yavin m. shaham, ph.d. behavioral neuroscience branch irp/nida/nih/dhhs, baltimore
DESCRIPTION
Role of VTA Glutamate in Contextual Cue-Induced Relapse to Heroin-Seeking. Yavin M. Shaham, Ph.D. Behavioral Neuroscience Branch IRP/NIDA/NIH/DHHS, Baltimore. Outline Role of VTA glutamate in context-induced relapse to heroin seeking - PowerPoint PPT PresentationTRANSCRIPT
Yavin M. Shaham, Ph.D.Behavioral Neuroscience BranchIRP/NIDA/NIH/DHHS, Baltimore
Role of VTA Glutamate in Contextual Cue-Induced Relapse to Heroin-Seeking
Outline
• Role of VTA glutamate in context-induced relapse to heroin seeking
• Role of central amygdala ERK signaling pathway and glutamate in incubation of cocaine craving
The reinstatement model of drug relapse
Drug primingDrug cuesStressR
esp
onse
s
Self-administration training Extinction TESTING
Drug is available Drug is NOT available
Active lever
Inactive lever
Reinstatement studies(1971-2004)
3 4 10 13
20
93
265
0
50
100
150
200
250
300
70 75 80 85 90 95 00 04
Year
cum
ula
tive #
Role of VTA glutamate in context-induced relapse to heroin seeking
Systemic injections of mGluR2/3 agonists attenuate:
Opiate withdrawal symptoms (Vandergriff and Rasmussen, 1999)
Amphetamine-induced locomotor sensitization (Vezina, 2004)
Discriminative cue-induced reinstatement of cocaine seeking (Baptista et al., 2004)
Dr. Jennifer Bossert
Intra-VTA injections of ionotropic glutamate receptor antagonists attenuate:
Morphine and cocaine place preference (Harris et al. 2003; Byrne et al. 2003)
Reinstatement of cocaine seeking induced by ventral subiculum stimulation (Vorel et al. 2001) or stress (Wang et al. SFN. 2004)
Also: Over-expression of VTA GluR1 enhances morphine place preference (Carlezon et al. 1997)
From Schoepp. JPET 2001
LY379268 a selective agonist of mGluR2/3 receptors
Types of relapse-provoking drug cues in humans and laboratory animals
• Humans: Two major types of cues that provoke relapse after abstinence:
Discrete cues (e.g., drug paraphernalia) that predict drug effects
Contextual cues (e.g., street corner, bar) that predict drug availability
• Laboratory animals: Two types of cues that provoke relapse to drug seeking after extinction of the operant responding in their absence:
Discrete cues (e.g., tone, light) paired with drug injections
Discriminative cues (e.g., specific odors) that become predictors of drug availability after discrimination training
• Research question: Can we study the role of the drug context in reinstatement of drug seeking after extinction of the operant responding in the presence of the discrete cues (an animal model of the cue exposure treatment method)?
• This issue can be addressed using a “renewal” procedure, commonly used to study the role of the environmental context in the resumption of conditioned fear responses to discrete cues after extinction (Bouton & Bolles 1979)
A “renewal” procedure to study the effect of contextual drug cues on drug seeking
Crombag & Shaham. Behavioral Neuroscience, 2002
Reinstatement test
Renewal
Novel
Control (1+2)*
NovelControlRenewal
0
25
50
75
100
125Extinction
5 10 15 20
Session1
Resp
onse
s (2
h)
Differences between contexts A and B:--type of grid floor --background noise --illumination level--type of odor
Control 1
Renewal
Novel
Control 2
Training (10 d)
Extinction (20 d)
Test (1 d)
Context A Context B
Context A
Context A Context B
Context A Context A
Context A
Context B
Context B
Context A
Context A
Context A
Reinstatement of heroin seeking by contextual drug cues
Control 1
Renewal
Novel
Control 2
Training (12 d)
Extinction (12-20 d)
Test (1 d)
Context A Context B
Context A
Context A Context B
Context A Context A
Context A
Context B
Context B
Context A
Context A
Context A Context ANo Extinction
Differences between contexts A and B:--Time of day (circadian cues)--Type of grid floor (tactile)--Background noise (auditory)--Distinct chamber cues--Illumination level (visual cues)
**
Control (1&2) Novel
RenewalNo
Extinction
Reinstatement test
0
15
30
45
60
75
1 2 3 4 5 6 7 8 9 10 1112
Extinction day
Resp
onse
s (1
h)
Same context
Different context
Extinction
Effects of systemic or intra-VTA injections of an mGluR2/3 agonist on context-induced reinstatement
of heroin seekingSystemic LY379268
0
15
30
45
60
75
Extinction(Context B)
Training(Context A)
Resp
onse
s (3
h) Vehicle
1 mg/kg3 mg/kg *
*
**
Intra-VTA LY379268
Vehicle0.3 µg
1.0 µg
Extinction(Context B)
Training(Context A)
VTA
Bossert et al. The Journal of Neuroscience, in press
Control experiments
SN
Lever presses for a 5% sucrose solution
0
25
50
75
100
0 1 3 6LY379268 dose
(mg/kg, i.p)
Rew
ard
s (3
0 m
in)
*
01530456075
Resp
onse
s (3
h)
Vehicle1.0 µg
Extinction(Context B)
Training(Context A)
Intra-substantia nigra LY379268
Conclusions and implications
As in the case of relapse to anxiety-related disorders (Bouton 2002), the role of the environmental context in drug relapse can be studied in laboratory rats using the renewal procedure
Glutamate transmission in the VTA plays an important role in context-induced relapse to heroin seeking
The present data and those from previous studies (see Baptista et al. 2004) suggest that mGluR2/3 agonists and other drugs that target metabotropic glutamate receptors (see Kenny & Markou 2004) should be considered in the treatment of drug relapse
A key regulator of synaptic plasticity and learning and memory (Sweatt 2001)
Amygdala ERK is involved in conditioned fear responses (Schaffe et al. 2000)
Mesolimbic ERK is activated by cocaine (Licata and Pierce 2003; Valjent et al. 2000)
ERK
MEK
Raf
U0126
NMDA receptor
NMDA/AP-5
From Thomas and Huganir. Nature Neuroscience, 2004
ERK (extracellular signal-regulated
kinase)
Role of central amygdala ERK and glutamate in incubation of cocaine
craving
Dr. Lin Lu
Collaborator: Dr. Bruce Hope
Grimm et al. Incubation of cocaine craving after withdrawal. Nature, 2001
1 day2 days4 days7 days15 days29 days60 days
Training phase Withdrawal phase
Test phase(drug is NOT available)
0
20
40
60
80
1 2 3 4 5 6 7 8 9 10Day
Tone+light cue(n=67)
Tone+light cueNo T+L6-860-minsessions
Infu
sions
(6 h
)
“Extinction” + Testing (same day)
0
60
120
180
240
300
1 2 4 7 15 29 60
Withdrawal day
Resp
onse
s (6
h) *
* *
*
Extinction responding *
*
*
*
0
20
40
60
80
100
1 2 4 7 15 29 60
Withdrawal day
Resp
onse
s (1
h)
Cue-induced reinstatement
Cue available
Last extinctionsession (no T+L)
Time-dependent changes in extinction responding and cue-induced reinstatement of cocaine seeking after
withdrawal
Incubation of reward craving after withdrawal from
drug and non-drug reinforcers
Alcohol Bienkowski et al. (2004) Withdrawal period in
home cage prior to extinction tests
1 6 12 25 66
* *
*
0
100
200
300
400
Withdrawal day
Resp
on
ses
(5 h
)
Heroin Shalev et al. 2001
1 30 90 180
Cocaine (4)Lu et al. 2004
* *
*
1 2 4 7 1529 60
Withdrawal day
*
* *
*
Cocaine (3)Grimm et al. 2001
0
75
150
225
300
Resp
on
ses
(6 h
)
Cocaine (2)Neisewander et al. 2000
Priming1 21
Cue Extinction
Cocaine (1)Tran-Nguyen et al. (1998)
Control1 day7 day1 month
Withdrawal day
7 60 180
*
Withdrawal day30 901
0
50
100
150
200
Resp
on
ses
(6 h
)
Sucrose Lu et al. 2004
MethamphetamineShepard et al. 2004
0
30
60
90
120
150
1 21 51
Withdrawal day
**
Resp
on
ses
(3 h
)
Training condition: saline versus cocaine
Withdrawal period: day 1 versus day 30
Test condition: no cue versus cue exposure (30 min extinction test)
Cocaine/saline SA training (10 Days)
Withdrawal period (1 or 30 Days)
Extinction testDay 1
Extinction test Day 30
4 groups
Cocaine/saline SA training (10 Days)
Withdrawal period (1 or 30 Days)
No test Day 1
No test Day 30
4 groups
Experiment 1: activation of amygdala ERK by cocaine cues
Withdrawal day
0
75
150
225
300
1 30 90 180
Resp
onse
s (6
h) * *
*
Cocaine/saline SA training (10 Days)
Withdrawal period (1 or 30 Days)
Extinction test Day 1
Extinction test Day 30
Behavioral data: Training and extinction test
Withdrawal day
Resp
onse
s (3
0 m
in)
Extinction test
0
15
30
45
60
1 30
*
Cocaine-trained rats
Saline-trained ratsLu, Hope et al. Submitted
Training day
0
20
40
60
80
100
1 2 3 4 5 6 7 8 9 10
Infu
sions
(6 h
)
Cocaine SA (n=34)
Saline SA (n=34)
Training
Exposure to cocaine cues increases ERK phosphorylation in the central amygdala after 30
days of withdrawal
DAY 30
Central amygdala
DAY 1
Saline SA Cocaine SA
DAY 30
DAY 1
Extinction test
No test
0
50
100
150
200
% o
f naiv
e r
ats *
pERK1
pERK2
Basolateral amygdala
DAY 1
DAY 30
DAY 1
DAY 30
Saline SA Cocaine SA
*
I G
R S G b
R S AM 2 M 1
S1T r
S1D Z
S1B F
S2
G I
A I P
D E n
B L A B L P
I M G
P i rV E n
B L V
P L C o
B M A
A C o
M eA DI
B A O T
M eA V
C eMC eCSI
A S tr
I P A C
L aD LI
C P u
L G P
B
M G P C eL
A r cM
A r cLA r cD
M E EM E I
V M H CV M H V L
Stg
A H PL H
P aP o
X i
D A
P e3V
A 13Z I
Su b
m t R e
V R e
R hV M
V LV P M
C M
I A M
P C
V P LR t
I M D
P V
L H b
M D M
M D CM D L C L
L D D M L D V L
D H CC A 3
C A 2C A 1
M H b D G
d h c
ccd f
cg
a lv
fi
st
ec
i cem l
im l
n s
a l
m fbf
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so x
SO R
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r f
D I
C xA
V M H D M
L V
D 3V
cst
CeABLA
Inhibition of ERK phosphorylation in the central amygdala attenuates cocaine seeking after 30 days of
withdrawal
0
20
40
60
80
Vehicle U0126
Resp
onse
s (3
0 m
in) Inactive lever
Active lever
*
Extinction responding
0
50
100
150
Centralamygdala
% o
f vehic
le v
alu
es
Basolateralamygdala
VehicleU0126
*
Phosphorylated ERK
U0126 ERK
MEK
Raf I G
R S G b
R S AM 2 M 1
S1T r
S1D Z
S1B F
S2
G I
A I P
D E n
B L A B L P
I M G
P i rV E n
B L V
P L C o
B M A
A C o
M eA DI
B A O T
M eA V
C eMC eCSI
A S tr
I P A C
L aD LI
C P u
L G P
B
M G P C eL
A r cM
A r cLA r cD
M E EM E I
V M H CV M H V L
Stg
A H PL H
P aP o
X i
D A
P e3V
A 13Z I
Su b
m t R e
V R e
R hV M
V LV P M
C M
I A M
P C
V P LR t
I M D
P V
L H b
M D M
M D CM D L C L
L D D M L D V L
D H CC A 3
C A 2C A 1
M H b D G
d h c
ccd f
cg
a lv
fi
st
ec
i cem l
im l
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a l
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so x
SO R
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D I
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V M H D M
L V
D 3V
cst
CeA
NMDAreceptor
0
20
40
60
80
Vehicle U0126
Resp
onse
s (3
0 m
in)
Extinction respondingInactive leverActive lever
% o
f vehic
le v
alu
es
0
50
100
150
*
Phosphorylated ERK
Centralamygdala
Basolateralamygdala
VehicleU0126
Inhibition of ERK phosphorylation in the basolateral amygdala has no effect on cocaine seeking after 30
days of withdrawal
I G
R S G b
R S AM 2 M 1
S1T r
S1D Z
S1B F
S2
G I
A I P
D E n
B L A B L P
I M G
P i rV E n
B L V
P L C o
B M A
A C o
M eA DI
B A O T
M eA V
C eMC eCSI
A S tr
I P A C
L aD LI
C P u
L G P
B
M G P C eL
A r cM
A r cLA r cD
M E EM E I
V M H CV M H V L
Stg
A H PL H
P aP o
X i
D A
P e3V
A 13Z I
Su b
m t R e
V R e
R hV M
V LV P M
C M
I A M
P C
V P LR t
I M D
P V
L H b
M D M
M D CM D L C L
L D D M L D V L
D H CC A 3
C A 2C A 1
M H b D G
d h c
ccd f
cg
a lv
fi
st
ec
i cem l
im l
n s
a l
m fbf
o p t
so x
SO R
T C
r f
D I
C xA
V M H D M
L V
D 3V
cstBLAU0126 ERK
MEK
Raf
NMDAreceptor
Extinction responding
Inactive leverActive lever
0 25 250
NMDA dose (ng/site)
0
20
40
60
80
Resp
onse
s (3
0 m
in)
*
Phosphorylated ERK
0
50
100
150
200
*
Centralamygdala
% o
f vehic
le v
alu
es
Basolateralamygdala
Vehicle
NMDA (25 ng)
NMDA (250 ng)
ERK
MEK
Raf
Induction of ERK phosphorylation in the central amygdala restores cocaine seeking after 1 day of
withdrawal
I G
R S G b
R S AM 2 M 1
S1T r
S1D Z
S1B F
S2
G I
A I P
D E n
B L A B L P
I M G
P i rV E n
B L V
P L C o
B M A
A C o
M eA DI
B A O T
M eA V
C eMC eCSI
A S tr
I P A C
L aD LI
C P u
L G P
B
M G P C eL
A r cM
A r cLA r cD
M E EM E I
V M H CV M H V L
Stg
A H PL H
P aP o
X i
D A
P e3V
A 13Z I
Su b
m t R e
V R e
R hV M
V LV P M
C M
I A M
P C
V P LR t
I M D
P V
L H b
M D M
M D CM D L C L
L D D M L D V L
D H CC A 3
C A 2C A 1
M H b D G
d h c
ccd f
cg
a lv
fi
st
ec
i cem l
im l
n s
a l
m fbf
o p t
so x
SO R
T C
r f
D I
C xA
V M H D M
L V
D 3V
cst
CeA
NMDA
NMDAreceptor
Extinction responding
Inactive leverActive lever
0
20
40
60
80
Veh
Veh
Veh
NMDA
U0126
VEH
U0126
NMDA
Resp
onse
s (3
0 m
in)
* **
Phosphorylated ERK
0
50
100
150
200
% o
f vehic
le v
alu
es
Veh
Veh
Veh
NMDA
U0126
VEH
U0126
NMDA
*
* #
*
Inhibition of ERK phosphorylation in the central amygdala reverses the effect of NMDA on cocaine seeking after 1 day
of withdrawal
I G
R S G b
R S AM 2 M 1
S1T r
S1D Z
S1B F
S2
G I
A I P
D E n
B L A B L P
I M G
P i rV E n
B L V
P L C o
B M A
A C o
M eA DI
B A O T
M eA V
C eMC eCSI
A S tr
I P A C
L aD LI
C P u
L G P
B
M G P C eL
A r cM
A r cLA r cD
M E EM E I
V M H CV M H V L
Stg
A H PL H
P aP o
X i
D A
P e3V
A 13Z I
Su b
m t R e
V R e
R hV M
V LV P M
C M
I A M
P C
V P LR t
I M D
P V
L H b
M D M
M D CM D L C L
L D D M L D V L
D H CC A 3
C A 2C A 1
M H b D G
d h c
ccd f
cg
a lv
fi
st
ec
i cem l
im l
n s
a l
m fbf
o p t
so x
SO R
T C
r f
D I
C xA
V M H D M
L V
D 3V
cst
CeAU0126 ERK
MEK
Raf
NMDA
NMDAreceptor
Blockade of NMDA receptors in the central amygdala attenuates cocaine seeking after 30
days of withdrawal
I G
R S G b
R S AM 2 M 1
S1T r
S1D Z
S1B F
S2
G I
A I P
D E n
B L A B L P
I M G
P i rV E n
B L V
P L C o
B M A
A C o
M eA DI
B A O T
M eA V
C eMC eCSI
A S tr
I P A C
L aD LI
C P u
L G P
B
M G P C eL
A r cM
A r cLA r cD
M E EM E I
V M H CV M H V L
Stg
A H PL H
P aP o
X i
D A
P e3V
A 13Z I
Su b
m t R e
V R e
R hV M
V LV P M
C M
I A M
P C
V P LR t
I M D
P V
L H b
M D M
M D CM D L C L
L D D M L D V L
D H CC A 3
C A 2C A 1
M H b D G
d h c
ccd f
cg
a lv
fi
st
ec
i cem l
im l
n s
a l
m fbf
o p t
so x
SO R
T C
r f
D I
C xA
V M H D M
L V
D 3V
cst
CeAERK
MEK
Raf
AP-5
Extinction responding
AP-5 dose (ug/site)
Inactive leverActive lever
0
20
40
60
80
0 3.0
Resp
onse
s (3
0 m
in)
*
Phosphorylated ERK
0
50
100
150
200
Centralamygdala
Basolateralamygdala
% o
f vehic
le v
alu
es
VehicleAP-5 (3 µg)
*
NMDAreceptor
Food self-administration
0
40
80
120
160
1 2 3 4 5 6
hour
Cocaine self-administration
VehicleU0126
0
10
20
30
40
1 2 3 4 5 6
hour
Lever
resp
onse
s
Control experiment Inhibition of ERK phosphorylation in the central amygdala
has no effect on cocaine or high-fat food self-administration
I G
R S G b
R S AM 2 M 1
S1T r
S1D Z
S1B F
S2
G I
A I P
D E n
B L A B L P
I M G
P i rV E n
B L V
P L C o
B M A
A C o
M eA DI
B A O T
M eA V
C eMC eCSI
A S tr
I P A C
L aD LI
C P u
L G P
B
M G P C eL
A r cM
A r cLA r cD
M E EM E I
V M H CV M H V L
Stg
A H PL H
P aP o
X i
D A
P e3V
A 13Z I
Su b
m t R e
V R e
R hV M
V LV P M
C M
I A M
P C
V P LR t
I M D
P V
L H b
M D M
M D CM D L C L
L D D M L D V L
D H CC A 3
C A 2C A 1
M H b D G
d h c
ccd f
cg
a lv
fi
st
ec
i cem l
im l
n s
a l
m fbf
o p t
so x
SO R
T C
r f
D I
C xA
V M H D M
L V
D 3V
cst
Bregma -2.3
CeA
Conclusions and implications• The phenomenon of incubation of reward craving has important implications for the treatment of relapse to a range of
addictive disorders (drug addiction, excessive eating, gambling?)
• Our results suggest that time-dependent increases in the responsiveness of central amygdala ERK signaling pathway to cocaine cues mediate the incubation of cocaine craving
• Our results also suggest a novel function of activation of the ERK pathway in the amygdala in associative learning: enhancement of the motivational impact of learned reward cues
Lu L, Grimm JW, Hope BT, Shaham Y (2004) Incubation of cocaine craving after withdrawal: a review of preclinical data. Neuropharmacology 47S1: 214-227 (NIDA special issue)
Courtesy of Taco de Vries
Animal models and FACE validity
Acknowledgements
Former post-baccalaureate studentsShirley LiuJack Dempsey
Present post-baccalaureate students
Sarah GrayRobert BuschDeepti Nagarkar