Neurobiology of Addiction

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Neurobiology of Addiction

• Mark Publicker, MD FASAM
• Medical Director
• Mercy Recovery Center

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Addiction

• A chronic but treatable brain disease
  characterized by
• loss of control
• compulsive use
• use despite known harm
• relapse

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Comorbid substance abuse

• Common problem in psychiatric patients
• Contributes to treatment refractoriness,
  non-compliance and increased health services
  utilization and cost

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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

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Co-morbid psychiatric disorders

• Depression
• Anxiety disorders
• Bipolar disorder

• Schizophrenia
• ADHD
• PTSD
• ASP
• Axis II disorders

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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

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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

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Epidemiology

• Unipolar depression 30-50
• Associated with treatment resistance and greater
  severity
• Worsens alcohol dependence treatment outcomes

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Epidemiology

• ADHD NIDA estimates up to 50 of substance
  abuse patients
• Increased risk of SUD up to 9 times
• Effective childhood treatment reduces risk

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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

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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

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Epidemiology - Nicotine

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

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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

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Havassy et al.

• Of 420 eligible patients, 54 (N226) met
  comorbid criteria
• More MI patients met comorbid criteria than did
  SA (60-49)

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Cloningers personality typology

• Reward dependence
• Harm avoidance
• Novelty seeking

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Covariation of risk behaviors

• Sex Tob Alc MJ
• Sex 100 83 88 74
• Tobacco 45 100 92 67
• Marijuana 56 94 95 100

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Family risk factors

• Tarter 1999 developmental window father stops
  use
• Before age 6 - childcontrol in sud and asp
• After age 6 - no decrease in later sud

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Culture

• Role of factors promoting or inhibiting use
• Age
• Gender
• Ethnicity
• Protective cultural boundaries

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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

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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

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Nerve cells
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Synapse and neurotransmission
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Dopamine neurotransmission
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Dopamine and c-AMP
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Dopamine receptors and reuptake pumps
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Cocaine binding to uptake pumps
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PET scan brain on cocaine
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Opiates binding to opiate receptors in the NA
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Increased cAMP activity
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THC binding sites
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THC binding increases dopamine release in NA
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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

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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

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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

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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

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Neurobiology

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

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Substance augmentation

• Koob feed-forward system increases stress
  reactivity
• Withdrawal states
• Problem-solution interaction

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Neurotransmitters

• Dopamine
• Opioids
• Glutamate
• GABA
• Cannabinoids
• Norepinephrine

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Dopamine

• Neurotransmitter - a chemical messenger
• Levels increase in the reward center when animals
  do those behaviors which ensure survival
• D2 receptor knockout mice

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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

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Dopamine and Withdrawal

• Decreased D2 receptors in withdrawal persisting
  for months
• Plays mediating role in drug craving and drug
  seeking, dysphoria and relapse

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Opioids

• Three major receptor subtypes mu, kappa, delta
• Mu key to opiate addiction Knockout mice no
  morphine dependence or withdrawal
• Neuroimaging increased mu receptors in
  abstinence
• Craving results

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Opioids

• Kappa stimulation decreases dopamine function in
  the NA resulting in dysphoria
• Dynorphin is a kappa agonist
• Buprenorphine is a kappa antagonist

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Glutamate

• Prinicpal excitatory neurotransmitter
• Pathways from the prefrontal cortex and amygdala
  project to NA
• Plays role in reinstatement of drug-seeking
  behavior

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Glutamate

• NMDA receptor implicated in multiple addictions
• Alcohol
• Nicotine
• Cannabinoids
• Cocaine
• Amphetamine
• Opioids

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Glutamate

• NMDA receptors upregulated in addiction as well
  as in chronic pain states
• NMDA receptor antagonists decrease sensitization
  and craving

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GABA

• Principle inhibitory neurotransmitter
• GABA-benzodiazepine receptor
• Benzodiazepines only class of drugs of abuse that
  dont increase dopamine
• GHB activates GABA complex
• GABA tone decreased with alcohol and opioid
  dependence

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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

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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

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Genetics

• No single gene
• 40 genetic
• Cloningers twin study
• COGA

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Pathophysiology

• Neural circuitry of reward and brain reward
  thresholds
• Tolerance
• Altered hedonic tone
• Sensitization
• Activation of HPA axis
• Genetic predisposition

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Neural circuitry of reward

• Present in all animals
• Produces pleasure for behaviors needed for
  survival
• Eating
• Drinking
• Sex
• Nurturing

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Self-stimulation studies
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All drugs of abuse bind to the neural circuitry
of reward
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All drugs abuse increase dopamine in the nucleus
accumbens

• alcohol
• cocaine
• heroin
• marijuana
• nicotine

• amphetamines
• sedatives
• hallucinogens
• pcp
• caffeine

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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.

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Neuroadaptation

• drugs change the brains 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

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Neuroadaptation - alcoholics drink

• To get high
• To get sedated
• To get numb

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Neuroadaptation alcohol

• High Depressed
• Sedated Anxious/sleepless
• Numb Anguish/pain

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NeuroadaptationAlcoholics drink

• To get high
• To get sedated
• To get numb

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Neuroadaptation alcohol

• High Depressed
• Sedated Anxious/sleepless
• Numb Anguish/pain

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Positive reinforcers

• Euphoria
• Sedation
• Anesthesia (numbing)

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Negative reinforcers

• Depression
• Anxiety
• Insomnia
• Boredom
• Loss of pleasure

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Neuroadaptation - Alcohol

• The brain on grain falls mainly in the pain.

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Neuroadaptation opioids

• To get high
• To get sedated
• To get numb

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Neuroadaptation - cocaine

• Cocaine addicts use cocaine
• To get high
• To get high
• To get high

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Neuroadaptation Cocaine

• High
• High
• High

• Depressed
• Depressed
• Depressed

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Cocaine and mood changes
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Opponent process theory
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Opponent process - heroin
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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

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Cocaine PET scan
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SPECT scan healthy brain top down and underside
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Heroin SPECT scans
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Alcohol
Intoxication
Sober 30 days
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Cannabis

• Prospective studies demonstrate increased risk
• Schizophrenia
• Major depressive disorder
• Anxiety disorders, including panic

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Volkow methamphetamine

• Persistent reductions in dopamine transport in
  striatum
• Long-term psychomotor impairment

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Methamphetamine
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MDMA Ecstacy

• Raves
• Neurotoxic to serotonin neurons
• Both animal model and now human findings

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Selective brain activation accompanies cocaine
craving
Neutral Edythe London
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Lateral prefrontal and visual cortex are
activated Edythe London
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Limbic regions are activated during cocaine
craving Edythe London
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Craving is correlated with activity in
orbitofrontal cortex Edythe London
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Conditioning

• Ivan Pavlov
• Conditioned dogs to salivate when they heard a
  bell
• 7-11

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Amygdala

• Emotional responses
• Filters all incoming sensations
• Identifies both high risk and high pleasure
  stimuli
• Very rapid response

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Limbic conditioning
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Brain organization
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Brain organization

• The right brain thinks with images, not words
• There is no DONT ELEPHANT in the right brain
• DONT ELEPHANT ELEPHANT!!

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Which step says Dont drink?

• None of them

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Medications

• Naltrexone (revia)
• Topiramate
• Acamprosate
• Methadone
• Buprenorphine
• Bupropion

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Antabuse (disulfiram)

• Can cause severe reactions
• Risks of hepatotoxicity, neuropathy
• Lack ofdouble-blind studies
• New use cocaine craving

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Methadone

• Abstinence rates 70-80
• Blocks craving
• Blocks euphoria
• Normalization of HPA axis
• Normalization of limbic function

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Methadone

• High rates of major depressive disorder and
  anxiety disorders
• Treatment research
• Tricyclic antidepressants, SSRIs and CBT
  effective
• Methadone supports treatment compliance over
  active using condition

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Buprenorphine/naloxone Suboxone

• Partial agonist pure antagonist
• t/2 gt24 hours
• Blocks craving and euphoria
• Less physical dependence
• Combo decreases diversion risk

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Suboxone

• DATA 2000 can be prescribed by office-based
  physicians
• DEA waiver
• 30 patient limit
• Adolescent/young adults
• September 2004 training

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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

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Revia - Naltrexone

• Pure opioid antagonist
• Effective in treatment of alcoholism and opiate
  addiction
• Blocks craving
• Blocks the high and increases the negatives

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Acamprosate - Campral

• NMDA receptor antagonist
• Blocks craving
• Doubles abstinence rates
• Additive with naltrexone

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Topiramate

• Anti-convulsant
• Anti-craving agent for alcohol, cocaine and
  cannabis
• Increases alcohol abstinence rates by 50
• Patients reports enhanced sense of well-being

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Zyban (bupropion)

• Antidepressant
• decreases craving
• decreases withdrawal
• can increase abstinence rates
• side effects GI, anxiety, headaches

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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

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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