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Models of addiction:
role of dopamine and other neurobiological substrates
Paul E. M. Phillips, Ph.D.
Department of Psychiatry and Behavioral Sciences
Department of Pharmacology
Mesostriatal, mesolimbic and mesocortical dopamine pathways
Dopamine is reward?
Hedonia
Motivation
Reinforcement
Direct action of psychostimulants on dopamine transmission
Drugs of abuse increase extracellular dopamine
Di Chiara & Imperato, 1988
Effects of cocaine on dopamine transmission measured with high temporal
resolution
Cocaine
Cocaine self administration
each operant response
Start
(0 min)
20 s
White noise
Cue light
Audiovisual cues
Cocaine delivery
Lever-press
response
Stop
(120 min)
Lever-press responding for cocaine
2.0
Number of lever presses
1.8
1.6
1.4
1.2
1.0
0.8
0
60
0.6
120
Time (min)
0.4
0.2
0.0
0
120
240
360
Inter-lever-press interval (s)
480
600
Dopamine increases during drug taking
100 nM
0
120
240
Time (s)
360
480
Dopamine increases to cocaine-related cues
50 nM
E (V vsapp
Ag/AgCl)
2s
Learned associations are required
*
50
25 nM
-5
0
5
Time (s)
10
Post-response encodes reward expectation
ns
[DA] (nM)
150
100
50
0
*
*
Dopamine increases during drug taking
50 nM
2s
Dopamine increases during drug taking
50 nM
Lever
approach
2s
Phillips et al (2003) Nature 422, 614-8
Dopamine triggers cocaine seeking
*
*
*
6
5
4
*
*
3
2
1
0
Stimulated
3
2
1
Number of lever presses
Number of lever presses
5
4
*
**
*
*
6
3
2
1
0
Stimulated
3
2
1
0
Control
0
120
240
360
480
600
Inter-lever press interval (s)
0
Control
-60
-30
0
Time (s)
30
60
“Ectopic” dopamine triggers behavioral switching
100 nM
60 s
Number of lever presses
Subsecond dopamine release promotes
reward seeking…
…but how is cost-benefit
• Cocaine
feelsaltered?
better?
decision making
being
**
**
*
6
5
4
3
2
1
0
• Cocaine costs less?
Stimulated
3
2
1
0
Control
-60
-30
0
30
Time (s)
60
Phillips et al (2003) Nature 422, 614-8
…but what does this
tell us about addiction?
Decision making
costs
benefits
benefits
minus
costs
“desirability”
Would you buy a hotdog for a dollar?
$1
2
1
+1
Would you buy a hotdog for three dollars?
$3
2
3
-1
Would you buy a steak for three dollars?
$3
4
3
+1
What’s the alternative?
$3
2
3
0
0
-1
0


Have I eaten today?
$3
2
3
0
2
-1
-2


What about drugs?

1
0
+1

0
0
0

Drugs feel really good but I get a hangover afterwards.
2
1
0
0
+1
0


My friend got busted for drug possession
2
2
0
0
0
0


I heard on the news that drugs are bad for me
2
3
0
0
-1
0


My partner threatened to leave me if I used drugs
2
4
0
0
-2
0


What happens to decision making during addiction?
“Rational” decision maker
2
3
0
Addict


0
-1
0
?
?




1. Drugs are really good
“Rational” decision maker
2
3
0
0
Addict
4
3
0
0
-1
0
+1
0




2. I don’t care about the consequences
“Rational” decision maker
2
3
0
0
Addict
2
1
0
0
-1
0
+1
0




3. It feels really bad if I don’t take drugs
“Rational” decision maker
2
3
0
0
Addict
2
3
0
2
-1
0
-1
-2




Opponency model of addiction
Opponency (negative reinforcement) model of addiction
“Rational” decision maker
2
3
0
0
Addict
1
3
0
4
-1
0
-2
-4




Opponency model of addiction
Incentive sensitization model of addiction
Incentive sensitization model of addiction
“Rational” decision maker
2
3
0
0
Addict
4
3
0
0
-1
0
+1
0




Taste reactivity as a measure of hedonia/aversion
Berridge, 2000
Taste reactivity as a measure of hedonia/aversion
Berridge, 2000
Taste reactivity as a measure of hedonia/aversion
Berridge, 2000
Taste reactivity is not altered after dopamine depletion
Berridge et al, 1989
Reward preference in the absence of dopamine
Cannon & Palmiter, 2003
Reward preference in the absence of dopamine
Cannon & Palmiter, 2003
Nucleus accumbens dopamine lesions suppress responding for
higher efforts
Salamone et al, 2003
Dopamine modulates cost-benefit analysis to acquire rewards
Salamone et al, 2003
Zhang et al, 2003
How does dopamine effect the decision-making process?
D=B-C
D = B - αC
D = desirability
B = benefits
C = costs
where 0 < α < 1
and α is a function of dopamine
(high DA → low α)
Incentive sensitization model of addiction
“Rational” decision maker
2
3
0
0
Addict
2
1
0
0
-1
0
2 – (⅓ x 3) = +1
0




Loss of inhibitory control model of addiction
“Rational” decision maker
2
3
0
0
Addict
2
1
0
0
-1
0
+1
0




Glutamate levels are reduced in the nucleus accumbens following repeated cocaine
exposure
Baker et al, 2003
Restoration of glutamate levels in the nucleus accumbens prevents reinstatement of
drug seeking
Baker et al, 2003
Aberrant learning models of addiction
“Rational” decision maker
2
3
0
0
Addict
4
3
0
0
-1
0
+1
0




Habit model of addiction
Habit model of addiction
Ito et al, 2002
Rescorla-Wagner model for Pavlovian learning
Dayan & Abbott, 2001
Temporal Difference (TD) learning
Dayan & Abbott, 2001
Dopamine neurons carry a reward prediction error signal
Schultz et al, 1997
Berns et al, 2001
McClure et al, 2003
McClure et al, 2003
McClure et al, 2003
Temporal Difference (TD) learning in addiction
50 nM
2s
Aberrant learning models of addiction
“Rational” decision maker
2
3
0
0
Addict
4
3
0
0
-1
0
+1
0




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