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The Neurobiology of Drug Addiction - CASAT

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					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                                                                                          82%

                                        Cancer                                                                                     78%

                                  Drunk driving                                                                                   75%

                                   Heart disease                                                                                 74%

                                      HIV/AIDS                                                                                   73%

                                       Violence                                                                             71%

                                    Child abuse                                                                           69%

                                       Smoking                                                                           68%

                                   Alcohol abuse                                                                      65%

                                          Stress                                                                      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                     hippocampus
  cortex


                                        substantia
                                        nigra/VTA
Functions
•reward (motivation)                                Serotonin Pathways
•pleasure,euphoria     nucleus
                       accumbens                      Functions
•motor function
 (fine tuning)                              raphe     •mood
•compulsion                                           •memory
•perserveration                                        processing
•decision making
                                                      •sleep
Neuronal structure

             (receiving)




                           (sending)
                 vesicle                Neuronal terminal
stimulation                   Drug :
                              • cocaine    transporter
                              • ritalin
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)
                                                Effects of Drugs on Dopamine Release
                     1100                           Accumbens        AMPHETAMINE                                                         Accumbens
                                                                                                                                                                 COCAINE
                     1000                                                                                                          400
% of Basal Release




                                                                                                              % of Basal Release
                      900
                      800                                          Much greater                                                                                           DA
                                                                                DA                                                 300                                    DOPAC
                      700                                                        any
                                                                   Activity thanDOPAC                                                                                     HVA
                      600                                                       HVA
                      500                                          Other drug of abuse                                             200
                      400
                      300
                                                                   -causes neurotoxicity
                      200                                                                                                          100
                      100
                         0
                                                    0         1      2       3       4       5 hr                                   0
                                                                                                                                         0       1       2        3      4          5 hr
                                                              Time After Amphetamine                                                                  Time After Cocaine

                                          250                                                                                      250
                                                                          NICOTINE                                                       Accumbens               ETHANOL
                     % of Basal Release




                                          200                                   Accumbens                                                                           Dose (g/kg ip)




                                                                                                          % of Basal Release
                                                                                                                                   200
                                                                                Caudate
                                                                                                                                                                             0.25
                                          150                                                                                                                                0.5
                                                                                                                                                                             1
                                                                                                                                   150                                       2.5
                                          100


                                                                                                                                   100
                                           0
                                                0         1          2        3 hr                                                   0
                                                                                                                                             0       1        2       3        4hr
                                                        Time After Nicotine                                                                          Time After Ethanol
                                                                                     Source: Di Chiara and Imperato
                       Natural Rewards Elevate Dopamine Levels
                                     FOOD                                                                                        SEX




                                                                       DA Concentration (% Baseline)
                       200                                                                             200
                                                   NAc shell
% of Basal DA Output




                       150                                                                             150




                                                                                                                                                                           Copulation Frequency
                       100                                                                             100
                                                                                                                                                                      15

                             Empty                                                                                                                                    10
                       50
                                 Box Feeding
                                                                                                                                                                      5

                        0                                                                                                                                             0
                             0          60          120          180                                     ScrScr                            Scr   Scr
                                                                                                         BasFemale 1 Present                       Female 2 Present
                                          Time (min)                   Sample 1 2 3 4 5                                  6 7 8         9 10 11 12 13 14 15 16 17
                                                                       Number
                                                                                                                                 Mounts
                                                                                                                                 Intromissions
                                                                                                                                 Ejaculations

                                      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          PFC
                CONTROL             ACG
                             OFC                 Hipp
                                   SCC
                                         NAcc         REWARD
                 MOTIVATION/                     VP

                    DRIVE                Amyg
                                                MEMORY/
                   (saliency)                   LEARNING
HOW DOES ADDICTION
   OCCUR?
      • Principles of Behavior Dynamics

          Behavior Tracts Compete for Expression

Prefrontal                             A
Cortex                                       behavior
                                       B     expressed   C
                                                         B
                                      C
                              dopamine initiated
Orbito-
frontal cortex

 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)
      • Principles of Behavior Dynamics


                                     C
Prefrontal
                                     A
                                       Addiction
Cortex                                 B
                                    BB behavior
                                    B expressed    B

Orbito-
frontal 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
                             DAT
                       Interference recall                                                                 Delayed recall
                  15                                                                              15
Number of words




                                                                                Number of words
                  12                                                                              12

                   9                                                                               9

                   6
                       Compromises Cognitive Functions
                                             6

                   3
                                               R = 0.70                                            3                      R = 0.64
                                               p < 0.005                                                                  p < 0.01
                   0                                                                               0
                       1    1.2      1.4      1.6      1.8      2                                      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




                                   treated
Alcohol

                                             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




                                                                  22
                                                             17




                        5       6          3 samples, > 2 labs
                                    r-SA   4 samples, > 3 labs

                        r-candidate        >2 samples, >2 labs
  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?
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                               Subordinate

                                                                    Dominant
                                  0.0

                                        .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       Schizophrenia, paranoia,
                                  anhedonia, compulsive
                                  behavior

Stimulants                       Anxiety, panic attacks,
                                  mania and sleep disorders

LSD, Ecstasy & psychedelics      Delusions and hallucinations

 Alcohol, sedatives, sleepaids    Depression and mood
  & narcotics                      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
                         Serotonin/dopamine synaptic
                                  terminal
                                    transporter
Synaptic vesicle                          Prozac,
                                          Ritalin, &
                                          Cocaine
                                          block




                                             Postsynaptic
                                             target


                               Causes an effect
         Activate transmitter receptors
 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
        Double
Have a Double Brain Disease

              Comorbid
              Disorders
    Mental                Addictive
   Disorder               Disorder
Role of Stress and Trauma
            The Stress Hormone Cycle

                                  Hypothalamus

                              CRF            Stress Responses
                                              Stress Responses
                Pituitary
                 Gland
                                               Stress Responses
                                                Stress Responses
                ACTH
                                         CORTISOL
                            Adrenal
                            Glands
CRF:
Corticotropin
Releasing
Factor
                            Kidneys
       Anxiety        DRUG USE
                     (Self-Medication)



CRF
      What Role Does Stress Play             CRF
       In Initiating Drug Use?


STRESS                                   Anxiety
                     Anxiety   RELAPSE

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




        Abstinence
Stress Reliably Reinstates Drug Seeking in Rats
                                                                                                *
                    Cocaine-trained rats                                 Alcohol-trained rats
              100
  Responses


               80        Inactive Lever
              60         Active Lever
                                                *
              40                   *
              20                                                                        *
               0
                    Saline   Cocaine Footshock                         Water Alcohol Footshock

                    Nicotine-trained rats                               Heroin-trained rats         *
              100
  Responses




               80
               60                                                                        *
                                   *                *
               40
               20
                0
                    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
Responses (1 hr)




                                                    Responses (3 hr)
                   45                                                  45                                Intermittent Footshock

                                                                                         *
                   30                                                  30                     *
                                            *                                                                  *
                                                                                                                      *
                   15                                                  15


                   0                                                   0
                          0      15      30                                    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                             A
Cortex                                       behavior
                                       B     expressed   B
                                                         C
                                      C
                              dopamine initiated
Orbito-
frontal cortex
• 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                             A
Cortex                                       behavior
                                       B     expressed   B
                                                         C
                                      C
                              dopamine initiated
Orbito-
frontal cortex
•Alter function of orbitofrontal
     (saliency) cortex

  motivational therapy

     family therapies
      • Principles of Behavior Dynamics




Prefrontal                             A
Cortex                                       behavior
                                       B     expressed   B
                                                         C
                                      C
                              dopamine initiated
Orbito-
frontal cortex
• Recovery of function (frontal and obito-
      frontal cortex)

   all treatments that keep brain away
     from drugs for extended time
      • Principles of Behavior Dynamics




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

				
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