Neurobiology of drug action andaddiction

Richard PalmiterDept Biochemistry

Substantia nigraVentral tegmental area

Nucleus accumbens

Prefrontal cortex

Hippocampus

The dopamine reward system

Wise (2002) Neuron

Striatum

Some dopamine circuit details

D1R

D2R

DA

GABAGABAAR

GABAAR

NAc

VTA

Drugs release dopamine

D1R

D2R

DA

NAcVTA

DA Cocaine, amphetamine

Morphine, heroin, nicotine

Ethanol ?

Animals like drugs that release dopamine

self administration

Animals like dopamineself stimulation

D1R

D2R

DA

NAcVTA

DA

Medial f orebrain bundle (MFB) passes through lateral hypothalamus

D1R

D2R

DA

NAcVTA

DA

Medial f orebrain bundle (MFB) passes through lateral hypothalamus

Glu

Dopamine help animals learn where important (salient) things happen

Animals like the effects of drugs

drugConditioned place preference

Animals learn to like the place where they experience the effects of drugs

Drugs usurp to dopamine system

Drugs have greatest effect when given in a novel environment

Voluntary drugadministration

Involuntary drugadministration

‘yoked situation’

Voluntary drug administration is more addictive than involuntary

administration

Chronic drug exposure changes the brain

Imagining the brain on

drugs

Volkow (2004) Nat Rev.

Is reduced D2R availability due to less receptor or more DA?

Robinson, TE (2004) D

ista

l sp

ines

Medium spiny neuron morphology in NAc changes

amphetamine

Drugs produce stable changes in the brain

What are these changes and do they explain addiction?

D1R

D2R

DA

NAcVTA

DA

cortex

glialcells

Glu

Glu

Glu R

•Morphological•Receptors•Signaling pathways•[Glutamate]

Glu

Drug-induced changes produce sensitization

loco

moti

on

PBS Drug

days 1 2 3 4 25

Sensitization reflects stable changesCross -sensitization

Presumably, when some of those drug-induced changes become large enough or persistent enough the associations between state and place become habitual

Which changes are addictive??

Are they reversible?

Hungry (stressed) animals will lever press more for drugs or electrical stimulation than fed animals

Bodily state influences drug-taking activity

How does stress enhance responding?

self administrationself administrationself administrationself administration

Lever

pre

sses

fed fasted

self administrationself administrationself administration self administrationself administrationself administration

salinedrug

Lever

pre

sses

training

extinction

cue

reinstatment

•Cue•Stress•Drug (i.v)

Reinstatement of drug taking activity

What happens during reinstatement?

Memories (associations) are recalled

•Long-term memories require protein synthesis•Memories become labile when recalled•Restoring memories requires protein synthesis again !!Could bad associations be

removed by blocking protein synthesis during recall (reinstatement)??

Alberini (2006) JN

Conditioned place preference for morphineremoved by blocking protein synthesis after recall

• Dopamine agonists are not addictive• Some drugs that release dopamine are not

addictive• Some aspects of reward learning are

intact in mice lacking dopamine• Mice with dopamine signaling restored to

dorsal striatum (not NAc) show normal appetitive behaviors

• Other neurotransmitters are involved

Problems with the VTA-dopamine hypothesis of addiction

Drugs release dopamine, but…

D1R

D2R

DA

NAcVTA

DA Cocaine, amphetamine

Morphine, heroin, nicotine

Dopamine receptor agonists are not drugs

Is dopamine action in nucleus accumbens critical for the

pleasurable effects of drugs and drug/place association ?

drugConditioned place preference

Animals learn to like the place where they experience the eff ects of drugs

drugConditioned place preference

Animals learn to like the place where they experience the eff ects of drugs

Mice without DA can learn CPP for morphine & cocaine

Mice without the cocaine receptor (DAT) can learn CPP for cocaineSerotoninHnasko (2005,2007) Nature, JN; Jones (2005) PNAS

drugConditioned place preference

Animals learn to like the place where they experience the eff ects of drugs

drugConditioned place preference

Animals learn to like the place where they experience the eff ects of drugs

Mice without norepinephrine do not learn CPP for morphine

Olson (2006) Science

Other neuromodulators are also required

Mice lacking mGlu5 do not show cocaine CPP

Drug taking does not necessarily lead to addiction

self administrationself administrationself administration self administrationself administrationself administrationsalinedrug

Lever

pre

sses

training

extinction

reinstatment

cue

•Cue•Stress•Drug (i.v)

Deroche-Gamonet..Piazza, 2004 Science

3 months

Hallmarks of Addiction

i. Subject has difficulty limiting drug intake

persistence

ii. Subject has high motivation to take drug

motivation

i. Subject continues to take drug despite adverse consequences

resistance

Many days of self administration, 5 days withdrawal, reinstatement with cocaine, then divide into groups based on response

40% lowest 40% highest40% lowest 40% highest

persistence resistance motivation

Piazza (2004)

Many days of self administration, 30 days withdrawal, reinstatement with cocaine or cue

cue

40% lowest 40% highest40% lowest 40% highest

very low doses Piazza (2004)

56 rats trained for a long time at self administration

Three tests: persistence, resistance, motivation Consider rats ranking in top 1/3rd of

group on each test: thus, individual rat could get score of 0, 1, 2 or 3

Piazza (2004)

Rat addiction as described here is:

•Requires long self-administration paradigm

•Independent of amount of cocaine delivered during training

•Independent of motor activity

•Vulnerability is function of individual

What are those individual differences???

Conclusions: