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 InstituteLa 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
Dopamine … “dysphoria”
Opioid peptides ... pain
Serotonin … “dysphoria”
GABA … anxiety, panic attacks
Dopamine
Opioid peptides
Serotonin
GABA
Positive Hedonic Effects Negative Hedonic Effectsof Withdrawal
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.
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.
Effect of -flupenthixol on Cocaine Self-Administration in Escalated and Non-Escalated Animals
From: Ahmed SH and Koob GF, unpublished results.
Decreased Dopamine D2 Receptor Activityin 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 ofCorticotropin-Releasing Factor (CRF)
Major CRF-Immunoreactive Cell Groups andFiber 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 Neurochemicalsby in vivo Microdialysis
Sampling of Interstitial Neurochemicalsby 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 inExtracellular 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 Self-Administration 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 Factorin Dependence
CRF antagonist effects on withdrawal-induced anxiety-like
responsesDrug
Cocaine
Opioids
Ethanol
Nicotine
9-tetrahydrocannabinol
Withdrawal-induced changes in extracellular
CRF in CeA
↑
↑
↑
↑
↑
CRF antagonist effects on
dependence-induced increases in self-
administration
↓
↓
↓
↓
nt
CRF antagonist reversal of
stress-induced reinstatement
↓
↓
↓
↓
nt
↓
↓
↓
↓
↓
*
= 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 self-administration 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
Reinstatement of Drug (Alcohol) Seeking with Drug-Associated Contextual Stimuli
SA EXT S- S+Daily Sessions of Self-Administration
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.
PositiveReinforcement
NegativeReinforcement
Non-dependentDependent
NegativeReinforcement
PositiveReinforcement
Stress and Anti-stress Neurotransmitters Implicated in the Motivational Effects of Drugs of Abuse
Corticotropin-releasing factor
Norepinephrine
Vasopressin
Orexin (hypocretin)
Dynoprhin
Neuropeptide Y
Nociceptin (orphanin FQ)
Substance P
Brain Arousal-Stress System Modulationin the Extended Amygdala
From: Koob, G.F. 2008 Neuron 59:11-34
Regulation of the Mesolimbic Dopamine Circuit and Hypothalamus by the Extended Amygdala
Neuroplasticity in Brain Circuits associated with the Development of Addiction
From: Koob and Volkow, Neurocircuitry of addiction, Neuropsychopharmacology Reviews, in press
Neuroplasticity with Increasing Use
Co
mp
uls
ivit
y –
Lo
ss o
f C
on
tro
l
Mesolimbic DA
NucleusAccumbens
DorsalStriatum
PrefrontalCortex
ExtendedAmygdala
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 AddictionKoob Laboratory
Post-Doctoral
Fellows
Cindy Funk
Brendan Walker
Tom Greenwell
Sandy Ghozland
Chitra Mandyam
Dong Ji
Candice Contet
Laura Orio
Nick Gilpin
Sunmee Wee
Kaushik Misra
Scott Edwards
Leandro Vendruscolo
Special thanks to:
Mike Arends
(Senior Research Assistant)
Research
Assistants
Bob Lintz
Richard Schroeder
Elena Crawford
Molly Brennan
Maury Cole
Tess Kimber
Yanabel Grant
Administrative
Assistants
Lisa Maturin
Mellany Santos
Marisa Gallego
Staff ScientistHeather Richardson
Olivier George
Support from:
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
Visiting ProfessorsChoon-Gon JangCharles Heyser
