Neuroadaptation in Addiction:

The Extended Amygdala and Brain Reward System

George F. Koob, Ph.D.Department of Neuropharmacology

The Scripps Research InstituteLa Jolla, California

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"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