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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 InstituteLa Jolla, California
template
"Absinthe Drinker"Pablo Picasso (1910)
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
From: Koob GF, Alcohol Clin Exp Res, 2003, 27:232-243.
Criteria for Substance Dependence (DSM-IV)
From: Koob GF and Le Moal M, Science, 1997, 278:52-58.
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.
ICSS Threshold Procedure
Adapted from: Markou A and Koob GF, Physiol Behav, 1992, 51:111-119.
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.
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 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, 692:47-56.
Potential Substrates in the Extended Amygdala for the Motivational Effects of Drug Dependence
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 ExperimentalMedicine and Biology, Vol. 295), Plenum Press, New York, 1991, pp 1-42.
Modified from:
Dependence:An 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.
From: Solomon RL and Corbit JD, Psychol Rev, 1974, 81:119-145.
Elevations in ICSS Reward Thresholds During Withdrawal
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, 17:191-195.
Protocol for Drug Escalation
All Rats (n=24):2-hr SA sessionFixed Ratio 10.25 mg cocaine/injection
1) Initial Training Phase
Short Access (n=12)22 x 1-hr SA session
2) Escalation Phase
Long Access (n=12)22 x 6-hr SA session
Cocaine doses (µg):
0, 15.6, 31.2, 62.5,125, 250
3) Dose-Effect Study
Protocol from: Ahmed SH and Koob, Science, 1998, 282:298-300.
Long Access to Cocaine (LgA group) Produces Escalation in Cocaine Intake
From: Ahmed SH and Koob GF, Science, 1998, 282:298-300.
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.
CNS Actions of Corticotropin Releasing Factor (CRF)
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, 36:165-186.
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, 32:254-261.
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, 145:21-30.
Effects of a Competitive CRF Antagonist on Stress-Induced Reinstatement of
Cocaine Self-Administration
From: Erb S and Stewart J, J Neurosci, 1999, 19:RC35.
A. D-Phe in BNST
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
Norepinephrine … stress
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].
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.
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
Allostatic Change in Mood State associated with Transition to Drug Addiction
Adapted from: Koob GF and Le Moal M, Neuropsychopharmacology, 2001, 24:97-129.
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 O’Dell
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