Drugs of Abuse

Americans’ Views of the Seriousness of Health Problems (Top 10 of 36 Problems) 65% 68% 69% 71% 73% 74% 75% 78% 82% Stress Alcohol abuse Smoking Child abuse Violence HIV/AIDS Heart disease Drunk driving Cancer Drug abuse % saying “very serious problem” Harvard School of Public Health/Robert Wood Johnson Foundation/ICR, August 2000 Drug abuse Cancer Drunk driving Heart disease HIV/AIDS Violence Child abuse Smoking Alcohol abuse Stress

Two Decades of Neurobiological Research Have Brought Us A New Understanding of Drug Abuse and Addiction, Their Complexity and their Solutions

Their Many Differences, Virtually All Abused Substances Enhance 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 Serotonin Pathways Functions mood memory processing nucleus accumbens hippocampus striatum frontal cortex substantia nigra/VTA raphe Functions reward (motivation) pleasure,euphoria motor function (fine tuning) compulsion perserveration decision making Serotonin Pathways Functions mood memory processing sleep cognition

Neuronal structure (receiving) (sending)

/serotonin Neuronal terminal Drug : cocaine ritalin transporter Vmat vesicle Neuronal terminal Drug : cocaine ritalin stimulation transporter Vmat /serotonin How some drugs of abuse cause dopamine release: opioids narcotics (activate opioid receptors) nicotine (activate nicotine receptors) marijuana (activate cannabinoid receptors) caffeine alcohol (activate GABA receptors; an inhibitory transmitter) DA/5HT

transporter Vmat serotonin/ Release DA from vesicles and reverse transporter DA/5HT Drug Types: Amphetamines -methamphetamine -MDMA (Ecstasy)

Effects of Drugs on Dopamine Release 100 200 300 400 500 600 700 800 900 1000 1100 1 2 3 4 5 hr Time After Amphetamine % of Basal Release DA DOPAC HVA Accumbens AMPHETAMINE 100 200 300 400 1 2 3 4 5 hr Time After Cocaine % of Basal Release DA DOPAC HVA Accumbens COCAINE Much greater Activity than any Other drug of abuse -causes neurotoxicity 100 150 200 250 1 2 3 hr Time After Nicotine % of Basal Release Accumbens Caudate NICOTINE 100 150 200 250 1 2 3 4hr Time After Ethanol % of Basal Release 0.25 0.5 2.5 Accumbens Dose (g/kg ip) ETHANOL Source: Di Chiara and Imperato

Natural Rewards Elevate Dopamine Levels 50 100 150 200 60 120 180 Time (min) % of Basal DA Output NAc shell Empty Box Feeding Source: Di Chiara et al. FOOD 100 150 200 DA Concentration (% Baseline) Mounts Intromissions Ejaculations 15 5 10 Copulation Frequency Sample Number 1 2 3 4 6 7 8 9 11 12 13 14 16 17 Scr Bas Female 1 Present Female 2 Present Source: Fiorino and Phillips SEX

Elucidation of the mechanism of drug addiction will help to Implication: Elucidation of the mechanism of drug addiction will help to understand other addictive and motivational behaviors/disorders

Addiction and tolerance can be synonymous

Pharmacodynamic mechanism of Tolerance

Induction of Tolerance to Morphine

Brain Circuits Involved in Drug Addiction PFC ACG INHIBITORY CONTROL OFC Hipp Amyg MEMORY/ LEARNING SCC NAcc VP REWARD MOTIVATION/ DRIVE (saliency)

Reward Pathways: Role of Opioids

HOW DOES ADDICTION OCCUR?

B C A B C Principles of Behavior Dynamics Behavior Tracts Compete for Expression Prefrontal Cortex A B behavior expressed C behavior expressed B C Orbito- frontal cortex dopamine initiated 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)

B How does a behavior become an addiction? C A B B B B Principles of Behavior Dynamics C Prefrontal Cortex A B Addiction behavior expressed B B B B Orbito- frontal cortex dopamine How does a behavior become an addiction?

Prolonged Drug Use Changes We Have Generated A Lot of Evidence Showing That… Prolonged Drug Use Changes the Brain and In Fundamental and Long-Lasting Ways

These Changes Can Be Both Structural and Functional We Have Evidence That These Changes Can Be Both Structural and Functional

Positron Emission Tomography BRAIN IMAGING Positron Emission Tomography Magnetic Resonance Imaging

Decreases in Metabolism in Orbito Frontal Cortex (OFC) 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 DAT Interference recall Delayed recall Compromises Cognitive Functions R = 0.70 p < 0.005 R = 0.64 p < 0.01 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

Brain changes resulting from prolonged use of psychostimulants, 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 Rewards Is Damaged Activity of Reward System METH controls treated Alcohol Less Food

Get Rewired by Drug Use Their Brains…

(genetic vulnerability-not inevitability) 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 r-SA r-candidate 5 6 3 samples, > 2 labs 4 samples, > 3 labs >2 samples, >2 labs Chromosomal Locations for Substance Abuse Vulnerability Loci Uhl et al Tr Genetics, updated June 03

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?

Contribution of Genetic Factors to: 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

Gene/ Environment Interaction Genetics Gene/ Environment Interaction Environment

Dopamine Receptor Density PET Images: Dopamine Receptor Density More likely to self- administer Cocaine

Devotes ~ 100 pages to describing 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 Schizophrenia, paranoia, anhedonia, compulsive behavior Stimulants Anxiety, panic attacks, mania and sleep disorders LSD, Ecstasy & psychedelics Delusions and hallucinations Alcohol, sedatives, sleepaids & narcotics Depression and mood disturbances PCP & Ketamine 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

Causes an effect Serotonin/dopamine synaptic terminal transporter Synaptic vesicle Prozac, Ritalin, & Cocaine block Postsynaptic target Causes an effect Activate transmitter receptors

Mechanism of action of amphetamine and cocaine

Chronic use of some of these drugs of abuse may alter the way the brain functions, making persons particularly susceptible to mental illness

Mental and Addictive Disorders Double People With Comorbid Mental and Addictive Disorders Have a Brain Disease Mental Disorder Addictive Disorder Comorbid Disorders

Role of Stress and Trauma

The Stress Hormone Cycle Stress Responses Hypothalamus Stress Responses Stress Responses Stress Responses CRF Pituitary Gland CORTISOL ACTH Adrenal Glands CRF: Corticotropin Releasing Factor Kidneys

DRUG USE (Self-Medication) Anxiety DRUG USE (Self-Medication) What Role Does Stress Play In Initiating Drug Use? CRF CRF STRESS Anxiety

What Happens When A Person Anxiety RELAPSE Prolonged DRUG USE What Happens When A Person Stops Taking A Drug? CRF Abstinence

Stress Reliably Reinstates Drug Seeking in Rats * Cocaine-trained rats Alcohol-trained rats 100 80 Inactive Lever Responses 60 Active Lever * 40 * 20 * Saline Cocaine Footshock Water Alcohol Footshock Nicotine-trained rats Heroin-trained rats * 100 80 Responses 60 * * * 40 20 Saline Nicotine Footshock Saline Heroin Footshock From: Psychopharmacology, 1996, 1998, 1999 ; J. Neurosci. 1996

CRF1 Receptor Antagonist Attenuates Stress-Induced Reinstatement of Drug Seeking Alcohol-trained rats Heroin-trained rats Cocaine-trained rats 60 60 No stress 45 45 Intermittent Footshock Responses (1 hr) * 30 Responses (3 hr) 30 * * * * 15 15 15 30 15 30 15 30 CP-154,526 Dose (mg/kg, SC) From: Shaham et al. Psychopharmacology 1998; Le et al. Psychopharmacology, 2000

Objectives of Intervention: Rearrange dominance of behavior tracks contingency management (vouchers) motivational enhancement therapeutic communities

B C A B C Principles of Behavior Dynamics Prefrontal Cortex Orbito- expressed C behavior expressed B C Orbito- frontal cortex dopamine initiated

Strengthen prefrontal cortex influence (change thinking process) cognitive and cognitive behavioral tx (unlearn old habits-suppress; learn new skills) assertiveness training (suppress and express)

B C A B C Principles of Behavior Dynamics Prefrontal Cortex Orbito- expressed C behavior expressed B C Orbito- frontal cortex dopamine initiated

Alter function of orbitofrontal (saliency) cortex motivational therapy family therapies

B C A B C Principles of Behavior Dynamics Prefrontal Cortex Orbito- expressed C behavior expressed B C Orbito- frontal cortex dopamine initiated

Recovery of function (frontal and obito- frontal cortex) all treatments that keep brain away from drugs for extended time

B C A B C Principles of Behavior Dynamics Prefrontal Cortex Orbito- expressed C behavior expressed B C Orbito- frontal cortex dopamine initiated

Alleviate underlying psychiatric disorder administer: Antidepressants for depression Ritalin for ADHD Sedatives for anxiety

Targets of Medication Methadone, LAAM and Buprenorphine Activate opioid receptors Naloxone Block opioid receptors Nicotine gum/patch Activate nicotinic receptors

How some drugs of abuse cause dopamine release: vesicle Neuronal terminal stimulation 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)

C B GABA and cannabinoid systems critical for function A B C Principles of Behavior Dynamics GABA and cannabinoid systems critical for function Prefrontal Cortex A C behavior expressed B behavior expressed B C Orbito- frontal cortex dopamine initiated

Relieve stress-related drug abuse CRF antagonist Anxiety RELAPSE Prolonged DRUG USE CRF Abstinence

No cure