosci, 2005, 8:1445-1449.
Withdrawal/Negative Affect Stage
Koob, G. F. and Volkow. N. D. Neurocircuitry of Addiction,
Neuropsychopharmacology reviews 35 (2010) 217-238
Affective Dynamics Produced by Drug
Administration in Non Dependent versus
Dependent Subjects
From: Solomon RL, American Psychologist, 1980, 35:691-712.
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
Protocol for Drug Escalation
1) Initial Training Phase
2) Escalation Phase
All Rats (n=24):
2-hr SA session
Fixed Ratio 1
0.25 mg cocaine/injection
Short Access (n=12)
22 x 1-hr SA session
Cocaine doses (µg):
Long Access (n=12)
22 x 6-hr SA session
0, 15.6, 31.2, 62.5,
125, 250
Protocol from: Ahmed SH and Koob, Science, 1998, 282:298-300.
3) Dose-Effect Study
Change in Brain Stimulation Reward Thresholds in LongAccess (Escalation) vs. Short-Access (Non-Escalation) Rats
From: Ahmed SH, Kenny PJ, Koob GF and Markou A, Nature Neurosci, 2002, 5:625-627.
Effect of a-flupenthixol on Cocaine Self-Administration in
Escalated and Non-Escalated Animals
From: Ahmed SH and Koob GF, unpublished results.
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.
Affective Dynamics Produced by Drug
Administration in Non Dependent versus
Dependent Subjects
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
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
Conditioned Place Aversion Produced by One
Pairing of Naloxone in Morphine-Dependent Rats
From: Gracy KN, Dankiewicz LA and Koob GF, Neuropsychopharmacology, 2001, 24:152-160.
CRF1 Specific Antagonists
Effects of Antalarmin on Place Aversion Induced
by Naloxone-Precipitated Morphine Withdrawal
From: Stinus L, Cador M, Zorrilla EP and Koob GF, Neuropsychopharmacology, 2005,
30:90-98.
Competitive CRF Antagonist Injected into the
Amygdala Blocks Conditioned Place Aversion
to Opiate Withdrawal
From: Heinrichs SC, Menzagi F, Schulteis G, Koob GF and Stinus L, Behav
Pharmacol, 1995, 6:74-80.
Increase in Brain Reward Thresholds during
Escalation in Heroin Intake in Rats with Prolonged
Access to Heroin (23-hr/day)
From: Kenny PJ, Chen SA, Markou A and Koob GF Journal of Neuroscience 26
(2006) 5894-5900
CRF1 Antagonist R121919 Decreases Heroin SelfAdministration in Rats with 12 h Extended Access
From: Greenwell TN, Funk CK, Cottone P, Richardson HN, Chen SA, Rice K, Lee MJ, Zorrilla EP
and Koob GF, Addict Biol, in press.
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.
From: Koob, G.F. 2008 Neuron 59:11-34
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
Reinstatement of Drug (Alcohol) Seeking with
Drug-Associated Contextual Stimuli
Reinstatement
Daily Sessions of Self-Administration
SA
EXT
S-
S+
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
Brain Circuits Critical for Stress-Induced
Reinstatement of Drug-Seeking Behavior
From: Shaham Y, Shalev U, Lu L, De Wit H and Stewart J, Psychopharmacology,
2003, 168:3-20.
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

Substance P
Brain Arousal-Stress System Modulation
in the Extended Amygdala
From: Koob, G.F. 2008 Neuron 59:11-34
Regulation of the Mesolimbic Dopamine Circuit and
Hypothalamus by the Extended Amygdala
Compulsivity – Loss of Control
Neuroplasticity in Brain Circuits associated with
the Development of Addiction
Extended
Amygdala
Prefrontal
Cortex
Dorsal
Striatum
Nucleus
Accumbens
Mesolimbic DA
Neuroplasticity with Increasing Use
From: Koob and Volkow, Neurocircuitry of addiction, Neuropsychopharmacology Reviews, in
press
Allostatic Change in Emotional State associated
with Transition to Drug Addiction
Adapted from: Koob GF and Le Moal M, Neuropsychopharmacology, 2001, 24:97-129.
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
“Craving” (Preoccupation/anticipation stage of addiction cycle)-- involves a
significant glutamate system dysregulation and a brain stress component also
mediated by CRF systems in the extended amygdala
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
Visiting Professors
Choon-Gon Jang
Charles Heyser
Post-Doctoral
Fellows
Cindy Funk
Brendan Walker
Tom Greenwell
Sandy Ghozland
Chitra Mandyam
Dong Ji
Research
Administrative
Assistants
Assistants
Bob Lintz
Lisa Maturin
Richard Schroeder
Mellany Santos
Elena Crawford
Marisa Gallego
Molly Brennan
Maury Cole
Tess Kimber
Yanabel Grant
Staff Scientist
Heather Richardson
Olivier George
Special thanks to:
Mike Arends
Candice Contet
Laura Orio
Nick Gilpin
Support from:
(Senior Research Assistant)
National Institute on Alcohol Abuse and Alcoholism
Sunmee Wee
National Institute on Drug Abuse
Kaushik Misra
Scott Edwards
National Institute of Diabetes and Digestive and Kidney
Diseases
Leandro Vendruscolo
Pearson Center for Alcoholism and Addiction Research