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 Reinforcement Motivation

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

Inter-lever-press interval (s) Number of lever presses Lever-press responding for cocaine

Dopamine increases during drug taking nM Time (s)

E (V vs Ag/AgCl) app Dopamine increases to cocaine-related cues 50 nM 2 s

25 nM 50 nM Learned associations are required * Time (s)

Post-response encodes reward expectation Maintenance Reinstatement ns * Extinction * [DA] (nM)

Dopamine increases during drug taking 2 s 50 nM

Dopamine increases during drug taking 2 s 50 nM Phillips et al (2003) Nature 422, Lever approach

Dopamine triggers cocaine seeking Control Inter-lever press interval (s) Number of lever presses * * * * * Stimulated Time (s) Number of lever presses Control * * * * * Stimulated

“Ectopic” dopamine triggers behavioral switching 100 nM 60 s

Subsecond dopamine release promotes reward seeking… Phillips et al (2003) Nature 422, Time (s) Number of lever presses Control * * * * * Stimulated …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 minus costs

Would you buy a hotdog for a dollar? $

Would you buy a hotdog for three dollars? $3 2 3

$ Would you buy a steak for three dollars?

What’s the alternative? $ 

Have I eaten today? $ 

What about drugs?  

Drugs feel really good but I get a hangover afterwards 

My friend got busted for drug possession  

I heard on the news that drugs are bad for me 

My partner threatened to leave me if I used drugs 

What happens to decision making during addiction?  ??  “Rational” decision makerAddict  

1. Drugs are really good  +10  “Rational” decision makerAddict 4300

2. I don’t care about the consequences  +10  “Rational” decision makerAddict 2100

3. It feels really bad if I don’t take drugs  -2  “Rational” decision makerAddict 2302

Opponency model of addiction

Opponency (negative reinforcement) model of addiction  -2-4  “Rational” decision makerAddict 1304

Opponency model of addiction

Incentive sensitization model of addiction

 +10  “Rational” decision makerAddict 4300

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, 2003 Salamone et al, 2003 Dopamine modulates cost-benefit analysis to acquire rewards

How does dopamine effect the decision-making process? D = desirability B = benefits C = costs D = B - C D = B - αC where 0 < α < 1 and α is a function of dopamine (high DA → low α)

Incentive sensitization model of addiction  2 – (⅓ x 3) = +10  “Rational” decision makerAddict 2100

Loss of inhibitory control model of addiction  +10  “Rational” decision makerAddict 2100

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  +10  “Rational” decision makerAddict 4300

Habit model of addiction

Ito et al, 2002

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

Temporal Difference (TD) learning

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

Berns et al, 2001

McClure et al, 2003

Temporal Difference (TD) learning in addiction 50 nM 2 s

Aberrant learning models of addiction  +10  “Rational” decision makerAddict 4300