The Neurobiology of Drug Addiction Glen R. Hanson, Ph.D., D.D.S. Director, Utah Addiction Center Professor of Pharmacology and Toxicology, U of U Senior Advisor, NIDA
Drug Abuse and Addiction are Among the Most Serious Public HealthProblems Facing Our Society and Frequently Coexist with Other Mental and Physical Disorders
Americans Views of the Seriousness of Health Problems (Top Ten of Thirty-Six Problems) % saying very serious problem Drug abuse Cancer Drunk driving Heart disease HIV/AIDS Violence Child abuse Smoking Alcohol abuse Stress 82% 78% 75% 74% 73% 71% 69% 68% 65% 65% Harvard School of Public Health/Robert Wood Johnson Foundation/ICR, August 2000
Two Decades of Neurobiological Research Have Brought Us A New Understanding of Drug Abuse and Addiction, Their Complexity and their Solutions
For Example We Know That Despite Their Many Differences, Virtually All Abused Substances Enhance Dopamine (neurotransmitter) Activity (particularly related to pleasure, motor, and cognitive function Other pathways also involved!
Dopamine Pathways striatum frontal cortex hippocampus Functions reward (motivation) pleasure,euphoria motor function (fine tuning) compulsion perserveration decision making nucleus accumbens substantia nigra/vta raphe Serotonin Pathways Functions mood memory processing sleep
Neuronal structure (receiving) (sending)
stimulation vesicle Drug : cocaine ritalin Neuronal terminal transporter Vmat /serotonin How some drugs of abuse cause dopamine release: opioids narcotics (activate opioid receptors) DA/5HT nicotine (activate nicotine receptors) marijuana (activate cannabinoid receptors) caffeine alcohol (activate GABA receptors; an inhibitory transmitter)
transporter Vmat serotonin/ Release DA from vesicles and reverse transporter DA/5HT Drug Types: Amphetamines -methamphetamine -MDMA (Ecstasy)
% of Basal Release 1100 1000 900 800 700 600 500 400 300 200 100 0 Effects of Drugs on Dopamine Release Accumbens AMPHETAMINE Much greater DA Activity than DOPAC any HVA Other drug of abuse -causes neurotoxicity 0 1 2 3 4 5 hr Time After Amphetamine % of Basal Release 400 300 200 100 0 Accumbens COCAINE DA DOPAC HVA 0 1 2 3 4 5 hr Time After Cocaine % of Basal Release 250 200 150 100 0 0 1 2 3 hr Time After Nicotine NICOTINE Accumbens Caudate % of Basal Release 250 200 150 100 Source: Di Chiara and Imperato 0 Accumbens ETHANOL Dose (g/kg ip) 0.25 0.5 1 2.5 0 1 2 3 4hr Time After Ethanol
Natural Rewards Elevate Dopamine Levels % of Basal DA Output 200 150 100 50 0 Empty FOOD Box Feeding NAc shell 0 60 120 180 Time (min) DA Concentration (% Baseline) 200 150 100 Sample Number Scr Scr Bas Female 1 Present SEX Scr 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 Mounts Intromissions Ejaculations Scr Female 2 Present 15 10 5 0 Copulation Frequency Source: Di Chiara et al. Source: Fiorino and Phillips
Implication: Elucidation of the mechanism of drug addiction will help to understand other addictive and motivational behaviors/disorders
Brain Circuits Involved in Drug Addiction INHIBITORY CONTROL PFC ACG OFC SCC NAcc MOTIVATION/ DRIVE (saliency) Hipp VP REWARD Amyg MEMORY/ LEARNING
HOW DOES ADDICTION OCCUR?
Principles of Behavior Dynamics Prefrontal Cortex Orbitofrontal cortex Behavior Tracts Compete for Expression Expression is Determined by (i) Dominance of Tracts, (ii) Strength of Prefrontal Cortex to Select, (iii) Relevance or saliency (orbitofrontal cortex) Activation of Dopamine reward pathway initiates a behavior track (Miller & Cohen, Annu. Rev. Neurosci. 24 [2001] 167) A B C dopamine initiated behavior expressed C B
Principles of Behavior Dynamics Prefrontal Cortex C A B B Addiction behavior expressed B Orbitofrontal cortex dopamine How does a behavior become an addiction?
We Have Generated A Lot of Evidence Showing That Prolonged Drug Use Changes the Brain and In Fundamental and Long-Lasting Ways
AND We Have Evidence That These Changes Can Be Both Structural and Functional
BRAIN IMAGING Positron Emission Tomography Magnetic Resonance Imaging
Decreases in Metabolism in Orbito Frontal Cortex (OFC) Compromise assigning appropriate Value control cocaine abuser Volkow et al. Am. J. Psychiatry 148, 621
METH Suppresses Expression of DAT (note: duration of use/3-20 yrs; abstinent/ 1-4 yrs) Source: McCann U.D. et al., The Journal of Neuroscience, 18(20), pp. 8417-8422, October 15, 1998.
Dopamine Transporter Loss After Heavy Methamphetamine Use (PET analysis) Comparison Subject METH Abuser Source: Volkow, N.D. et al., Am J. Psychiatry, 158(3), pp. 377-382, 2001.
Dependence of Verbal Memory on Striatal 15 Interference recall DAT 15 Delayed recall Number of words 12 9 6 3 0 R = 0.70 p < 0.005 Number of words Compromises Cognitive Functions 12 0 1 1.2 1.4 1.6 1.8 2 9 6 3 R = 0.64 p < 0.01 1 1.2 1.4 1.6 1.8 2 Dopamine transporter Dopamine transporter (Bmax/Kd) (Bmax/Kd) Source: Volkow, N.D. et al., Am J. Psychiatry, 158(3), pp. 377-382, 2001.
MOTOR FUNCTION Slowed gait Impaired balance Impairment correlates with damage to dopamine system
Implication: Brain changes resulting from prolonged use of psychostimulants, such as methamphetamine may be reflected in compromised cognitive and motor functioning
Is There Recovery? Good News: After 2 years some of the dopamine deficits are recovering Bad News: Functional deficits persist What does this mean???
Reward System in Addiction More Cocaine Ability to Experience METH Rewards Is Damaged Alcohol treated Less Food
Their Brains Get Rewired by Drug Use
INHERITED FACTORS (genetic vulnerability-not inevitability) Common strategy to investigate are Twin Studies
In General: Inheritability for Drug Abuse Ranges From 40-60% Some Variability Between Drugs Some Gender Variability
Chromosomal Locations for Substance Abuse Vulnerability Loci 17 22 5 6 3 samples, > 2 labs r-sa 4 samples, > 3 labs r-candidate Uhl et al Tr Genetics, updated June 03 >2 samples, >2 labs
Complex genetics Complex phenotypes (expressions) (Relation to Risk Factors?)
VULNERABILITY to What? Starting Drug Use? Liking Drugs More? Continuing Drug Use? Becoming Addicted? Specific to A Particular Drug?
For Example- Contribution of Genetic Factors to: Nicotine- Liability to initiate=56% Transition to dependence=70% Smoking persistence= >50% (Lerman & Berrettine, Amer. J. Med. Gen. 54 (2003) 48)
Genetics May Influence How Neurobiology Interacts With Environment
Genetics Gene/ Environment Interaction Environment
PET Images: Dopamine Receptor Density More likely to self- administer Cocaine
Effect of Social Dominance on Cocaine Self -Administration 2.0 TOTAL INTAKE (mg/kg/session) Mean intake/session (mg/kg) 1.5 1.0 0.5 0.0 * * Subordinate Dominant.003.01.03.1 Cocaine (mg/kg/injection)
Addictive Disorders Often Co-Exist with or Predispose to Mental Disorders DSM IV Manual: Devotes ~ 100 pages to describing addiction and dependence disorders Discusses substance abuse as a confound to diagnosis and Tx
National Comorbidity Survey (NCS) Nearly half of individuals with a past year substance use disorder also had a mental disorder Mental disorders found to be most prevalent included affective disorders, anxiety disorders, personality disorders, and psychotic disorders (Note: can we have parity for mental health with- out considering drug abuse?)
Common Underlying Neurobiological Factors Can Be: Neurochemical (imbalance of neurotransmitters) Structural/anatomical (same regions and pathways) Genetic (inherited factors that compromise function)
Because of this overlap, drugs of abuse can cause symptoms that mimic most forms of mental illness
Drug Disorder Cocaine and Methamphetamine Stimulants LSD, Ecstasy & psychedelics Alcohol, sedatives, sleepaids & narcotics PCP & Ketamine Schizophrenia, paranoia, anhedonia, compulsive behavior Anxiety, panic attacks, mania and sleep disorders Delusions and hallucinations Depression and mood disturbances Antisocial behavior
Some drugs of abuse have a mechanism of action similar to that of drugs used as psychotherapeutic agents Significance: rationale for self-administration
Synaptic vesicle Serotonin/dopamine synaptic terminal transporter Prozac, Ritalin, & Cocaine block Activate transmitter receptors Postsynaptic target Causes an effect
Chronic use of some of these drugs of abuse may alter the way the brain functions, making persons particularly susceptible to mental illness
People With Comorbid Mental and Addictive Disorders Have a Brain Disease Double Mental Disorder Comorbid Disorders Addictive Disorder
Role of Stress and Trauma
The Stress Hormone Cycle Pituitary Gland CRF Hypothalamus Stress Stress Responses Stress Responses Stress Responses Responses CRF: Corticotropin Releasing Factor ACTH Adrenal Glands Kidneys CORTISOL
Anxiety DRUG USE (Self-Medication) CRF What Role Does Stress Play In Initiating Drug Use? CRF STRESS Anxiety
Anxiety RELAPSE Prolonged DRUG USE What Happens When A Person Stops Taking A Drug? CRF Abstinence
Stress Reliably Reinstates Drug Seeking in Rats Responses 100 80 60 40 20 0 Cocaine-trained rats Saline Inactive Lever Active Lever * Cocaine * Footshock Alcohol-trained rats * Water Alcohol Footshock * Responses 100 80 60 40 20 0 Nicotine-trained rats Saline Nicotine * * Footshock Heroin-trained rats Saline * Heroin Footshock * From: Psychopharmacology, 1996, 1998, 1999 ; J. Neurosci. 1996
CRF 1 Receptor Antagonist Attenuates Stress-Induced Reinstatement of Drug Seeking Alcohol-trained rats Heroin-trained rats Cocaine-trained rats 60 60 Responses (1 hr) 45 30 15 * Responses (3 hr) 45 30 15 * * No stress Intermittent Footshock * * 0 0 15 30 0 0 15 30 0 15 30 CP-154,526 Dose (mg/kg, SC) From: Shaham et al. Psychopharmacology 1998; Le et al. Psychopharmacology, 2000
Use the Science
We Are Capitalizing on Basic Science Discoveries in the Design Of Behavior Therapies and Medications To Treat Addiction
Objectives of Intervention: Rearrange dominance of behavior tracks contingency management (vouchers) motivational enhancement therapeutic communities
Principles of Behavior Dynamics Prefrontal Cortex Orbitofrontal cortex A B C dopamine initiated behavior expressed C B
Strengthen prefrontal cortex influence (change thinking process) cognitive and cognitive behavioral tx (unlearn old habits-suppress; learn new skills) assertiveness training (suppress and express)
Principles of Behavior Dynamics Prefrontal Cortex Orbitofrontal cortex A B C dopamine initiated behavior expressed C B
Alter function of orbitofrontal (saliency) cortex motivational therapy family therapies
Principles of Behavior Dynamics Prefrontal Cortex Orbitofrontal cortex A B C dopamine initiated behavior expressed C B
Recovery of function (frontal and obito- frontal cortex) all treatments that keep brain away from drugs for extended time
Principles of Behavior Dynamics Prefrontal Cortex Orbitofrontal cortex A B C dopamine initiated behavior expressed C B
Alleviate underlying psychiatric disorder administer: Antidepressants for depression Ritalin for ADHD Sedatives for anxiety
Targets of Medication Methadone, LAAM and Buprenorphine Naloxone Activate opioid receptors Block opioid receptors Nicotine gum/patch Activate nicotinic receptors
stimulation vesicle Neuronal terminal transporter Vmat How some drugs of abuse cause dopamine release: opioids narcotics (activate opioid receptors) nicotine (activate nicotine receptors) DA
Psychostimulants Enhancing GABA-ergic inhibition (baclofen-muscle relaxant; anti-seizure- Tiagabine) Cannabinoid antagonist (rimonabant)
Principles of Behavior Dynamics Prefrontal Cortex Orbitofrontal cortex GABA and cannabinoid systems critical for A function B C dopamine initiated behavior expressed C B
Relieve stress-related drug abuse CRF antagonist Anxiety RELAPSE Prolonged DRUG USE CRF Abstinence
Consequence: There is no cure To be successful, treatment is a Lifetime Process Science is helping to improve our strategies and successes