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Glucocorticoid-Dependent Neuroplasticity: Fueling the Cycle of Stress and Addiction
John Mantsch, Ph.D.Department of Biomedical Sciences
Marquette UniversityMilwaukee, WI
DRUG EFFECTS ENVIRONMENT
GENETICS
RISK FACTORS FOR COCAINE ADDICTION
DRUG-ASSOCIATED CUESDRUG-ASSOCIATED CONTEXTSTRESS
ACUTE REWARDING EFFECTSWITHDRAWAL EFFECTSDRUG-INDUCED NEUROPLASTICITY
PERSONALITY TRAITSGENETIC POLYMORPHISMS
CLINICAL EVIDENCE FOR A LINK BETWEEN STRESS AND COCAINE ADDICTION:
• High incidence of anxiety/mood disorders in cocaine-addicted populations.
• Link between drug dependence and post-traumatic stress disorder (PTSD)
• Personalized stress imagery precipitates cocaine craving in recovering cocaine addicts.
• Surgical implantation of silastic catheter into jugular vein
• Exit via head- or back-mounted cannula port• Drug delivery line attached to a counter-
balanced leak-proof swivel to allow unrestricted movement
• Tested in operant chamber (modified Skinner box) - experimenter-controlled environment
• Pressing a response lever activates a pump resulting in infusion of set volume of drug solution
• In general - drugs with abuse potential in humans will be self-administered by rats (e.g., cocaine, heroin, alcohol, benzodiazepines,methamphetamine, nicotine, and cannabinoids).
IV DRUG SELF-ADMINISTRATION COCAINE
RELAPSE OF DRUG USE/DRUG CRAVING: REINSTATEMENT PROTOCOLS
POSITIVE REINFORCING (EUPHORIC) EFFECTS OF DRUGS: MAINTENANCE PROTOCOLS
PREDISPOSITION TO USE DRUGS: ACQUISITION PROTOCOLS
LOSS OF CONTROL OVER DRUG USE (ADDICTION): ESCALATION PROTOCOLS
Acute Stress Reinstates Extinguished Cocaine-Seeking Behavior in Rats
BAS COC EFS BAS COC EFS0
50
100
150 #
#
ACTIVE LEVER INACTIVE LEVER
Res
po
nse
s/2-
h S
essi
on
BAS = Last day of EXTCOC = IP Cocaine (10 mg/kg)EFS = 3 x 0.6 mA/0.5-s shocks
ave every 45 sec for 15 min
1 2 3 4 5 6 7 8 9 100
20
40
60
80
100
Extinction Day
Res
po
nse
s/2-
h S
essi
on
12 13 140
100
200
300
400
SA Day
Res
po
nse
s/6-
h S
essi
on
1. Self-Administration 2. Extinction 3. Reinstatement
In syringe: Cocaine (1.0 mg/kg/inf) Saline Saline
Ahmed and Koob 1997Erb et al 1997Mantsch et al 1999
EFFECTS OF CHRONIC-STRESS ON COCAINE-INDUCED NEUROPLASTICITY
COCAINE ALONE COCAINE AND STRESS
MODELING HUMAN ADDICTION
HUMANS
• LOSS OF CONTROL OVER DRUG USE
• LONG-TERM SUSCEPTIBILITY TO DRUG RELAPSE
RATS
• ESCALATING PATTERNS OF DRUG SELF-ADMINISTRATION
• AUGMENTED REINSTATEMENT OF EXTINGUISHED COCAINE-SEEKING BEHAVIOR
EFFECTS OF REPEATED ELECTRIC FOOTSHOCK (EFS) STRESS ON COCAINE SELF-ADMINISTRATION
4 X 30-min Cocaine Self-Administration Sessions0.5 mg/kg/inf; Fixed-ratio 4 schedule
Groups (tested for 14 days):1. EFS: received footshock during 5-min components2. No EFS: did not receive footshock during 5-min components
Five Minutes Intermittent Electric Footshock3 x 0.6 mA shocks; 100 msec duration/frequencyAverage of 45 sec
CHRONIC STRESS PRODUCES AN ESCALATION OF COCAINE BUT NOT FOOD SELF-ADMINISTRATION BY RATS
•EFS: Electric footshock in the SA chamber at the time of SA testing •No EFS: control group
Mantsch and Katz, 2007; Neuropsychopharmacology
BAS0
5
10
15
20
25
30
35
40
45
50
No EFSEFS
1 2 3 4 5 6 7 8 9 10 11 12 13 14
* * * ** *
Coc Self-Administration Day
Co
c In
fusi
on
s/S
essi
on
BAS0
50
100
150
200
250
300
350
1 2 3 4 5 6 7 8 9 10 11 12 13 14
No EFSEFS
Food Self-Administration Day
Fo
od
Pel
lets
/Ses
sio
n
Food
Cocaine
EFS ONLY ESCALATES SA IF DELIVERED AT THE TIME OF SA TESTING WITHIN THE SA ENVIRONMENT
•EFS/SA Context/SA: Electric footshock in the SA chamber at the time of SA testing •EFS/Non-SA Context/Post-SA: EFS in a non-SA context at the time of SA testing .•EFS/SA Context/Post-SA: EFS the SA context at the time of SA testing.•No EFS: control
BAS0
5
10
15
20
25
30
35
40
45
50
No EFSEFS/SA Context/SA
1 2 3 4 5 6 7 8 9 10 11 12 13 14
* * * ** *
EFS/Non-SA Context/Post-SA
EFS/SA Context/Post-SA
Self-Administration Day
Infu
sio
ns
/Se
ss
ion
Mantsch and Katz, 2007; Neuropsychopharmacology
THE CHRONIC VARIABLE STRESS PROTOCOL
• Chronic: 14 days; twice daily exposure• Mild: non-noxious stressors• Variable: 7 stressor presented in randomized sequence
WEEK 1 WEEK 2DAY AM PM DAY AM PM
1 Forced Swim Restraint 8 Cold Noise
2 Noise Cold Swim 9 Open Field Cold Swim
3 Rotation Open Field 10 Restraint Rotation
4 Cold Forced Swim 11 Noise Forced Swim
5 Restraint Cold 12 Restraint Open Field
6 Open Field Rotation 13 Cold Swim Restraint
7 Cold Swim Noise 14 Forced Swim Cold
References: JP Herman et al (1995) Neuroendocrinology 61: 180-90; WE Cullinan et al (2000) Brain Research 887: 118-124.
THE CHRONIC VARIABLE STRESS PROTOCOL…
3. Does not result in attenuation of the stress response with repeated exposure
Group Basal CORT(ng/ml)
CORT response to EFS (ng/ml)
No CVS 50.56 ± 10.69 295.63 ± 6.73
CVS 80.22 ± 38.87 294.58 ± 8.46
Group Adrenal Weight(mg)
Thymus Weight(mg)
No CVS 52.7 ± 2.6 449 ± 17
CVS 64.8 ± 2.8* 372 ± 15*
2. Produces physiological signs of chronic stress
1. Does not affect body weight or produce noticable changes in health/vitality
Group Basal Body Wt (mg)
Post-CVS Body Weight (mg)
No CVS 334 ± 2.3 357 ± 4.0
CVS 337 ± 2.3 348 ± 3.0
EFFECTS OF CVS ON COCAINE-INDUCED NEUROPLASTICITY
8 AM 12 PM 4 PM
Room TempSwim Restraint
CocaineSA/Injection
A. A sample experimental test day
SA TESTING/ EXTINCTION/ INDUCTION WITHDRAWAL
14 DAYS+/- CVS
14 DAYSNo CVS
SA TRAINING/HABITUATION
REINSTATEMENT/DRUG CHALLENGE
B. General experimental time-line
Saline/No CVS Saline/CVS Cocaine/No CVS Cocaine/CVS0
10000
20000
30000
40000
Saline
Cocaine (10 mg/kg)
*
*#
Treatment (x 14 days)
Co
cain
e-In
du
ced
Act
ivit
y (T
ota
lP
ho
tob
eam
Bre
aks)
CHRONIC VARIABLE STRESS ACROSS A PERIOD OF COCAINE ADMINISTRATION POTENTIATES COCAINE-INDUCED LOCOMOTOR
SENSITIZATION
• CVS across a period of cocaine administration augments cocaine-induced locomotor sensitization
• CVS does not produce locomotor sensitization when delivered in the absence of cocaine
Withdrawal D12 Challenge:
CHRONIC VARIABLE STRESS DURING BUT NOT AFTER A PERIOD OF COCAINE SA AUGMENTS LATER COCAINE-INDUCED
REINSTATEMENT
#
##
Corticotropin Releasing Hormone/Factor PVN of the Hypothalamus
KIDNEYAdrenocorticotropic Hormone
The Hypothalamic Pituitary Adrenal (HPA) Axis
Corticosterone (in rats)
WHY GLUCOCORTICOIDS?
• Glucocorticoids = mediate adaptational responses to stressors (physiological and behavioral)
• Neurocircuitry underlying drug-seeking behavior is a direct and indirect target of glucocorticoids
STRESS
Peak Nadir Post-EFS0
100
200
300Sham ADX+CORT
*
SAMPLE TIME
PL
AS
MA
CO
RT
(n
g/m
l)
CIRCADIAN AND EFS-INDUCED CORT SECRETION IN ADX RATS WITH DIURNAL CORT REPLACEMENT AND SHAM-TREATED CONTROLS
• Surgical adrenalectomy• Subcutaneous 25% CORT Pellet Implantation• Inclusion of CORT (0.25%) in drinking water (0.9% NaCl)
• Sham surgery• 100% cholesterol pellet• 0.9% NaCl for drinking water
BAS0
5
10
15
20
25
30
35
40
45
50
SHAM NO EFS
SHAM + EFS
1 2 3 4 5 6 7 8 9 10 11 12 13 14
* * * ** *
ADX/C + EFS
ADX/C + NO EFS
Self-Administration Day
Infu
sio
ns/
Ses
sio
n
THE ESCALATION OF COCAINE SELF-ADMINISTRATION BY REPEATED STRESS REQUIRES STRESSOR-INDUCED
GLUCOCORTICOID SECRETION
ADX/C = surgical adrenalectomy with diurnal CORT replacement
BAS0
5
10
15
20
25
30
35
40
45
50EFS + CORT
NO EFS + CORT
1 2 3 4 5 6 7 8 9 10 11 12 13 14
EFS + NO CORTNO EFS + NOCORT
******
Self-Administration Day
Infu
sio
ns/
Se
ssio
nCORT ADMINISTRATION RESTORES BUT DOES NOT REPRODUCE
THE ESCALATING EFFECTS OF EFS ON SA IN ADX/C RATS
• IP CORT (3.0 mg/kg) to ADX/C rats alone or prior to EFS
• IP CORT does not escalate cocaine SA by itself
• IP CORT given along with EFS restores the escalating effects of EFS on cocaine SA
ADX/C +:
0 4 8 12 16 20 240
100
200
300
400
500
HOURS POST-INJECTION
Pla
sma
CO
RT
(ng
/ml)
Plasma CORT after3.0 mg/kg IP CORT Injection
• Stress promotes cocaine-induced neuroplasticity that may be pathogenic for addiction:
1.Repeated exposure to a stressor (EFS) produces a context/timing-dependent escalation of cocaine SA that is specific to drug-seeking behavior.
2.Exposure to chronic variable stress (CVS) across a period of experimenter-delivered or self-administered cocaine exposure augments the expression of behavioral sensitization or cocaine-induced reinstatement after a stress-free withdrawal period.
• The escalating effects of repeated EFS are prevented by eliminating the corticosterone response to EFS.
• EFS-induced corticosterone secretion is necessary but not sufficient for the escalation of cocaine SA by repeated EFS.
• Corticosterone functions as an “enabler” that permits stressors to promote cocaine-seeking behavior and addiction.
• Cocaine-induced corticosterone secretion is NOT required for the escalation of cocaine SA under LgA conditions but does facilitate SA under long-access conditions.
• CORT is likely functioning as an enabler of stressor-induced neuroplasticity and appears to be working in concert with other neurobiological mediators that are active during periods of stress.
Summary
EFFECTS OF COCAINE ON STRESS RESPONSES
VICIOUS CYCLE OF ADDICTION
COCAINE USE
WITHDRAWAL
STRESS
Cocaine-Induced Neuroplasticity: Long-Term Effects of Cocaine SA on Responses to Stressors
BAS 1 2 3 4 5 6 7 8 9 10 11 12 13 140
20
40
60
80
ShA SA (Short-Access, 2 hrs daily)LgA SA (Long-Access, 6 hrs daily)
*******
****
Self-Administration Day
Coc
aine
Int
ake
(mg/
kgpe
r se
ssio
n)
Studying Cocaine-Induced Neuroplasticity Using the Long-Access Cocaine Self-Administration Model
References:Ahmed and Koob, 1998Ahmed and Koob, 1999Mantsch et al 2004
BAS COC EFS BAS COC EFS0
50
100
150
ShA SALgA SA*
#
*
ACTIVE LEVER INACTIVE LEVER
*#
Res
po
nse
s/2-
h S
essi
on
LgA Cocaine SA Produces a Persistently Heightened Susceptibility to Cocaine and Stressor-Induces Reinstatement
Mantsch et al Neuropsychopharmacology, submitted
700h 900h 1300h0
50
100
150
200
250
300
BasLgA SAShA SA
ShA SA
LgA SA
Time
Pla
sma
CO
RT
(n
g/m
l)
GroupSAL ShA LgA
Body Weight (g) 424.71 11.06 435.17 7.56 406.93 9.47Adrenal Weight (mg) 33.56 4.67 48.78 5.22* 52.38 5.78*
Adr Wt/100 g Body Wt 0.82 0.12 1.13 0.10 1.29 0.15*Thymus Weight (mg) 242.72 16.19 250.59 18.13 191.24 14.87**
Thy Wt/100 g Body Wt 5.73 0.36 5.75 0.41 4.70 0.38
Activation of the HPA Axis by ShA and LgA Cocaine SA
Lights off
• Acute cocaine SA increases plasma CORT
• Chronic cocaine SA produces adrenal hypertrophy and reduces thymus mass
21 days after 14 days of daily ShA, LgA or saline SA
Peak Nadir0
100
200
300ShamADX+CORT
SAMPLE TIME
PL
AS
MA
CO
RT
(n
g/m
l)
700h 900h 1300h0
50
100
150
200
250
300ADX/CSham
LgA SA
TimeP
lasm
a C
OR
T (
ng
/ml)
ADX with Diurnal CORT Replacement Reproduces Circadian Fluctuations in CORT Levels but Prevents SA-Induced Increases in
CORT Secretion
Mantsch et al Neuropsychopharmacology, submitted
BAS 1 2 3 4 5 6 7 8 9 10 11 12 13 140
20
40
60
80
ShA/ADX Sham
LgA/ADX ShamShA/ADX-CLgA/ ADX-C
* ** * * * * * * *
#
## # #
# ##
## #
@@@ @ @ @
@
Self-Administration Day
Co
cain
e In
fusi
on
s/S
essi
on
Eliminating SA-Induced Increases in CORT Slows but Does Not Prevent Escalating SA Patterns in LgA Rats and Has No Effect on
ShA SA
Mantsch et al Neuropsychopharmacology, submitted
BAS COC EFS BAS COC EFS0
50
100
150 ADX ShamPre-ADX
*
#* *
#
ShA LgA
Post-SA ADX/C
*
*
*
* *
Res
po
nse
s/2-
h S
essi
on
ADX/C Prior To But Not After Repeated LgA SA Prevents the Augmentation of Cocaine- or EFS-Induced Reinstatement Without
Altering Reinstatement in ShA Rats
Mantsch et al Neuropsychopharmacology, 2007
700h 900h 1300h 1900h0
50
100
150
200
250
300
IP CORT + ShA SA
BasLgA SAShA SA
ShA SA
LgA SA
IP CORT
Time
Pla
sma
CO
RT
(n
g/m
l)
Administration of 2.0 mg/kg CORT Immediately Prior to ShA SA Mimics the Effects of LgA SA on Plasma CORT
Mantsch et al Neuropsychopharmacology, 2007
SAL COC0
25
50
75ShA + NoCORTShA +CORT
Reinstatment Condition
Res
pons
es/S
essi
on
B 1 2 3 4 5 6 7 8 9 10 11 12 13 140
5
10
15
20
25
30ShA + No CORT (n=17)ShA + CORT (n=7)
Self-Administration Day
Coc
aine
Infu
sion
s/2-
hS
essi
on
Reproduction of LgA-Induced Increases in Plasma CORT is Insufficient to Produce Escalation or Augment Reinstatement in
ShA Rats
Mantsch et al Neuropsychopharmacology, 2007
Summary• Daily cocaine SA under LgA conditions results in a progressive escalation of daily cocaine
intake and a long-term heightened susceptibility to cocaine- and stressor-induced reinstatement.
• These effects of LgA SA are the consequence of cocaine-induced neuroplasticity that likely contributes to addiction.
• Elevated CORT lat the time of SA testing is at least partly required for cocaine-induced neuroplasticity in LgA rats but is not necessary for the acute reinforcing or reinstating effect of cocaine and/or stressors.
• Administration of CORT using doses that reproduce increases in circulating CORT level observed in LgA rats alone is insufficient to induce escalate drug use or augment later cocaine-induced reinstatement.
• CORT is likely functioning as an enabler of cocaine-induced neuroplasticity and appears to be working in concert with other neurobiological mediators that are active during LgA cocaine SA. .
SAL ShA LgA0
10
20
30
40
50
60
70
80
90
Tim
e S
pe
nt
in O
pe
nA
rms
(s
ec
on
ds
) *
Elevated Plus Maze
OPEN-ARM ACTIVITY ON THE ELEVATED PLUS MAZE IS INCREASED 2 WEEKS AFTER LONG-ACCESS COCAINE SELF-ADMINISTRATION
ShA = short-access ratsLgA = long-accessSAL = saline SA controls
Mantsch et al Pychopharmacology, Submitted
Sal ShA LgA0
50
100
150
200
250
300
350
400
450
*
Group
Lat
ency
to
En
ter
Lig
ht
Co
mp
artm
ent
(sec
)
Sal ShA LgA0
50
100
150
200
250 *
Group
Tim
e S
pen
t in
Lig
ht
Co
mp
artm
ent
(sec
)
Sal ShA LgA0
1
2
3
4
5
6
7
8
9 *
Group
Lig
ht
Co
mp
artm
ent
En
trie
s/ 1
0 M
in
Mantsch et al Pychopharmacology, Submitted
SA Produces An Augmentation of Exploratory Behavior Measured Using the Light-Dark Box Model 2 Weeks After SA Repeated SA Testing
Latency to Enter Light Time Spent in Light Number of Light Entries
Light-Dark Box
First 30 Min Second 30 Min0
250
500
750*
ShA LgASal
Time
Cen
ter
Tim
e (S
ec)
1 30 600
500
1000
1500
2000
2500LgA
ShASAL
Time (Min)
To
tal
Dis
tan
ce (
cm)
1 30 600
200
400
600
800
1000
1200LgA
ShASal
*
Time (Min)
Cen
ter
Dis
tan
ce (
cm)
Center
SA Increases Center Activity, But Not Total Activity, Within A Novel Environment Measured 2 Weeks After Repeated SA
Time Spent in CenterCenter ActivityTotal Activity
Mantsch et al Pychopharmacology, Submitted
CRF mediates behavioral responses to stressors (Dunn and Berridge 1990, Brain Res Rev 15: 71-100).
CRF underlies stressor-induced reinstatement of cocaine seeking (Sarnyai et al 2001, Pharmacol Rev 53:209-243).
Potential sites of CRF-induced drug seeking include:•The CeA (Richter and Weiss 1999, Synapse 32: 254-261; Fu et al 2007, J Neurophysiol 97: 937-41)•The BNST via CRF projections originating in the CeA (Erb et al 2001, Psychopharm 158: 360-65; Erb et al 1999; J Neurosci 19: RC35)•The VTA presumably via CRF projections originating in the CeA (Wang et al 2005; J Neurosci 25: 5389-5396)
Role of Corticotropin Releasing Factor (CRF)
CeA vlBNST al/dl BNST0
10
20
30
40
50 Sal ShA LgA
Po
st-R
estr
ain
t C
RF
mR
NA
(m
CG
L)
Post-Restraint CRF mRNA in the BNST is not Altered As a Consequence of Prior Cocaine SA
Unpublished findings (J Mantsch, D Ziegler, W Cullinan)
Determined using in situ hybridization
Guide Cannula
Lateral Ventricle
Reinstatement by ICV CRF is Augmented in LgA Rats
Sal ShA LgA Sal ShA LgA0
10
20
30
40
50
60
70
80
90
100
1.0 g CRF
0.5 g CRF
Veh
Sham
*
*
*#
Active Lever Inactive Lever
Res
po
nse
s/S
essi
on
Mantsch et al Pychopharmacology, Submitted
Summary• Cocaine SA alters anxiety-related behaviors in a manner dependent on the amount and/or
pattern of cocaine intake.
• When measured several weeks into withdrawal SA promotes a shift from a more passive response pattern when confronted with a stressful situation to a more active reponses patterns as measured using:
1.The elevated plus maze2.The light-dark box3.Testing in a novel environment
• This more active response pattern during times of stress may be manifest as drug use/drug-seeking behavior.
• Changes in stressor-responsiveness may be attributable to altered responsiveness to CRF.
• Reinstatement by ICV CRF was augmented by LgA cocaine SA, suggesting a recruitment or augmentation of CRF regulation of neurocircuitry underlying cocaine-seeking behavior.
EFFECTS OF COCAINE ON STRESSOR-INDUCED HPA FUNCTION
SAL COC0
10
20
30
40BASALRESTRAINT *
14-DAY TREATMENT GROUP
PV
N C
RH
mR
NA
(Mea
n C
orr
ecte
d G
ray
Le
ve
l)
BASAL RESTRAINT 1.5HR POST0
100
200
300
400
500
14 x Daily SAL14 x Daily COC (30 mg/kg, IP)
*
#
#
Pla
sma
Cor
ticos
tero
ne(n
g/m
l)Glucocorticoid and PVN CRH mRNA Responses to Restraint are
Augmented During Acute (24-h) Withdrawal from Chronic Experimenter-Delivered Cocaine Administration
Plasma CORT
PVN CRH mRNAMantsch et al Neurosci Lett 2007
Restraint Dex0
100
200
300
400
500
SALShALgA
**
*
PL
AS
MA
CO
RT
(%
BA
S)
Basal Restraint Dex0
50
100
150
200
250
300
350
SALShALgA
**
*
PL
AS
MA
CO
RT
(n
g/m
l)
Mantsch et al submitted Brain Res
Cocaine SA Intake-Dependently Augments the Stressor-Induced
CORT Secretion and Impair Dexamethasone Suppression of
Plasma CORT Levels
Measured approx 3 weeks after SA testing
SAL ShA LgA0
25
50
75
100
125
Sal
ShA
LgA
*
98 kD GRLgAShASal
GR
Den
sity
Exp
ress
edas
% S
AL
Co
ntr
ol
GR Protein is Selectively Reduced in the Doromedial Hypothalamus (includes the PVN) of LgA
Other Regions Examined: Ventromedial Hypothalamus, Pituitary, Amygdala, Dorsal Hippocampus, Ventral Subiculum, Medial Prefrontal Cortex
Mantsch et al submitted Brain Res
Sal ShA LgA0
25
50
75
100No Restraint Restraint
SA GROUP
Mea
n C
orr
ecte
d G
ray
Lev
el
No Res Res0
25
50
75
Mea
n C
orr
ecte
d G
ray
Lev
el
*
Basal or Restraint-Induced Increases in CRH mRNA in the PVN
is not Altered by Cocaine SA
• Measured 1.5 hrs after 30 min of restraint• 21 day after 14 days of ShA, LgA, or SAL SA
Mantsch et al submitted Brain Res
Summary
• The response of the HPA axis to stressors is augmented by prior cocaine exposure.
• Long-term augmentation of HPA responsiveness to stressors may be partly attributable to impaired negative feedback regulation due to reduced GR protein expression in the hypothalamus.
• However long-term augmentation of stressor-induce CRH mRNA in the PVN measured at a single time-point following restraint was not oberved.
• Augmented HPA responsiveness during times of stress may promote glucocorticoid-dependent plasticity, thus fueling the addiction cycle.
Acknowledgements
NIDA Grant Number DA 15758
CollaboratorsDavid BakerWilliam CullinanM. Behnam GhasemzadehDana Ziegler
Research AssistantsLee TangEric KatzMichael Hoks
StudentsTayyiba KhanDavid FrancisJoe SergeTanveer SajanLoren Cooper
Ventral Tegmental AreaCRF-R2 Receptor
Medial Prefrontal Cortex Nucleus Accumbens
DOPAMINEGLUTAMATE
CRF,GLUCORTICOIDS
DRUG-SEEKINGBEHAVIOR
Nucleus Accumbens
Ventral Tegmental AreaCRF-R2 Receptor
Medial Prefrontal Cortex
GLUTAMATE
DOPAMINE
DRUG CRAVING/USE
CRF,GLUCORTICOIDS
STRESS
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