models of addiction: role of dopamine and other neurobiological substrates paul e. m. phillips,...
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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?
HedoniaHedonia
ReinforcementReinforcementMotivationMotivation
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
Start(0 min)
White noise
Cue light
Audiovisual cues
Cocaine delivery
Stop(120 min)
20 s
Lever-pressresponse
each operant response
0 120 240 360 480 600
Inter-lever-press interval (s)
0.0
0.2
0.4
0.6
0.8
1.0
1.2
1.4
1.6
1.8
2.0
Num
ber
of
leve
r pr
ess
es
0 60 120
Time (min)
Lever-press responding for cocaine
Dopamine increases during drug taking
0 120 240 360 480
100 nM
Time (s)
Dopamine increases to cocaine-related cues
50 nM
2 s
25 nM50 nM
Learned associations are required
*
-5 0 5 10
Time (s)
Post-response encodes reward expectation
Main
tena
nce
Reinsta
tem
ent
ns
*
Extinc
tion
*
0
50
100
150
[DA
] (n
M)
Dopamine increases during drug taking
2 s
50 nM
Dopamine increases during drug taking
2 s
50 nM
Phillips et al (2003) Nature 422, 614-8
Leverapproach
Dopamine triggers cocaine seeking
0
1
2
3
Control
0 120 240 360 480 600
Inter-lever press interval (s)
Num
ber
of
leve
r pr
ess
es
0
1
2
3
4
5
6***
**
Stimulated
-60 -30 0 30 60
Time (s)
Num
ber
of
leve
r pr
ess
es
0
1
2
3
Control
***
**
Stimulated0
1
2
3
4
5
6
“Ectopic” dopamine triggers behavioral switching
100 nM
60 s
Subsecond dopamine release promotes
reward seeking…
Phillips et al (2003) Nature 422, 614-8
-60 -30 0 30 60Time (s)
Num
ber
of
leve
r pr
ess
es
0123
Control
***
**
Stimulated0123456
…but what does this
tell us about addiction?
…but how is cost-benefit
decision making being altered?• Cocaine feels better?• Cocaine costs less?
Decision making
costs
“desirability”
benefits
benefitsminuscosts
Would you buy a hotdog for a dollar?
$1
2 1
+1
Would you buy a hotdog for three dollars?
$3
2 3
-1
$3
4 3
+1
Would you buy a steak for three dollars?
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 0 0
+1 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?
2 3 0 0
-1 0
? ?
“Rational” decision maker Addict
1. Drugs are really good
2 3 0 0
-1 0
+1 0
“Rational” decision maker Addict
4 3 0 0
2. I don’t care about the consequences
2 3 0 0
-1 0
+1 0
“Rational” decision maker Addict
2 1 0 0
3. It feels really bad if I don’t take drugs
2 3 0 0
-1 0
-1 -2
“Rational” decision maker Addict
2 3 0 2
Opponency model of addiction
Opponency (negative reinforcement) model of addiction
2 3 0 0
-1 0
-2 -4
“Rational” decision maker Addict
1 3 0 4
Opponency model of addiction
Incentive sensitization model of addiction
Incentive sensitization model of addiction
2 3 0 0
-1 0
+1 0
“Rational” decision maker Addict
4 3 0 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
Cannon & Palmiter, 2003
Reward preference in the absence of dopamine
Cannon & Palmiter, 2003
Reward preference in the absence of dopamine
Nucleus accumbens dopamine lesions suppress responding for higher efforts
Salamone et al, 2003
Zhang et al, 2003Salamone et al, 2003
Dopamine modulates cost-benefit analysis to acquire rewards
How does dopamine effect the decision-making process?
D = desirabilityB = benefitsC = costsD = B - C
D = B - αCwhere 0 < α < 1and α is a function of dopamine(high DA → low α)
Incentive sensitization model of addiction
2 3 0 0
-1 0
2 – (⅓ x 3) = +1 0
“Rational” decision maker Addict
2 1 0 0
Loss of inhibitory control model of addiction
2 3 0 0
-1 0
+1 0
“Rational” decision maker Addict
2 1 0 0
Baker et al, 2003
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
Aberrant learning models of addiction
2 3 0 0
-1 0
+1 0
“Rational” decision maker Addict
4 3 0 0
Habit model of addiction
Habit model of addiction
Ito et al, 2002
Rescorla-Wagner model for Pavlovian learning
Dayan & Abbott, 2001
Dayan & Abbott, 2001
Temporal Difference (TD) learning
Schultz et al, 1997
Dopamine neurons carry a reward prediction error signal
McClure et al, 2003
McClure et al, 2003
McClure et al, 2003
Temporal Difference (TD) learning in addiction
50 nM
2 s
Aberrant learning models of addiction
2 3 0 0
-1 0
+1 0
“Rational” decision maker Addict
4 3 0 0