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Neurocircuitry of Relapse. Opioids Cocaine Amphetamines. Anterior Cingulate. Drug Reward. Basal Ganglia. Opioids Ethanol THC Nicotine. Ventral Orbital. VTA dopamine. Glutamate. Amygdala Hippocampus. Circuitry Mediating Motivated Behavior. - PowerPoint PPT Presentation
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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))