Neurocircuitry of Relapse

Circuitry Mediating Motivated Behavior

VTAdopamine

BasalGanglia

AnteriorCingulate

VentralOrbital

AmygdalaHippocampus

OpioidsEthanolTHCNicotine

OpioidsCocaineAmphetamines

DrugReward

Glutamate

PET/fMRI of Cocaine CravingChildress et al., 1999; Am.J.Psychiat

Self-administration of Cocaine

Rats Taking Cocaine

Dopamine

GABA

Glutamate

GABAPeptides

MOTORMEMORY

PrefrontalCortex

NucAccum

DrugSeeking

COKE

LIMBICPRIME

AmygdalaBasolateral

DopamineCells

DopamineCells

ExtendedAmygdala

CRF; NorepinephrineSTRESS

CUE

McFarland and Kalivas, JNeurosci, 2001; McFarland et al., JNeurosci, 2003, 2004

Role of Cortical Glutamate in Regulating Drug-Seeking Behavior

DrugSeeking

dPFCNA

core

RecordGlutamate

HereInhibit Here

Krista McFarland

Inhibition of the Dorsal PFC Blocks Cocaine-induced Glutamate Release in the Accumbens and Reinstatement

McFarland et al., J. Neuroscience, 2003

0

50

150

200

250

300

-120-90 -60 -30 0 30 60 90 120

Time (min)

**

***

*

Cocaine

Saline

Bac/Mus

0

20

40

60

80

100

120

140

160

180

200

220

Acti

ve L

ever

Pre

sses

Glu

tam

ate

(% c

han

ge)

100

Conclusion

The circuit mediating reinstatement of drug-seeking includes the glutamatergic projection from the prefrontal cortex to the nucleus accumbens.

Hypothesis

Changes in protein function in the projection from the prefrontal cortex to the nucleus accumbens are targets for developing drugs to treat addiction

Leap BetweenBehavior

and Proteins

Daily Cocaine Withdrawal

Ch

ange

in G

ene

Exp

ress

ion

3 Weeks

QuickTime™ and aTIFF (Uncompressed) decompressor

are needed to see this picture.

Drug Seeking

pfc

N. Acc

Cortico-accumbens PathologyDysregulated Glutamatergic Response to Motivational Stimuli

xCT

AGS3

N

C

AGS3 Structure/ Function

And Steve Lanier, LSU Med Ctr, New OrleansBowers et al., Neuron (2004)

Scott Bowers

AGS3 and Receptor - G Protein Coupling

GDP

GTP

Transmitter

G

Gi

GDP

EE

E SecondMessenger

AGS3

GDP

MetabotropicReceptor

C S SS C C

Accumbens core

AG

S-3

50

150

100

0

200

Repeated Saline

Repeated Cocaine

*

Withdrawal from CocaineIncreases AGS3 in PFC

and NAcore

GDP

GTP

Reversing Cocaine-induced Rise in AGS-3 in the PFC Prevents Reinstatement

Act

ive

Lev

er P

ress

es

0

50

100

150

200

Antisense In

0

50

100

150

200

0

50

100

150

200

0

50

100

150

200

0

50

100

150

200

0

50

100

150

200

Scrambled In

8

8

Pumpin

PumpOut

Self-admin

Extinction

ReinstateReinstate

Extinction

Antisense Out

Scrambled Out

* No effect on food reinstatement; 2nd antisense oligo also works

AS ASRn Rn

2 weeks

Conclusions

Cocaine withdrawal increases AGS3 and decreases Gi signaling in the PFC. Increased AGS3 partly underlies cocaine-primed reinstatement.

Hypothesis

AGS3 contributes to the dysregulation of prefrontal cortex in addiction.

Basal Extracellular Glutamate is Reduced in the Accumbens after Withdrawal From Cocaine

Pierce et al., J. Neuroscience, 1996

-10

-5

0

5

10[G

lu]i

- [

Glu

]o

0 2 4 6 8 10

[Glu]i

Cocaine (2.5 µM)

Saline (5.7 µM)

What Regulates Extracellular Glutamate Levels?Baker et al., J. Neuroscience, 2002

CaCaCaCa

CaCaCaCa

CaCaCaCa

G

G

GGG

G

GG

NeuronalVesicular Release

Calcium Dependent

Glial Release

G

G

GGG

G

GG

CaCaCaCa

G

G

GG

G

G

GG

G

G

GG

Glutamate Transport

G

G

GG

CC

C

CC

C

CC

CC

G

G

GG

G

G

GG

Cys/Glu Exchange

DaveBaker

N-acetylcysteine Blocks Reinstatement-induced Rise in Glutamate

0

20

40

60

80

100

120

Saline NAC

TestExtinction

*Act

ive

Lev

er P

ress

es

Glu

tam

ate

(pm

ol/s

amp

le)

0

20

40

60

80

100

120

-300 -240 -180 -120 -60 0 60 120

Time (min)

Saline

NAC

Cocaine

NACor

Saline

Baker et al., Nature Neuroscience, 2003

Effect of N-acetylcysteine is dose-related N-acetylcysteine does not alter food reinstatement or cocaine self-administration

mGluR2/3

PKAGlu

Glu

Glu

Glu

Glu

Cys

Glu

Cys/Glu exchanger

N-acetylcysteine (NAC):

NAC GSH Cys

1) Increases Cys/Glu exchange

3) Stimulates mGluR2/3 autoreceptors4) Inhibits synaptic glutamate release

2) Restores extracellular glutamate

pfc

N. Acc

RelapseCortico-accumbens Pathology

Drug AssociatedStimulus

Relapse toDrug-Seeking

N. Acc

pfc

Reduced PFC FunctionIncreased AGS3 (Bowers et al, Neuron, 2004)

Altered Accumbens FunctionReduced xCT (Baker et al., NatNeuro, 2003)Reduced Homer (Swanson et al., JNeurosci, 2001;Szumlinski et al., Neuron, 2004)Decreased Glutamate (Pierce et al., JNeurosci, 1996))