Models of addiction: role of dopamine and other neurobiological substrates
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Transcript of Models of addiction: role of dopamine and other neurobiological substrates
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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
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Mesostriatal, mesolimbic and mesocortical dopamine pathways
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Dopamine is reward?
Hedonia
ReinforcementMotivation
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Direct action of psychostimulants on dopamine transmission
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Drugs of abuse increase extracellular dopamine
Di Chiara & Imperato, 1988
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Effects of cocaine on dopamine transmission measured with high temporal resolution
Cocaine
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Cocaine self administration
Start(0 min)
White noise
Cue light
Audiovisual cues
Cocaine delivery
Stop(120 min)
20 s
Lever-pressresponse
each operant response
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0 120 240 360 480 600Inter-lever-press interval (s)
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Lever-press responding for cocaine
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Dopamine increases during drug taking
0 120 240 360 480
100 nM
Time (s)
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Dopamine increases to cocaine-related cues
50 nM
2 s
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25 nM50 nM
Learned associations are required
*
-5 0 5 10
Time (s)
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Post-response encodes reward expectation
Mainten
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Extinc
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[DA
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Dopamine increases during drug taking
2 s
50 nM
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Dopamine increases during drug taking
2 s
50 nM
Phillips et al (2003) Nature 422, 614-8
Leverapproach
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Dopamine triggers cocaine seeking
0123
Control
0 120 240 360 480 600Inter-lever press interval (s)
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Stimulated
-60 -30 0 30 60Time (s)
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“Ectopic” dopamine triggers behavioral switching
100 nM
60 s
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Subsecond dopamine release promotesreward seeking…
Phillips et al (2003) Nature 422, 614-8
-60 -30 0 30 60Time (s)
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…but what does thistell us about addiction?
…but how is cost-benefit decision making being altered?• Cocaine feels better?
• Cocaine costs less?
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Decision making
costs
“desirability”
benefits
benefitsminuscosts
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Would you buy a hotdog for a dollar?
$1
2 1
+1
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Would you buy a hotdog for three dollars?
$3
2 3
-1
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$3
4 3
+1
Would you buy a steak for three dollars?
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What’s the alternative?
$3
2 3 0 0
-1 0
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Have I eaten today?
$3
2 3 0 2
-1 -2
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What about drugs?
1 0 0 0
+1 0
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Drugs feel really good but I get a hangover afterwards.
2 1 0 0
+1 0
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My friend got busted for drug possession
2 2 0 0
0 0
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I heard on the news that drugs are bad for me
2 3 0 0
-1 0
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My partner threatened to leave me if I used drugs
2 4 0 0
-2 0
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What happens to decision making during addiction?
2 3 0 0
-1 0
? ?
“Rational” decision maker Addict
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1. Drugs are really good
2 3 0 0
-1 0
+1 0
“Rational” decision maker Addict
4 3 0 0
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2. I don’t care about the consequences
2 3 0 0
-1 0
+1 0
“Rational” decision maker Addict
2 1 0 0
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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
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Opponency model of addiction
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Opponency (negative reinforcement) model of addiction
2 3 0 0
-1 0
-2 -4
“Rational” decision maker Addict
1 3 0 4
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Opponency model of addiction
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Incentive sensitization model of addiction
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Incentive sensitization model of addiction
2 3 0 0
-1 0
+1 0
“Rational” decision maker Addict
4 3 0 0
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Taste reactivity as a measure of hedonia/aversion
Berridge, 2000
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Taste reactivity as a measure of hedonia/aversion
Berridge, 2000
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Taste reactivity as a measure of hedonia/aversion
Berridge, 2000
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Taste reactivity is not altered after dopamine depletion
Berridge et al, 1989
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Cannon & Palmiter, 2003
Reward preference in the absence of dopamine
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Cannon & Palmiter, 2003
Reward preference in the absence of dopamine
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Nucleus accumbens dopamine lesions suppress responding for higher efforts
Salamone et al, 2003
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Zhang et al, 2003Salamone et al, 2003
Dopamine modulates cost-benefit analysis to acquire rewards
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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)
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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
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Loss of inhibitory control model of addiction
2 3 0 0
-1 0
+1 0
“Rational” decision maker Addict
2 1 0 0
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Baker et al, 2003
Glutamate levels are reduced in the nucleus accumbens following repeated cocaine exposure
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Baker et al, 2003
Restoration of glutamate levels in the nucleus accumbens prevents reinstatement of drug seeking
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Aberrant learning models of addiction
2 3 0 0
-1 0
+1 0
“Rational” decision maker Addict
4 3 0 0
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Habit model of addiction
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Habit model of addiction
Ito et al, 2002
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Rescorla-Wagner model for Pavlovian learning
Dayan & Abbott, 2001
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Dayan & Abbott, 2001
Temporal Difference (TD) learning
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Schultz et al, 1997
Dopamine neurons carry a reward prediction error signal
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McClure et al, 2003
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McClure et al, 2003
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McClure et al, 2003
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Temporal Difference (TD) learning in addiction
50 nM
2 s
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Aberrant learning models of addiction
2 3 0 0
-1 0
+1 0
“Rational” decision maker Addict
4 3 0 0