neurobiology of drug addiction: a dysregulated neuroadaptive view

The Neuroscience of Addiction

George F. Koob, Ph.D.Professor and Chairman

Committee on the Neurobiology of Addictive Disorders

The Scripps Research InstituteLa Jolla, California

Cost and Scope of Addiction

• Alcohol– 18 million Americans abuse or are dependent on Alcohol.

• 2.2 million - approximately 10% currently seek treatment• Cost to society estimated at $185B/year

• Smoking --In US, approximately 440,000 persons die per year of a cigarette smoking-

attributable illness• This is approx. $75 billion in direct medical costs, and $82 billion

in lost productivity/year• Opioid Dependency

– Dependency has been growing rapidly: • From 1990 to 2001, the number of people who used prescription

painkillers recreationally for the first time grew by 335% to include almost 2.5 million people.

• Over an 8-year period (1994-2002):• Admissions involving oxycodone rose 450%• Admissions involving hydrocodone rose 170%

Estimated Prevalence Among 15-54 Year Olds ofNonmedical Use and Dependence Among Users

(1990-1992) (NCS)

Tobacco

Alcohol

Illicit Drugs

Cannabis

Cocaine

Stimulants

Anxiolytics

Analgesics

Psychedelics

Heroin

Inhalants

75.6

91.5

51.0

46.3

16.2

15.3

12.7

9.7

10.6

1.5

6.8

Ever Used24.1

14.1

7.5

4.2

2.7

1.7

1.2

0.7

0.5

0.4

0.3

Prevalence of Dependence

31.9

15.4

14.7

9.1

16.7

11.2

9.2

7.5

4.9

23.1

3.7

Dependence Among Users

From: Anthony JC, Warner LA and Kessler RC, Exp Clin Psychopharmacol, 1994, 2:244-268.

The San Diego Union-TribuneThursday, August 30, 2001

Key Definitions

Drug Addiction — Chronically relapsing disorder that is characterized by a compulsion to seek and take drug, loss of control in limiting intake, and emergence of a negative emotional state (e.g. dysphoria, anxiety, irritability) when access to the drug is prevented (here, defined as the “dark side” of addiction)

Nucleus Accumbens and Extended Amygdala — Forebrain structures involved in the rewarding effects of drugs of abuse. Composed of central nucleus of the amygdala, bed nucleus of the stria terminalis, and a transition zone in the medial part of the nucleus accumbens

Corticotropin-Releasing Factor — “brain stress” neurotransmitter, 41 amino acid polypeptide that controls hormonal, sympathetic, and behavioral responses to stressors

Transcription Factors — brain chemicals involved in the longterm neuroadaptive changes within neurocircuits associated with chronic administration of drugs of abuse. Transcription factors can gene expression

“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

From: Koob GF, Alcohol Clin Exp Res, 2003, 27:232-243.

Stages of the Addiction Cycle

Animal Models for the Different Stages of the Addiction Cycle

• Animal Models for the Binge/Intoxication Stage1. Oral or intravenous drug self-administration2. Brain stimulation reward3. Place preference

• Animal models for the Withdrawal/Negative Affect Stage1. Brain stimulation reward2. Place aversion

• Animal Models for the Transition to Addiction1. Dependence-induced drug taking2. Escalation in drug self-administration with prolonged

access 3. Drug taking despite aversive consequences

• Animal Models for the Preoccupation/Anticipation (“Craving”) Stage

1. Drug- induced reinstatement2. Cue- induced reinstatement3. Alcohol Deprivation Effect4. Stress- induced reinstatement

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.

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.

Neurochemical Circuitry in Drug Reward

Neurobiological Substrates for the Acute Reinforcing Effects of Drugs of Abuse

Neurotransmitter

Dopamine

Opioid Peptides

GABA

Glutamate

Site

Ventral tegmental area, nucleus accumbens

Nucleus accumbens, amygdala, ventral tegmental area

Amygdala, bed nucleus of stria terminalis

Nucleus accumbens

Converging Acute Actions of Drugs of Abuse on the Ventral Tegmental Area and Nucleus Accumbens

From: Nestler EJ, Nat Neurosci, 2005, 8:1445-1449.

Reward Transmitters Implicated in the Positive Motivational Effects of Drugs of Abuse

Dopamine

Opioid peptides

GABA

Glutamate

Serotonin

Positive Hedonic Effects

From: Solomon RL and Corbit JD, Psychol Rev, 1974, 81:119-145.

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.

Extracellular DA and 5-HT in the Nucleus Accumbens During Cocaine Self-Administration

and Withdrawal

From: Parsons LH, Koob GF and Weiss F, J Pharmacol Exp Ther, 1995, 274:1182-1191.

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

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:

Pieter Bruegel

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.

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

Protocol for Initiation of Lever Pressing forOral Ethanol Self-Administration in the Rat

Initiation of the free-choice operant task: ethanol (10%) and water

Rats trained to lever press on a FR-1 schedule

Ethanol added to the saccharin solution

Access to ethanol and water or ethanol + saccharin and water

1-3

4-9

10

11-12

13

14

15-16

17

18+

Days

Days

Day

Days

Day

Day

Days

Day

Day

0.2%

0.2%

-

0.2%

-

0.2%

-

0.2%

-

0%

5%

5%

5%

5%

8%

8%

10%

10%

*

*

*

*

Training Saccharin (w/v)

EtOH (w/v)

Ethanol Dependence Induction

From: Rassnick S, Heinrichs SC, Britton KT and Koob GF,Brain Res, 1993, 605:25-32.

From: Rogers J, Wiener SG and Bloom FE,Behav Neural Biol, 1979, 27:466-486.

The AWOL System(Alcohol WithOut Liquid)

• Patented by Spirit Partners, Inc.

• Available as 1, 2, or 4 user machines (cost $299 to $2845).

• Legal in U.S.

• Consists of oxygen generator and hand-held vaporizer.

• 80-proof alcohol (40% alcohol by volume) is poured into vaporizer, and vapor is inhaled.

Extracellular CRF Levels in the CentralAmygdala During Ethanol Withdrawal

Effect of CRF Antagonist D-Phe-CRF12-41

– Central Nucleus of the Amygdala –

From: Funk C, O’Dell LE and Koob GF, Journal of Neuroscience, 2006, 44:11324-11332

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

Glutamate….hyperexcitability

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].

Craving-Type 1

• “Craving”- induced by stimuli that have been paired with ethanol self-administration such as environmental cues

• Termed conditioned positive reinforcement in experimental psychology

• An animal model of craving- type 1 is cue induced reinstatement where a cue previously paired with access to ethanol reinstates responding for a lever that has been extinguished.

Craving-Type 2

• State of protracted abstinence in alcoholics weeks after acute withdrawal

• Conceptualized as a state change characterized by anxiety and dysphoria or a residual negative affective state that combines with Craving-Type 1 situations to produce relapse to excessive drinking

• Animal models of Craving-Type 2 include stress-induced reinstatement, or increased drinking in animals after a prolonged deprivation (Alcohol Deprivation Effect)

Reinstatement

Neurobiological Effects of Exposure to Drug-Associated Contextual Stimuli

SA EXT S- S+Daily Sessions of Self-Administration

Effects of D-Phe-CRF12-41 and Naltrexone on Stress- and Cue-Induced Reinstatement of Ethanol-Seeking

Liu & Weiss (2002) J Neurosci

Neurochemical Changes Associated with the Drug Use, Dependence and Relapse

Common Molecular Changes Associated with Dependence

• Dopamine D-2 receptor binding- decreased in human imaging studies in dependent subjects

• CREB ( cyclic adenosine monophosphate response element binding protein) transcription factor- decreased in nucleus accumbens and extended amygdala during the development of dependence

• Delta-FosB transcription factor-changed during protracted abstinence to drugs of abuse

Key Common Neurocircuitry Elements in Drug Seeking Behavior of Addiction

Summary- Neurocircuitry of Addiction

• Reward Circuit- nucleus accumbens and extended amygdala (bed nucleus of the stria terminalis and central nucleus of the amygdala)

• “Craving” Circuit- dorsal prefrontal cortex, basolateral amygdala

• “Compulsivity” Circuit- ventral striatum, ventral pallidum,medial thalamic- orbitofrontal cortical loop

Medications for Alcohol Dependence

• Disulfiram (Antabuse)- FDA approved 1954

• Naltrexone (ReVia)- FDA approved 1994

• Acamprosate- FDA approved 2004

Effects of Drugs on Animal Models of Different Components of the Addiction Cycle

Relevant for Medications Development

Naltrexone Acamprosate

CRFAntagonist

NMDA/GABA

Allosteric Modulator

Orphanin FQ /Nociceptin

Agonist

mGluR Group II Agonist

Baseline Drinking

— — — —

Dependence-Induced drinking

Cue-Induced Reinstatement

—

Stress-Induced Reinstatement

—

ADE / Protracted Abstinence

Medications Development

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