Neurobiology of addiction
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Neurobiology of Addiction. Mark Publicker, MD FASAM Medical Director Mercy Recovery Center. Addiction. A chronic but treatable brain disease characterized by loss of control compulsive use use despite known harm relapse. Comorbid substance abuse. Common problem in psychiatric patients

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Neurobiology of Addiction

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Neurobiology of addiction

Neurobiology of Addiction

Mark Publicker, MD FASAM

Medical Director

Mercy Recovery Center


Addiction

Addiction

  • A chronic but treatable brain disease characterized by

    • loss of control

    • compulsive use

    • use despite known harm

    • relapse


Comorbid substance abuse

Comorbid substance abuse

  • Common problem in psychiatric patients

  • Contributes to treatment refractoriness, non-compliance and increased health services utilization and cost


Rand survey of care 2001

Rand Survey of Care, 2001

  • 3% US population has co-occuring disorders

  • Of these:

    • 72% received no treatment in previous 12 months

    • Only 8% received both mental and substance abuse treatment

    • Only 23% of those in treatment received “appropriate treatment”


Co morbid psychiatric disorders

Depression

Anxiety disorders

Bipolar disorder

Schizophrenia

ADHD

PTSD

ASP

Axis II disorders

Co-morbid psychiatric disorders


Epidemiology

Epidemiology

  • 50% lifetime prevalence of substance abuse disorders for psychiatric patients

  • Schizophrenia: prevalence rates of 70% in some surverys

    • Onset of symptoms earlier in drug-abusing schizophrenics


Epidemiology1

Epidemiology

  • Schizophrenia: substance abuse associated with higher rates of homelessness, non-compliance, medical illness and violence

  • Bipolar disorder: rates estimated to be 50-70%

    • Associated with worse prognosis


Epidemiology2

Epidemiology

  • Unipolar depression: 30-50%

    • Associated with treatment resistance and greater severity

    • Worsens alcohol dependence treatment outcomes


Epidemiology3

Epidemiology

  • ADHD: NIDA estimates up to 50% of substance abuse patients

    • Increased risk of SUD up to 9 times

    • Effective childhood treatment reduces risk


Epidemiology4

Epidemiology

  • PTSD: increased risk of SUD

    • Hypothalamic and noradrenergic mechanisms

    • PTSD precedes SUD

    • Substance abuse modifies neurobiologic substrate, intensifying PTSD symptoms which in turn intensify SUD


Neurobiology of addiction

PTSD

  • In course of use, drug abusers place selves in dangerous situations

  • Withdrawal symptoms overlap with arousal symptoms

  • Increased CRH sensitizes LC, increasing noradrenergic tone which increases CRH release

  • Increased CRH by both substance abuse and PTSD potentiate fear responses in amygdala


Epidemiology nicotine

Epidemiology - Nicotine

  • Nicotine-dependent patients with comorbid disorders: 7.1% US population consume 34.2% of all cigarettes smoked


Havassy et al ajp 1 2004

Havassy et al. AJP 1/2004

  • Comparison study of comorbid patients recruited in two treatment settings

    • Residential (non-hospital) psychiatric for seriously mentally ill patients

    • Equivalent Substance abuse residential program


Havassy et al

Havassy et al.

  • Of 420 eligible patients, 54% (N=226) met comorbid criteria

  • More MI patients met comorbid criteria than did SA (60%-49%)


Cloninger s personality typology

Cloninger’s personality typology

  • Reward dependence

  • Harm avoidance

  • Novelty seeking


Covariation of risk behaviors

Covariation of risk behaviors

  • %SexTobAlcMJ

  • Sex:100 83 88 74

  • Tobacco: 45 100 92 67

  • Marijuana: 56 94 95100


Family risk factors

Family risk factors

  • Tarter 1999: developmental window: father stops use:

    • Before age 6 - child=control in sud and asp

    • After age 6 - no decrease in later sud


Culture

Culture

  • Role of factors promoting or inhibiting use

    • Age

    • Gender

    • Ethnicity

  • Protective cultural boundaries


Women and injection drug abuse

Women and injection drug abuse

  • Sexual and/or physical abuse significant risk factor for initiation and maintenance

  • NYC study:

    • 39% sexually abused before 16

    • 27% before 13


Women and injection drug abuse1

Women and injection drug abuse

  • Women much more likely to have psychiatric diagnoses

  • NYC study: 65% women in methadone maintenance therapy have been abused as adults

  • Differences in needle-sharing behavior


Nerve cells

Nerve cells


Synapse and neurotransmission

Synapse and neurotransmission


Dopamine neurotransmission

Dopamine neurotransmission


Dopamine and c amp

Dopamine and c-AMP


Dopamine receptors and reuptake pumps

Dopamine receptors and reuptake pumps


Cocaine binding to uptake pumps

Cocaine binding to uptake pumps


Pet scan brain on cocaine

PET scan: brain on cocaine


Opiates binding to opiate receptors in the na

Opiates binding to opiate receptors in the NA


Increased camp activity

Increased cAMP activity


Thc binding sites

THC binding sites


Thc binding increases dopamine release in na

THC binding increases dopamine release in NA


Havassy et al1

Havassy et al

  • No significant differences in overall rates of mental disorders

  • Higher prevalence of schizophrenic spectrum disorders in MI setting (43%-31%)

  • No signficant difference in bipolar prevalence


Havassy et al2

Havassy et al

  • SA setting: decreased likelihood of suicide and psychiatric hospitalization history

  • No significant differences in rates of substance abuse

    • Severity of SA higher in SA setting


Havassy et al3

Havassy et al

  • SA prevalence

    • Less opiate and cocaine use in schizophrenic patients

    • No difference in days of use

      More similarities than

      differences in two settings


Self medication hypothesis

Self-medication hypothesis

  • Evidence nicotine attenuates stress reactivity

  • Schizophrenia: use nicotine to deal with negative symptoms: sleep, dysphoria, antipsychotic adverse effects and to improve cognitive function


Neurobiology

Neurobiology

  • Drugs of abuse interact and alter neural substrates related to the pathobiology of psychiatric disorders

  • More neuropsychologic impairment


Substance augmentation

Substance augmentation

  • Koob: ‘feed-forward system’ increases stress reactivity

  • Withdrawal states

  • Problem-solution interaction


Neurotransmitters

Neurotransmitters

  • Dopamine

  • Opioids

  • Glutamate

  • GABA

  • Cannabinoids

  • Norepinephrine


Dopamine

Dopamine

  • Neurotransmitter - a chemical messenger

  • Levels increase in the reward center when animals do those behaviors which ensure survival

  • D2 receptor: knockout mice


Dopamine and anticipation

Dopamine and Anticipation

  • Dopamine levels increase in response to cue

  • If reward not presented, dopamine levels decrease

  • Decreased dopamine causes dysphoria

  • Example: drug cue but no drug leads to dysphoria and increased drive to obtain the drug


Dopamine and withdrawal

Dopamine and Withdrawal

  • Decreased D2 receptors in withdrawal persisting for months

  • Plays mediating role in drug craving and drug seeking, dysphoria and relapse


Opioids

Opioids

  • Three major receptor subtypes:mu, kappa, delta

  • Mu key to opiate addictionKnockout mice: no morphine dependence or withdrawal

  • Neuroimaging: increased mu receptors in abstinence

    • Craving results


Opioids1

Opioids

  • Kappa stimulation decreases dopamine function in the NA resulting in dysphoria

  • Dynorphin is a kappa agonist

  • Buprenorphine is a kappa antagonist


Glutamate

Glutamate

  • Prinicpal excitatory neurotransmitter

  • Pathways from the prefrontal cortex and amygdala project to NA

  • Plays role in reinstatement of drug-seeking behavior


Glutamate1

Glutamate

  • NMDA receptor implicated in multiple addictions:

    • Alcohol

    • Nicotine

    • Cannabinoids

    • Cocaine

    • Amphetamine

    • Opioids


Glutamate2

Glutamate

  • NMDA receptors upregulated in addiction as well as in chronic pain states

  • NMDA receptor antagonists decrease sensitization and craving


Neurobiology of addiction

GABA

  • Principle inhibitory neurotransmitter

  • GABA-benzodiazepine receptor

  • Benzodiazepines only class of drugs of abuse that don’t increase dopamine

  • GHB activates GABA complex

  • GABA tone decreased with alcohol and opioid dependence


Cannabinoids

Cannabinoids

  • Two receptors: CB1 (Brain) and CB2 (immune)

  • Activation: inhibits GABA leading to increase in dopamine in NA

  • Share properties with opioids

    • anti-nociception

    • sedation


Definition

Definition

  • “Addiction is a cycle of spiraling dysregulation of brain reward systems that progressively increases, resulting in compulsive drug use and a loss of control over drug taking” George Koob


Genetics

Genetics

  • No single gene

  • 40% genetic

  • Cloninger’s twin study

  • COGA


Pathophysiology

Pathophysiology

  • Neural circuitry of reward and brain reward thresholds

  • Tolerance

  • Altered hedonic tone

  • Sensitization

  • Activation of HPA axis

  • Genetic predisposition


Neural circuitry of reward

Neural circuitry of reward

  • Present in all animals

  • Produces pleasure for behaviors needed for survival:

  • Eating

  • Drinking

  • Sex

  • Nurturing


Self stimulation studies

Self-stimulation studies


All drugs of abuse bind to the neural circuitry of reward

All drugs of abuse bind to the neural circuitry of reward


All drugs abuse increase dopamine in the nucleus accumbens

alcohol

cocaine

heroin

marijuana

nicotine

amphetamines

sedatives

hallucinogens

pcp

caffeine

All drugs abuse increase dopamine in the nucleus accumbens


Drugs of abuse hijack the reward center

Drugs of abuse hijack the Reward Center

  • Instead of eating, drinking and making love, drugs tell you that you need to take them in order to survive.

  • This is obviously a lie, and one that leads to sickness and death.


Neuroadaptation

Neuroadaptation

  • drugs change the brain’s balance

  • the brain has mechanisms to oppose this change

  • the balancing action ‘overshoots’:

  • the stronger the drug, the higher the dosage and the longer the use, the more the opposing change


Neuroadaptation alcoholics drink

Neuroadaptation - alcoholics drink:

  • To get high

  • To get sedated

  • To get numb


Neuroadaptation alcohol

Neuroadaptation: alcohol

  • High Depressed

  • Sedated Anxious/sleepless

  • Numb Anguish/pain


Neuroadaptation alcoholics drink1

Neuroadaptation:Alcoholics drink:

  • To get high

  • To get sedated

  • To get numb


Neuroadaptation alcohol1

Neuroadaptation: alcohol

  • High Depressed

  • Sedated Anxious/sleepless

  • Numb Anguish/pain


Positive reinforcers

Positive reinforcers

  • Euphoria

  • Sedation

  • Anesthesia (numbing)


Negative reinforcers

Negative reinforcers

  • Depression

  • Anxiety

  • Insomnia

  • Boredom

  • Loss of pleasure


Neuroadaptation alcohol2

Neuroadaptation - Alcohol

The brain on grain falls mainly in the pain.


Neuroadaptation opioids

Neuroadaptation: opioids

  • To get high

  • To get sedated

  • To get numb


Neuroadaptation cocaine

Neuroadaptation - cocaine

  • Cocaine addicts use cocaine

  • To get high

  • To get high

  • To get high


Neuroadaptation cocaine1

High

High

High

Depressed

Depressed

Depressed

Neuroadaptation: Cocaine


Cocaine and mood changes

Cocaine and mood changes


Opponent process theory

Opponent process theory


Opponent process heroin

Opponent process - heroin


Allostasis

Allostasis

  • change to new, vulnerable state

  • deficit states: inhibition of brain reward circuitry

  • altered hedonic tone (Koob)

  • reward thresholds increase

  • opponent process theory

  • counteradaptive hedonic dysregulation


Cocaine pet scan

Cocaine PET scan


Spect scan healthy brain top down and underside

SPECT scan: healthy brain top down and underside


Heroin spect scans

Heroin SPECT scans


Alcohol

Alcohol:

Intoxication

Sober: 30 days


Cannabis

Cannabis

  • Prospective studies demonstrate increased risk:

    • Schizophrenia

    • Major depressive disorder

    • Anxiety disorders, including panic


Volkow methamphetamine

Volkow: methamphetamine

  • Persistent reductions in dopamine transport in striatum

  • Long-term psychomotor impairment


Methamphetamine

Methamphetamine


Mdma ecstacy

MDMA – Ecstacy

  • Raves

  • Neurotoxic to serotonin neurons

  • Both animal model and now human findings


Selective brain activation accompanies cocaine craving

Selective brain activation accompanies cocaine craving

Neutral Edythe London


Lateral prefrontal and visual cortex are activated edythe london

Lateral prefrontal and visual cortex are activated Edythe London


Limbic regions are activated during cocaine craving edythe london

Limbic regions are activated during cocaine craving Edythe London


Craving is correlated with activity in orbitofrontal cortex edythe london

Craving is correlated with activity in orbitofrontal cortex Edythe London


Conditioning

Conditioning

  • Ivan Pavlov

  • Conditioned dogs to salivate when they heard a bell

  • 7-11


Amygdala

Amygdala

  • Emotional responses

  • Filters all incoming sensations

  • Identifies both high risk and high pleasure stimuli

  • Very rapid response


Limbic conditioning

Limbic conditioning


Brain organization

Brain organization


Brain organization1

Brain organization

  • The right brain thinks with images, not words

  • There is no DON’T ELEPHANT in the right brain

  • DON’T ELEPHANT= ELEPHANT!!


Which step says don t drink

Which step says “Don’t drink”?

None of them


Medications

Medications

  • Naltrexone (revia)

  • Topiramate

  • Acamprosate

  • Methadone

  • Buprenorphine

  • Bupropion


Antabuse disulfiram

Antabuse (disulfiram)

  • Can cause severe reactions

  • Risks of hepatotoxicity, neuropathy

  • Lack ofdouble-blind studies

  • New use: cocaine craving


Methadone

Methadone

  • Abstinence rates: 70-80%

  • Blocks craving

  • Blocks euphoria

  • Normalization of HPA axis

  • Normalization of limbic function


Methadone1

Methadone

  • High rates of major depressive disorder and anxiety disorders

  • Treatment research:

    • Tricyclic antidepressants, SSRI’s and CBT effective

    • Methadone supports treatment compliance over active using condition


Buprenorphine naloxone suboxone

Buprenorphine/naloxone: Suboxone

  • Partial agonist + pure antagonist

  • t/2 >24 hours

  • Blocks craving and euphoria

  • Less physical dependence

  • Combo decreases diversion risk


Suboxone

Suboxone

  • DATA 2000: can be prescribed by office-based physicians

  • DEA waiver

  • 30 patient limit

  • Adolescent/young adults

  • September 2004 training


Therapeutic effects

Therapeutic effects

  • blocking effect on euphoria with administration of heroin

  • blocking effect on withdrawal.

  • relieves craving

  • stabilization of brain function:

  • decrease in HPA stress state

  • improvement in mood and

  • behavioral stability


Revia naltrexone

Revia - Naltrexone

  • Pure opioid antagonist

  • Effective in treatment of alcoholism and opiate addiction

  • Blocks craving

  • Blocks the ‘high’ and increases the negatives


Acamprosate campral

Acamprosate - Campral

  • NMDA receptor antagonist

  • Blocks craving

  • Doubles abstinence rates

  • Additive with naltrexone


Topiramate

Topiramate

  • Anti-convulsant

  • Anti-craving agent for alcohol, cocaine and cannabis

  • Increases alcohol abstinence rates by 50%

  • Patients reports enhanced sense of well-being


Zyban bupropion

Zyban (bupropion)

  • Antidepressant

  • decreases craving

  • decreases withdrawal

  • can increase abstinence rates

  • side effects: GI, anxiety, headaches


Summary

Summary

  • Addictive disorders are treatable brain diseases

  • Research is edifying the biological mechanisms involved

  • Increased understanding of neurobiology is allowing for the development of effective, targeted pharmacotherapies


Summary1

Summary

  • An understanding of the neurobiology of addiction:

    • Destigmatizes both the patient and the treatment

    • Helps everyone understand the ‘why’ and the ‘how’ of otherwise baffling symptoms


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