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

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:

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:

ICSS Threshold Procedure Adapted from: Markou A and Koob GF, Physiol Behav, 1992, 51:

Effects of Cocaine on Thresholds of Brain Stimulation Reward and Brain 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

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

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 Experimental Medicine and Biology, Vol. 295), Plenum Press, New York, 1991, pp 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

From: Solomon RL and Corbit JD, Psychol Rev, 1974, 81:

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:

Protocol for Drug Escalation All Rats (n=24): 2-hr SA session Fixed Ratio 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:

Long Access to Cocaine (LgA group) Produces Escalation in Cocaine Intake From: Ahmed SH and Koob GF, Science, 1998, 282:

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:

CNS Actions of Corticotropin Releasing Factor (CRF)

Major CRF-IR Cell Groups and Fiber Systems Illustrated Schematically in a Sagittal View of the Rat Brain From: Swanson LW, Sawchenko PE, Rivier J and Vale W, Neuroendocrinology, 1983, 36:

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:

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 [

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

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:

Neurobiology of Drug Addiction Current 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