Neurobiology of Addiction (PowerPoint)

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					Neurobiology of Addiction
 Degrees of Substance Use
Occasional, controlled, or social use
Abuse or harmful use
Addiction
          Drug Addiction
A chronic relapsing syndrome that
moves from an impulse control
disorder involving positive
reinforcement to a compulsive disorder
involving negative reinforcement
      Why do people use?
Feel Good (Sensation Seeking)

Feel Better (Self Medication)
   What is driving addiction?
Positive Reinforcement - rewards that strengthen a
conditioned response after it has occurred, such as the
feeling of euphoria after taking a hit

Negative Reinforcement – stimuli (e.g., stress) that are
removed when the desired response (e.g., drug use) has
been obtained
– Escape conditioning - learning to escape an unpleasant or
  aversive stimulus (using drugs to reduce stress)
– Avoidance conditioning – Learning to avoid an aversive stimulus
  (e.g., stress) before it occurs (e.g., using drugs before going to a
  stressful mtg)
  A Major Reason People
 Take a Drug is They Like
What it Does to Their Brains
Positive Reinforcement

      ―Go!‖ System
PET/fMRI of Cocaine Craving
      Childress et al., 1999; Am.J.Psychiat
      Cocaine Cue Reactivity
Drug Cues can trigger a strong, affect-positive
state of drug desire (GO!)
Cues can be used to study brain substrates of
―GO!‖ in the imaging setting
Brain substrates: Limbic Activation
–   Anterior cingulate
–   Amygdala
–   Insula
–   Ventral Striatum (NAc)
–   Orbitofrontal Cortex
Same processes present in…
Opiates – heroin craving correlated with
inferior frontal lobe, prefrontal cortex,
insula
Nicotine – smoking videos correlated with
OFC, insula, anterior cingulate, DLPFC
Sex – arousal correlated with anterior
cingulate, mPFC, OFC, insular, amygdala,
ventral striatum
But ―GO!‖ isn‘t the whole story…
            STOP System
Frontal Lobes
– Critical for good decision making, disinhibition

– Lower activity (blood flow and glucose metabolism)
  in cocaine users

– Less concentrated gray matter (fewer nerve cells) in
  cocaine users and alcoholics

– Unclear if cause or consequence, yet children
  w/ADHD and CD have poor frontal lobe functioning
 Neurotransmitters - the Big Two:

Serotonin: mood, emotion, sleep and appetite
Dopamine: pleasure and elation
                         Natural Rewards Elevate Dopamine
                            FOOD
                                      Levels    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                                        Scr
                                                                                                          Scr                            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
                                           Effects of Drugs on Dopamine Levels
                     1100                           Accumbens      AMPHETAMINE                                                            Accumbens
                                                                                                                                                            COCAINE
                     1000                                                                                                  400
% of Basal Release




                                                                                                    % of Basal Release
                      900
                      800                                                                                                                                          DA
                                                                                 DA                                        300                                     DOPAC
                      700                                                        DOPAC                                                                             HVA
                      600                                                        HVA
                      500                                                                                                  200
                      400
                      300
                      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
                                                                        NICOTINE                                                    250   Accumbens          MORPHINE
                     % of Basal Release




                                                                                                               % of Basal Release
                                                                                                                                                                    Dose (mg/kg)
                                          200                              Accumbens
                                                                                                                                    200                                   0.5
                                                                           Caudate                                                                                        1.0
                                          150                                                                                                                             2.5
                                                                                                                                    150                                   10
                                          100
                                                                                                                                    100


                                           0
                                                0         1        2      3 hr                                                       0
                                                                                                                                          0    1      2       3      4      5hr
                                                        Time After Nicotine                                                                        Time After Morphine
                                                                                 Source: Di Chiara and Imperato
 Prolonged Drug Use Changes
The Brain In Fundamental and
      Long-Lasting Ways
Dopamine Transporters in Methamphetamine Abusers

                                                    2.4

                                                    2.2




                            Dopamine Transporters
                                                    2.0




                                 (Bmax/Kd)
                                                    1.8
   Normal Control                                   1.6

                                                    1.4

                                                    1.2

                                                    1.0
                                                          Normal          Meth
                                                          Controls       Abusers

Methamphetamine Abuser                                           p < 0.0002

  Methamphetamine abusers have significant reductions in dopamine
  transporters.                                    BNL - UCLA - SUNY
                                                                      NIDA - ONDCP - DOE
Dopamine Transporters in Methamphetamine Abusers


                         2.0
                                                          Motor Task
                         1.8                         Loss of dopamine transporters
                         1.6                         in the meth abusers may result
  Dopamine Transporter




                         1.4                         in slowing of motor reactions.
                         1.2
     Bmax/Kd




                         1.07   8   9 10 11 12 13
                                    Time Gait
                                    (seconds)

                         2.0
                         1.8
                                                          Memory Task
                         1.6                         Loss of dopamine transporters
                         1.4                         in the meth abusers may result
                         1.2                         in memory impairment.
                         1.0
                           16 14 12 10 8 6       4
                                  Delayed Recall
                                (words remembered)
                                                                       BNL/UCLA/SUNY
                                                                      NIDA, ONDCP, DOE
        Normal




 Cocaine Abuser (10 Days)




Cocaine Abuser (100 Days)
  Implications – Down Regulation
Immediate effect of drug use is an increase
in dopamine or NT‘s
Continued use of drugs reduces the brain’s
dopamine (or NT) production
Because dopamine is part of the reward
system, the brain is ―fooled‖ that the drug
has survival value for the organism
The reward system responds with ―drug
seeking behaviors‖
National Institute on Drug Abuse, 2002; Monkey Brain
Volkow
http://switchboard.real.com/player/email.ht
ml?PV=6.0.12&&title=CMHC&link=http%3
A%2F%2Fmedia.med.yale.edu%3A8080
%2Framgen%2Fpsych%2Flectures%2Fc
mhc3%5F5%5F04.rm
Negative Reinforcement

   Transition to Addiction
   Oponent-process Model
‗a‘ process – unconditional response –
positive mood state

‗b‘ process – unconditional,
counteradaptive negative opposite
response – negative mood state
   Brain Dysregulation in Addiction
    (CNS activity, mood, behavior)
Normal




Addicted

    Koob & LeMoal, Neurobiology of Addiction, 2006
Allostasis: maintaining stability (or
homeostasis) through change
Allostatic Load: the wear and tear that the
body experiences due to repeated cycles
of allostasis as well as the inefficient
turning-on or shutting off of these
responses
                  Definitions
Extended Amygdala — Forebrain macrostructure
composed of central medial amygdala, bed nucleus of
the stria terminalis (BNST), and a transition zone in the
medial part of the nucleus accumbens. A rich substrate
for neurochemical and neurocircuitry interactions that
produce the ―dark side‖ of motivation.

Corticotropin-Releasing Factor — 41 amino acid
polypeptide ―brain stress‖ neurotransmitter that controls
hormonal, sympathetic, and behavioral responses to
stressors
Neurochemical Changes in the Extended Amygdala
     during the Development of Dependence:
      Implications for Emotional Processing
Major neurocircuits underlying addiction
  1.   Acute reinforcing effects of drugs
         Activation of extended amygdala system, ventral tegmental
         area, arcuate nucleus, ventral striatal-ventral pallidal thalamic
         cortical loops

  2.   Acute withdrawal, negative affect, anxiety
         Decrease function in extended amygdala reward system
         Increase in brain stress neurocircuitry

  3.   Preoccupation/anticipation/craving
         Increase activity in extended amygdala (prefrontal cortex &
         basolateral amygdala)

  4.   Transition to addiction
         Positive reinforcement –  extended amygdala
         Negative reinforcement -  stress neurocircuits
          Neurochemical Changes Associated with the
           Transition from Drug Use to Dependence




From: Roberts AJ and Koob GF, Alcohol: ethanol antagonists/amethystic agents. in Adelman G and Smith BH (Eds.),
      Encyclopedia of Neuroscience, 3rd edn, Elsevier, New York, 2003 [http://203.200.24.140:8080/Neuroscience].
 How can we measure
negative reinforcement?
          Distress Tolerance
Definition: An individuals‘ ability to persist in goal
directed activity when experiencing affective
distress
Tools for measuring negative reinforcement
behavior
• Paced Auditory Serial Addition Task (PASAT-C)
• Mirror Tracing Persistence Task (MTPT-C)
For the sequence 2, 5,13, 6, 3, 12
Correct answers are 7, 18, 19, 9, 15                 Score

                                                          0

                             2
         1   2    3    4    5    6    7    8    9    10


        11   12   13   14   15   16   17   18   19   20
For the sequence 2, 5,13, 6, 3, 12
Correct answers are 7, 18, 19, 9, 15                 Score

                                                          1

                             5
         1   2    3    4    5    6    7    8    9    10


        11   12   13   14   15   16   17   18   19   20
For the sequence 2, 5,13, 6, 3, 12
Correct answers are 7, 18, 19, 9, 15                 Score

                                                          2

                            13
         1   2    3    4    5    6    7    8    9    10


        11   12   13   14   15   16   17   18   19   20
For the sequence 2, 5,13, 6, 3, 12
Correct answers are 7, 18, 19, 9, 15                 Score

                                                          3

                             6
         1   2    3    4    5    6    7    8    9    10


        11   12   13   14   15   16   17   18   19   20
For the sequence 2, 5,13, 6, 3, 12
Correct answers are 7, 18, 19, 9, 15                 Score

                                                          3

                             3
         1   2    3    4    5    6    7    8    9    10


        11   12   13   14   15   16   17   18   19   20
For the sequence 2, 5,13, 6, 3, 12
Correct answers are 7, 18, 19, 9, 15                 Score

                                                          3

                            12
         1   2    3    4    5    6    7    8    9    10


        11   12   13   14   15   16   17   18   19   20
                                             Score

                                                  3

                    12
1    2    3    4    5    6    7    8    9    10


11   12   13   14   15   16   17   18   19   20




                    Quit
Level 1 (Warm up – 3 minutes)
– 5 second latency between number presentations
– Latency titrated based upon performance

Level 2 (Measurement Level – 5 minutes)
– Average latency of Level 1 for first 4 minutes
– Last minute extremely difficult (Latency ½ of first 4 minutes)

Level 3 (Quit Option – up to 5 minutes)
– Latency equivalent to last minute of Level 2
– Continues to be extremely difficult
– Participant can quit at any time

Negative Affect Scale completed pre and post
Distress Tolerance can be measured continuously or
dichotomously as ‗Quit‘ or ‗Persist‘
   Mirror Tracing Persistence Task
• Trace circle across star
• All movements reversed
• If center of circle goes
out of line or stops for
500ms buzz and restart

• Clearly impossible, but will
last for 300 seconds

• Participants have
termination option –
termination latency is DV
Low distress tolerance significantly related to:

  Increased frequency of substance use
   (Quinn, Brandon, & Copeland, 1996)
  Shorter durations of smoking, gambling, and illicit
  drug use abstinence attempts
   (Brown, Lejuez, Kahler, & Strong, 2002; Daughters, Lejuez,
    Strong, et al., 2005; Daughters, Lejuez, Kahler et al.,
    2005)
  Increased rates of smoking treatment failure
   (Brandon et al., 2003)
  Increased rates of dropout from substance abuse
  treatment
  (Daughters, Lejuez, Bornovalova, et al., 2005)
Distress Tolerance Paradigm
Elicits real-time distress in the context of
goal directed activity
Repeatedly demonstrated a relationship
with a number of ―real-world‖ substance
abuse outcomes
Allows for the study of one‘s behavioral
response to distress (i.e. quitting the task)
during the experimental procedure
              Study Overview
Purpose
• Collect pilot data on the neural indices of
  distress tolerance using fMRI (n = 25)
• Examine the relationship between neural
  indices and important physiological,
  biological, and genetic correlates
      HPA Axis reactivity
      Genetic indicators
      Galvanic skin response
      Heart rate
               PASAT for fMRI

               Score                       Score

3, 4             2        4, 9
                                             2


           4                          9
       2   6                     6    11


       8   7                     13   14
          Latency Test     Relaxation
              3 Min            60s




Control   Anticipation          Distress
                                           Relaxation
 Level      Period               Level                  X8
                                               60s
  60s         15s                 60s




                     Distress
                    Tolerance
                    5 min max
            Questions
So…is addiction a Choice or disease?

How does someone become an ‗addict?‘
How can we treat addiction?

				
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