Neuroadaptation in Addiction: The Extended Amygdala and Brain Reward System

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Neuroadaptation in Addiction The Extended
Amygdala and Brain Reward System

• George F. Koob, Ph.D.
• Department of Neuropharmacology
• The Scripps Research Institute
• La Jolla, California

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template
"Absinthe Drinker" Pablo Picasso (1910)
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Key Definitions

• Allostasis- literally,other stability in
  physiology, the ability to achieve stability
  through change
• Extended Amygdala- forebrain macrostructure
  composed of central medial amygdala, bed nucleus
  of the stria terminalis and a transition zone in
  the medial part of the nucleus accumbens
• Corticotropin Releasing Factor- 41 amino acid
  polypeptide brain stress neurotransmitter that
  controls hormonal, sympathetic and behavioral
  responses to stressors

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From Koob GF, Alcohol Clin Exp Res, 2003,
27232-243.
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Criteria for Substance Dependence (DSM-IV)
From Koob GF and Le Moal M, Science, 1997,
27852-58.
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Mood Changes Associated with Plasma Levels of
Cocaine during Coca Paste Smoking
From Van Dyke C and Byck R, Cocaine, Scientific
American, 1982, 246123-141.
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ICSS Threshold Procedure
Adapted from Markou A and Koob GF, Physiol
Behav, 1992, 51111-119.
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Effects of Cocaine on Thresholds ofBrain
Stimulation Reward andBrain Stimulation Detection
From Kornetsky C and Bain G, Biobehavioral bases
of the reinforcing properties of opiate drugs. In
Verebey K (ed), Opioids in Mental Illness
Clinical Observations, and Treatment
Possibilities (series title Annals of the New
York Academy of Sciences, vol. 398), New York
Academy of Sciences, New York, 1982, pp. 241-259.
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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.
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Effects of SCH23390 Microinjected into the
Accumbens Shell, Central Amygdala or Dorsal
Striatum on Cocaine Self-Administration
From Caine SB, Heinrichs SC, Coffin VL and Koob
GF, Brain Res, 1995, 69247-56.
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Potential Substrates in the Extended Amygdala for
the Motivational Effects of Drug Dependence
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DependenceAn Affective Definition
The notion of dependence on a drug, object,
role, activity or any other stimulus-source
requires the crucial feature of negative affect
experienced in its absence. The degree of
dependence can be equated with the amount of this
negative affect, which may range from mild
discomfort to extreme distress, or it may be
equated with the amount of difficulty or effort
required to do without the drug, object, etc.
From Russell MAH, What is dependence? In Edwards
G (ed), Drugs and Drug Dependence, Lexington
Books, Lexington, MA, 1976, pp. 182-187.
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From Solomon RL and Corbit JD, Psychol Rev,
1974, 81119-145.
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Elevations in ICSS Reward Thresholds During
Withdrawal
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Effects of Intravenous Self-Administration of
Cocaine on Reward Thresholds After a Single
Session of Different Amounts of Infusions
From Kenny PJ, Polis I, Koob GF and Markou A,
Eur J Neurosci, 2003, 17191-195.
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Protocol for Drug Escalation
1) Initial Training Phase
2) Escalation Phase
3) Dose-Effect Study
Short Access (n12)22 x 1-hr SA session
All Rats (n24)2-hr SA sessionFixed Ratio
10.25 mg cocaine/injection
Cocaine doses (µg)0, 15.6, 31.2, 62.5,125, 250
Long Access (n12)22 x 6-hr SA session
Protocol from Ahmed SH and Koob, Science, 1998,
282298-300.
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Long Access to Cocaine (LgA group) Produces
Escalation in Cocaine Intake
From Ahmed SH and Koob GF, Science, 1998,
282298-300.
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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, 5625-627.
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CNS Actions of Corticotropin Releasing Factor
(CRF)
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Major CRF-IR Cell Groups and Fiber Systems
Illustrated Schematically in aSagittal View of
the Rat Brain
From Swanson LW, Sawchenko PE, Rivier J and Vale
W, Neuroendocrinology, 1983, 36165-186.
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Extracellular CRF Levels in the Central Nucleus
of the Amgydala During Cocaine Self-Administration
and Subsequent Withdrawal
From Richter RM and Weiss F, Synapse, 1999,
32254-261.
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Effect of CRF Antagonist D-Phe-CRF(12-41)
Administered ICV on Anxiogenic-Like Effect
Following Chronic Cocaine Administration
From Basso AM, Spina M, Rivier J, Vale W and
Koob GF, Psychopharmacology, 1999, 14521-30.
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Effects of a Competitive CRF Antagonist on
Stress-Induced Reinstatement ofCocaine
Self-Administration
A. D-Phe in BNST
From Erb S and Stewart J, J Neurosci, 1999,
19RC35.
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Neurotransmitters Implicated in the Motivational
Effects of Withdrawal from Drug of Abuse
Dopamine dysphoria Serotonin
dysphoria GABA anxiety, panic attacks NPY
anti-stress
Dynorphin dysphoria CRF stress Norepinephrin
e stress
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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//203.200.24.1408080/Neuroscience.
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Allostasis - Definition

• The ability to achieve stability through change
• To obtain stability, an organism must vary all
  of the parameters of its internal milieu and
  match them appropriately to environmental
  demands.

From Sterling P and Eyer J, Allostasis a new
paradigm to explain arousal pathology. In Fisher
S and Reason J (eds), Handbook of Life Stress,
Cognition and Health, John Wiley, New York, 1988,
pp. 629-647.
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Homeostasis vs. Allostasis

• Homeostasis
• normal set point
• physiologic equilibrium
• no anticipation of demand
• no adjustment based on history
• adjustment carries no price
• no pathology

Allostasis changing set point compensated
equilibrium anticipation of demand adjustment
based on history adjustment and accomodation
carry a price leads to pathology
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Allostatic Change in Mood State associated with
Transition to Drug Addiction
Adapted from Koob GF and Le Moal M,
Neuropsychopharmacology, 2001, 2497-129.
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Neurobiology of Drug AddictionCurrent
Collaborators
Floyd Bloom Friedbert Weiss Karen Britton Michel
Le Moal Luis Stinus Athina Markou Larry
Parsons Pietro Sanna Luigi Pulvirenti Amanda
Roberts Support from the National Institutes of
Health 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
Eric Zorrilla Laura ODell Serge Ahmed Gery
Schulteis John Walker Charles Heyser Noelle
Gracy Andrew Morse Kyle Frantz Emanuela Izzo
Marc Azar Angelo Contarino Monique Vallee Robert
Purdy Glenn Valdez Stephanie Caille Scott
Chen Benjamin Boutrel Sheila Specio