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Gaetano Di Chiara Gaetano Di Chiara
University of Cagliari University of Cagliari –– Department Department of of ToxicologyToxicology,,Centre for Studies Centre for Studies on on DependenceDependence,MIUR and CNR ,MIUR and CNR Institute Institute of of NeuroscienceNeuroscience
Verona, Verona, JuneJune 20062006
Neurobiology Neurobiology of of vulnerability to drug dependencevulnerability to drug dependence. .
University of Cagliari University of Cagliari -- Department of Toxicology and CNR Department of Toxicology and CNR -- Center for NeuropharmacologyCenter for Neuropharmacology
W.C. Drevets, C. Gautier, J.C. Price, D.J. Kupfer, P.E. Kinahan, A.A. Grace,J.L. Price, and C.A. Mathis Amphetamine-Induced Dopamine Release in Human Ventral Striatum Correlates with EuphoriaBiol. Psychiatry 2001;49:81–96
Wayne C. Drevets, M.D., Julie C. Price, Ph.D., David J. Kupfer, M.D., Paul E. Kinahan, PBrian Lopresti, B.S., Daniel Holt, B.S., and Chester Mathis, Ph.DPET Measures of Amphetamine-Induced Dopamine Releasein Ventral versus Dorsal StriatumNEUROPSYCHOPHARMACOLOGY 1999–VOL. 21, NO. 6
W.C. Drevets, C. Gautier, J.C. Price, D.J. Kupfer, P.E. Kinahan, A.A. Grace,J.L. Price, and C.A. Mathis Amphetamine-Induced Dopamine Release in Human Ventral Striatum Correlates with EuphoriaBiol. Psychiatry 2001;49:81–96
0 60 120 1800
100
200
300
400
Fischer (n=9)Lewis (n=6)
SHELL
0 60 120 1800
100
200
300
400
Fischer (n=5)Lewis (n=8)
SHELL
* *****
0 60 120 1800
100
200
300
400
Fischer (n=8)Lewis (n=8)
** *
SHELL
0 60 120 1800
100
200
300
400
Fischer (n=7)Lewis (n=8)
CORE
* * * ****
0 60 120 1800
100
200
300
400
Fischer (n=7)Lewis (n=11)
CORE
0 60 120 1800
100
200
300
400
Fischer (n=7)Lewis (n=7)
* *
CORE
1 mg/kg s.c. 5 mg/kg s.c.%
of b
asal
DA
outp
ut
time (min) after morphine
2.5 mg/kg s.c.
Morphine on dialysate dopamine in n.accumbens shell and core
0 60 120 1800
100
200
300
400
500
600
700
Fischer (n=5)Lewis (n=6)
SHELL
* **
* *
0 60 120 1800
100
200
300
400
500
600
700
Fischer (n=9)Lewis (n=6)
SHELL
0 60 120 1800
100
200
300
400
500
600
700
Fischer (n=10)Lewis (n=5)
SHELL
0 60 120 1800
100
200
300
400
500
600
700
Fischer (n=6)Lewis (n=6)
CORE
* * * *****
0 60 120 1800
100
200
300
400
500
600
700
Fischer (n=8)Lewis (n=8)
************
**
CORE
0 60 120 1800
100
200
300
400
500
600
700
Fischer (n=6)Lewis (n=5)
CORE
****
**
% o
f bas
al D
A ou
tput
time (min) after amphetamine
0.25 mg/kg sc.c 0.5 mg/kg s.c. 1 mg/kg s.c.
Amphetamine on dialysate dopamine in n.accumbens shell and core
0 60 120 1800
100
200
300
400
500
600
Fischer (n=7)Lewis (n=6)
SHELL
0 60 120 1800
100
200
300
400
500
600
Fischer (n=10)Lewis (n=8)
SHELL
0 60 120 1800
100
200
300
400
500
600
Fischer (n=6)Lewis (n=7)
SHELL
** ***
0 60 120 1800
100
200
300
400
500
600
Fischer (n=6)Lewis (n=10)
CORE
** ** *
0 60 120 1800
100
200
300
400
500
600
Fischer (n=6)Lewis (n=8)
**
CORE
0 60 120 1800
100
200
300
400
500
600
Fischer (n=7)Lewis (n=8)
CORE
5 mg/kg i.p. 10 mg/kg i.p. 20 mg/kg i.p.%
of b
asal
DA
outp
ut
time (min) after cocaine
Cocaine on dialysate dopamine in n.accumbens shell and core
0 60 120 1800
100
200
300
Fischer (n=4)Lewis (n=6)
SHELL
0 60 120 1800
100
200
300
Fischer (n=4)Lewis (n=5)
SHELL
0 60 120 1800
100
200
300
Fischer (n=3)Lewis (n=6)
SHELL
* * ** *
0 60 120 1800
100
200
300
Fischer (n=6)Lewis (n=6)
SHELL
0 60 120 1800
100
200
300
Fischer (n=3)Lewis (n=5)
CORE
0 60 120 1800
100
200
300
Fischer (n=5)Lewis (n=5)
CORE
0 60 120 1800
100
200
300
Fischer (n=3)Lewis (n=4)
CORE
* *
0 60 120 1800
100
200
300
Fischer (n=3)Lewis (n=7)
* * *
CORE
time (min) after nicotine
% o
f bas
al D
A ou
tput
0.2 mg/kg s.c. 0.4 mg/kg s.c.0.1 mg/kg s.c.0.05 mg/kg s.c.
Nicotine on dialysate dopamine in n.accumbens shell and core
concentric microdialysis probe
A.P. 1.7
A.P. 1.6
A.P. 1.2
SHELL CORE0
25
50
75
100
125
DA
BA
SAL
VALU
ES(fm
oles
/10
min
)
Location of microdialysis probes in rats responding for i.v. cocaine
Lecca et al
0 5 10 15 20 25
0
10
20
30
40
50
60FR1 FR5
EXTINCTION
×
ACTIVEINACTIVE
FALSE ACTIVE
MASTER RATS YOKED RATS
FALSE INACTIVE
NO
SE-P
OK
ES
0 5 10 15 20 25
0.00
0.25
0.50
0
5
10
FR1 FR5
EXTINCTION
DAYSH
ER
OIN
IN
TA
KE
(mg/
kg)
INFU
SION
S(num
ber / 1 h)
*: p<0.05 vs. respective inactivex: p<0.05 vs. yoked false active nose-poke
MASTER RATS(n= 5)
0 10 20 30 40 50 60 70 80 90
100
150
200
250
300shell 1st WEEKcore
DO
PAM
INE
OU
TPU
T(%
of b
asal
val
ues)
YOKED RATS(n=5)
0 10 20 30 40 50 60 70 80 90
100
150
200
250
300shell 1st WEEKcore
0 10 20 30 40 50 60 70 80 90
100
150
200
250
300shell 2nd WEEKcore
DO
PAM
INE
OU
TPU
T(%
of b
asal
val
ues)
0 10 20 30 40 50 60 70 80 9050
100
150
200
250
300shell 2nd WEEKcore
0 10 20 30 40 50 60 70 80 90
100
150
200
250
300shell 3rd WEEKcore
DO
PAM
INE
OU
TPU
T(%
of b
asal
val
ues)
0 10 20 30 40 50 60 70 80 90
100
150
200
250
300shell 3rd WEEKcore
0 10 20 30 40 50 60 70 80 90
100
150
200
250
300shell 4th WEEKcore
TIME (minutes)
DO
PAM
INE
OU
TPU
T(%
of b
asal
val
ues)
0 10 20 30 40 50 60 70 80 90
100
150
200
250
300shell 4th WEEKcore
TIME (minutes)
Filled symbols: p<0.05 vs basal values;*: p<0.05 vs core [master rats] or vs shell [yoked rats]x: p<0.05 vs yoked shell or vs master core
MASTER RATS(n=5)
0 10 20 30 40 50 60 70 80 90
100
150
200
250
shellcore
TIME (minutes)
DO
PAM
INE
OU
TPU
T(%
of b
asal
val
ues)
YOKED RATS(n=5)
0 10 20 30 40 50 60 70 80 90
shellcore
TIME (minutes)
Filled symbols: p<0.05 vs basal values;*: p<0.05 vs core [master rats] or vs shell [yoked rats]x: p<0.05 vs yoked shell or vs master core
0.0
0.1
0.2
0.3
0.4
HERO
IN IN
TAKE
(mg/
kg)
MASTER RATS:SHELL
0.0 0.2 0.4 0.6 0.8 1.0
0
500
1000
1500
2000
2500
slope= 1878±497
HEROIN INTAKE (mg/kg)
NET
DA
REL
EASE
(fmol
es/9
0 m
in)
MASTER RATS:CORE
0.0 0.2 0.4 0.6 0.8 1.0
0
500
1000
1500
2000
2500
slope= 656±205
HEROIN INTAKE (mg/kg)
YOKED RATS:SHELL
0.0 0.2 0.4 0.6 0.8 1.0
0
500
1000
1500
2000
2500
slope= 110±189
HEROIN INTAKE (mg/kg)
NET
DA
REL
EASE
(fmol
es/9
0 m
in)
YOKED RATS:CORE
0.0 0.2 0.4 0.6 0.8 1.0-500
0
500
1000
1500
2000
2500
slope= 1531±328
HEROIN INTAKE (mg/kg)
0 10 20 30 40 50 60 70 80 90
100
150
200
250
300shell 5th WEEK: EXTINCTIONcore
TIME (minutes)
DO
PAM
INE
OUT
PUT
(% o
f bas
al v
alue
s)
0 10 20 30 40 50 60 70 80 90
shell 5th WEEK: EXTINCTIONcore
TIME (minutes)20
0
10
20
30
40
50
60
21 22 23 24 25
MASTER RATS YOKED RATSACTIVEINACTIVE FALSE ACTIVE
FALSE INACTIVE
×
DAYS
NO
SE-P
OK
ES
*: p<0.05 vs. respective inactivex: p<0.05 vs. yoked false active nose-poke
Non-stereotyped activity• Still• Locomotion• Sniffing upward• Grooming• Rearing
Stereotyped activity• Gnawing (self-mutilation)• Gnawing confined• Sniffing down confined• Licking
MASTER RATS
1 5 10 15 200
25
50
75
100
STEREOTYPED ACTIVITYNON-STEREOTYPED ACTIVITY
DAYS
% O
F TI
ME
SPEN
T *
** * ** * *
* * **
**
YOKED RATS
1 5 10 15 200
25
50
75
100
DAYS
* * ***
***
**
* *
*
* P < 0.05 VS. CORRESPONDING DAY-MATCHED COUNTERPART RATS ACTIVITY
MASTER RATS
1 2 3 40
25
50
75
100
NON-STEREOTYPED ACTIVITY
STEREOTYPED ACTIVITY
WEEKS
% O
F TI
ME
SPEN
T *
**
YOKED RATS
1 2 3 40
25
50
75
100
*
WEEKS
*
*
* P < 0.05 VS. CORRESPONDING WEEK-MATCHED COUNTERPART RATS ACTIVITY
MASTER RATSSHELL
0 10 20 30 40 50 60 70 80 900
200
400
600
800
1000D
A O
UTP
UT
(% o
f bas
al v
alue
s)
MASTER RATSCORE
0 10 20 30 40 50 60 70 80 900
200
400
600
800
1000
YOKED RATSSHELL
0 10 20 30 40 50 60 70 80 900
200
400
600
800
1000
TIME (minutes)
DA
OU
TPU
T(%
of b
asal
val
ues)
YOKED RATSCORE
0 10 20 30 40 50 60 70 80 900
200
400
600
800
1000
TIME (minutes)
DAY 1
DAY 2
DAY 3
DAY 4
DAY 5
DAY 6
DAY 7
DAY 8
DAY 9
DAY 10
DAY 11
DAY 12
DAY 13
DAY 14
DAY 15
MASTER RATS
0 10 20 30 40 50 60 70 80 900
100
200
300
400
500 CORESHELL
TIME (minutes)
DO
PAM
INE
OU
TPU
T(%
of b
asal
val
ues)
YOKED RATS
0 10 20 30 40 50 60 70 80 90
CORESHELL
TIME (minutes)SHELL CORE
0.0
2.5
5.0
7.5
10.0
CO
CA
INE
INTA
KE
(mg/
kg)
MASTER RATS:1ST WEEK
0 10 20 30 40 50 60 70 80 900
100
200
300
400
500CORESHELL
TIME (minutes)
DO
PAM
INE
OU
TPU
T(%
of b
asal
val
ues)
YOKED RATS:1ST WEEK
0 10 20 30 40 50 60 70 80 900
100
200
300
400
500CORESHELL
TIME (minutes)
SHELL CORE0.0
2.5
5.0
7.5
10.0
12.5
CO
CA
INE
INTA
KE
(mg/
kg)
MASTER RATS:2ND WEEK
0 10 20 30 40 50 60 70 80 900
100
200
300
400
500CORESHELL
TIME (minutes)
DO
PAM
INE
OU
TPU
T(%
of b
asal
val
ues)
YOKED RATS:2ND WEEK
0 10 20 30 40 50 60 70 80 900
100
200
300
400
500CORESHELL
TIME (minutes)
SHELL CORE0.0
2.5
5.0
7.5
10.0
12.5
CO
CA
INE
INTA
KE
(mg/
kg)
MASTER RATS:3RD WEEK
0 10 20 30 40 50 60 70 80 900
100
200
300
400
500CORESHELL
TIME (minutes)
DO
PAM
INE
OU
TPU
T(%
of b
asal
val
ues)
YOKED RATS:3RD WEEK
0 10 20 30 40 50 60 70 80 900
100
200
300
400
500CORESHELL
TIME (minutes)
SHELL CORE0.0
2.5
5.0
7.5
10.0
12.5
CO
CA
INE
INTA
KE
(mg/
kg)
MASTER RATS:SHELL
0 10 20 30 40
0
1000
2000
3000
4000
5000
slope= 152.5±30.5
COCAINE INTAKE (mg/kg)
NET
DA
REL
EASE
(fmol
es/9
0 m
in)
MASTER RATS:CORE
0 10 20 30 40
slope= 89.7±24.4
COCAINE INTAKE (mg/kg)
YOKED RATS:SHELL
0 10 20 30 40
0
1000
2000
3000
4000
5000
slope= 37.8±8.6
COCAINE INTAKE (mg/kg)
NET
DA
REL
EASE
(fmol
es/9
0 m
in)
YOKED RATS:CORE
0 10 20 30 40
slope= 74.6±16.4
COCAINE INTAKE (mg/kg)
Non-stereotyped activity• Still• Locomotion• Sniffing upward• Grooming• Rearing
Stereotyped activity• Sniffing down• Gnawing• Head bobbing• Licking
MASTER RATS
1 2 3 4 5 6 7 8 9 10 11 12 13 14 150
25
50
75
100
STEREOTYPED ACTIVITYNON-STEREOTYPED ACTIVITY
* ***
** **
DAYS
% O
F TI
ME
SPEN
TYOKED RATS
1 2 3 4 5 6 7 8 9 10 11 12 13 14 150
25
50
75
100
* * **
* ** *
DAYS
* P < 0.05 VS. THE CORRESPONDING DAY-MATCHED COUNTERPART RATS ACTIVITY
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