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Models of addiction: role of dopamine and other neurobiological substrates Paul E. M. Phillips, 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 Mesostriatal, mesolimbic and mesocortical dopamine pathways

Dopamine is reward? Hedonia Motivation Reinforcement Dopamine is reward? Hedonia Motivation Reinforcement

Direct action of psychostimulants on dopamine transmission Direct action of psychostimulants on dopamine transmission

Drugs of abuse increase extracellular dopamine Di Chiara & Imperato, 1988 Drugs of abuse increase extracellular dopamine Di Chiara & Imperato, 1988

Effects of cocaine on dopamine transmission measured with high temporal resolution Cocaine Effects of cocaine on dopamine transmission measured with high temporal resolution Cocaine

Cocaine self administration each operant response Cocaine self administration each operant response

Lever-press responding for cocaine 2. 0 Number of lever presses 1. 8 1. 6 Lever-press responding for cocaine 2. 0 Number of lever presses 1. 8 1. 6 1. 4 1. 2 1. 0 0. 8 0. 6 0. 4 0. 2 0. 0 0 120 240 360 Inter-lever-press interval (s) 480 600

Dopamine increases during drug taking 100 n. M 0 120 240 Time (s) 360 Dopamine increases during drug taking 100 n. M 0 120 240 Time (s) 360 480

Dopamine increases to cocaine-related cues 50 n. M E (V vsapp Ag/Ag. Cl) 2 Dopamine increases to cocaine-related cues 50 n. M E (V vsapp Ag/Ag. Cl) 2 s

Learned associations are required * 50 n. M 25 -5 0 5 Time (s) Learned associations are required * 50 n. M 25 -5 0 5 Time (s) 10

Post-response encodes reward expectation ns * 100 50 t at em en io n Post-response encodes reward expectation ns * 100 50 t at em en io n R ei ns t in ct Ex t ai n te na nc e 0 M [DA] (n. M) 150 *

Dopamine increases during drug taking 50 n. M 2 s Dopamine increases during drug taking 50 n. M 2 s

Dopamine increases during drug taking 50 n. M Lever approach 2 s Phillips et Dopamine increases during drug taking 50 n. M Lever approach 2 s Phillips et al (2003) Nature 422, 614 -8

Dopamine triggers cocaine seeking * * * 6 5 4 * * 3 2 Dopamine triggers cocaine seeking * * * 6 5 4 * * 3 2 1 0 Stimulated 3 2 1 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 n. M 60 s “Ectopic” dopamine triggers behavioral switching 100 n. M 60 s

Number of lever presses Subsecond dopamine release promotes reward seeking… …but how is cost-benefit Number of lever presses Subsecond dopamine release promotes reward seeking… …but how is cost-benefit • Cocaine feels better? decision making being altered? * ** * * 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 minus costs “desirability” Decision making costs benefits minus costs “desirability”

Would you buy a hotdog for a dollar? $1 2 1 +1 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 hotdog for three dollars? $3 2 3 -1

Would you buy a steak for three dollars? $3 4 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 What’s the alternative? $3 2 3 0 0 -1 0

Have I eaten today? $3 2 3 0 2 -1 -2 Have I eaten today? $3 2 3 0 2 -1 -2

What about drugs? 1 0 +1 0 0 0 What about drugs? 1 0 +1 0 0 0

Drugs feel really good but I get a hangover afterwards. 2 1 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 My friend got busted for drug possession 2 2 0 0

I heard on the news that drugs are bad for me 2 3 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 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 Addict 2 3 0 What happens to decision making during addiction? “Rational” decision maker Addict 2 3 0 0 -1 0 ? ?

1. Drugs are really good “Rational” decision maker 2 3 0 0 Addict 4 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 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. 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 model of addiction

Opponency (negative reinforcement) model of addiction “Rational” decision maker 2 3 0 0 Addict 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 Opponency model of addiction

Incentive sensitization model of addiction Incentive sensitization model of addiction

Incentive sensitization model of addiction “Rational” decision maker 2 3 0 0 Addict 4 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 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 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

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 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, 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 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 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 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 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 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 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

Habit model of addiction Ito et al, 2002 Habit model of addiction Ito et al, 2002

Rescorla-Wagner model for Pavlovian learning Dayan & Abbott, 2001 Rescorla-Wagner model for Pavlovian learning Dayan & Abbott, 2001

Temporal Difference (TD) learning Dayan & Abbott, 2001 Temporal Difference (TD) learning Dayan & Abbott, 2001

Dopamine neurons carry a reward prediction error signal Schultz et al, 1997 Dopamine neurons carry a reward prediction error signal Schultz et al, 1997

Berns et al, 2001 Berns et al, 2001

Mc. Clure et al, 2003 Mc. Clure et al, 2003

Mc. Clure et al, 2003 Mc. Clure et al, 2003

Mc. Clure et al, 2003 Mc. Clure et al, 2003

Temporal Difference (TD) learning in addiction 50 n. M 2 s Temporal Difference (TD) learning in addiction 50 n. M 2 s

Aberrant learning models of addiction “Rational” decision maker 2 3 0 0 Addict 4 Aberrant learning models of addiction “Rational” decision maker 2 3 0 0 Addict 4 3 0 0 -1 0 +1 0