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C. Heidbreder - Frontiers in Addiction Research 2004 NIDA Mini-Convention
The Dopamine D3 Receptor System: New Possibilities for Dopamine-Based Reward
Christian A. Heidbreder, Ph.D.
C. Heidbreder - Frontiers in Addiction Research 2004 NIDA Mini-Convention
Selective Dopamine D3 Antagonists:Commitment to Target for Drug Abuse (I)
• Distribution:– Contrary to DA D1 and D2 receptors, DA D3 receptors are expressed
preferentially in granule cells of the islands of Calleja and in medium-sized spiny neurons of the rostral and ventromedial shell of the NAc, regions in which the D2 receptors are scarcely expressed (Gurevitch and Joyce, 1999)
– The distribution of the D3 receptor in the human brain appears to follow a rather similar pattern to that observed in the rat brain (Hall et al., 1996; Shafer and Levant, 1998; Suzuki et al., 1998; Gurevich and Joyce, 1999)
C. Heidbreder - Frontiers in Addiction Research 2004 NIDA Mini-Convention
Dopamine D3 Antagonists:Commitment to Target for Drug Dependence (II)
• Expression in disease tissues:– The density of DA D3 receptors is elevated one-to-threefold in the
NAc and ventromedial subregions of the caudate-putamen in the brains of cocaine overdose fatalities (Staley and Mash, 1996; Mash and Staley, 1999)
– The expression of DA D3 receptor mRNA in the human NAc is increased six-fold in cocaine overdose victims (Segal et al., 1997)
C. Heidbreder - Frontiers in Addiction Research 2004 NIDA Mini-Convention
Dopamine D3 Antagonists:Commitment to Target for Drug Dependence (III)
• Expression in disease models:– Termination of a cocaine self-administration regimen increases DA D3 binding
over time (Neisewander et al., 2004)– D3 mRNA and receptors are increased in cocaine cue-conditioned locomotion (Le
Foll et al., 2002)– Nicotine-induced conditioned locomotion and nicotine-induced behavioural
sensitisation are associated with significant increases in D3 receptor binding and mRNA levels in the shell subregion of the NAc (Le Foll et al., 2003)
– Sub-chronic exposure to morphine was shown to produce a significant increase in D3 receptor mRNA in the caudate-putamen and ventral midbrain, including the substantia nigra and VTA (Spangler et al., 2003)
C. Heidbreder - Frontiers in Addiction Research 2004 NIDA Mini-Convention
Why has the Role of DA D3 Receptorsin Drug Addiction been Hampered so far?
• Lack of pharmacological tools showing significant selectivity for DA D3 over DA D2 receptors• Most compounds used in animal models of drug addiction have a 10- to 30-fold selectivity for DA D 3 over D2 receptors in
vivo:AJ76: 2-6DS 121: 4UH 232: 4-8Nafadotride: 6-9U99194: 10-14S14297: 23-61
C. Heidbreder - Frontiers in Addiction Research 2004 NIDA Mini-Convention
Target Validation with Tool Compound
• 100 fold selective for hD3 over hD2 in radioligand binding assays
• Potent, competitive D3 receptor antagonist (pKb 8.4, 80 fold functional selectivity over hD2)
• 100 fold selective over 66 other receptors, ion channels and enzymes• Lacks agonist activity at hD2 and hD3 receptors• No effects on spontaneous locomotor activity (2-42 mg/kg p.o.)• No effects on open field exploration (3-51mg/kg p.o.)• Non-cataleptogenic up to 80 mg/kg p.o.• No elevation of plasma prolactin at 93 mg/kg p.o.• No proconvulsant effects up to 93 mg/kg p.o.
SB-277011-AN
NH
N
O
NC
C. Heidbreder - Frontiers in Addiction Research 2004 NIDA Mini-Convention
Efficacy Against Nicotine Dependence
C. Heidbreder - Frontiers in Addiction Research 2004 NIDA Mini-Convention
Effect of SB-277011-A on Nicotine-TriggeredRelapse to Nicotine-Seeking
Andreoli et al. (2003)
0
50
100
150
200
250
30 60 90 120
Session duration (min)
**
**
*
**
*
**
*
*
Cum
ulat
ive
nico
tine-
paire
dle
ver p
ress
es
*
Veh/SalVeh/Nic011-3/Nic011-10/Nic
Saline vs. Nicotine
C. Heidbreder - Frontiers in Addiction Research 2004 NIDA Mini-Convention
Effect of SB-277011-A on NicotineCue-Conditioned Hyperlocomotor Activity
N
NH
N
O
NC
SB-277011 0
500
1000
1500
2000
2500
3000
3500
0-5 5-10 10-15 15-20 20-25 25-30
Time (min)
Hac
tv
0
1
3
10
30
0
20000
40000
60000
80000
100000
0 1 3 10 30
SB-277011-A (mg/ kg)
Hac
tv (
AU
C 0
-20
)***
***
Pilla et al. (2004)
C. Heidbreder - Frontiers in Addiction Research 2004 NIDA Mini-Convention
Effect of SB-277011-A on Nicotine-Induced Conditioned Place Preference
N
NH
N
O
NC
SB-277011
0
3
6
9
12
PAIRED (min)
UNPAIRED (min)
A
A: Veh/Veh/Veh
B
B: Veh/Nico/Veh
C D E
C: Veh/Nico/1mg D: Veh/Nico/3mg E: Veh/Nico/10mg
? ?
Vehicle
Nicotine
Test
Ashby et al. (2004)
C. Heidbreder - Frontiers in Addiction Research 2004 NIDA Mini-Convention
Effect of SB-277011-A on Nicotine Enhancementof Brain Stimulation Reward
*
0
5
10
15
20
25
% E
nhan
cem
ent o
f BSR
Vehicle 0 3 6 12
SB-277011-A (mg/kg)Campos et al. (2003)
N
NH
N
O
NC
SB-277011
0
10
20
30
40
50
60
70
Vehicle + saline
Vehicle + nicotine
SB-277011-A +nicotine
Frequency (Hz) Log Scale
Leve
r Pre
sses
/30
sec
C. Heidbreder - Frontiers in Addiction Research 2004 NIDA Mini-Convention
Efficacy Against Cocaine Dependence
C. Heidbreder - Frontiers in Addiction Research 2004 NIDA Mini-Convention
Effect of SB-277011-A on Cocaine-TriggeredRelapse to Cocaine-Seeking
Extin
ctio
n
Prime
+ Veh
Prime
+ SB 3
mg/k
g
Prime
+ SB 6
mg/k
g
Prime
+ SB 1
2 m
g/kg
0
10
20
30
40
50
Non
- rew
arde
d le
ver p
ress
esC
ocai
ne s
eek i
ng
* **
Vorel et al. (2003)
N
NH
N
O
NC
SB-277011
C. Heidbreder - Frontiers in Addiction Research 2004 NIDA Mini-Convention
SB-277011-A Dose-Dependently ReducesCocaine-Related Cue-Induced Relapse to Cocaine Seeking
0
10
20
30
40
0
10
0 3 10 30Last three days
Last three days
*
*
§
§
0
SB-277011-A, mg/kg, i.p.
Self-administration Extinction Reinstatement
Saline & cuesCocaine & cues
Act
ive
leve
rIn
acti
ve le
ver
Nu
mb
er o
f re
spon
ses
Saline associated-cuesCocaine associated-cues
Cervo et al. (2003)
•0 •10 •20 •30 •40 •50 •60
Vehicle
Vehicle
SB 277011-A 3 mg/kg
SB 277011-A 10 mg/kg
SB 277011-A 30 mg/kg
Saline-associated cues
Co
cain
e-as
soci
ated
cu
es
•Vehicle
•Vehicle
•SB 277011-A 3 mg/kg
•SB 277011-A 10 mg/kg
•SB 277011-A 30 mg/kg
•Saline-associated •cues
• Co
cain
e-as
soci
ated
• c
ues
•0 •10 •20 •30 •40 •50 •60
N
NH
N
O
NC
SB-277011
C. Heidbreder - Frontiers in Addiction Research 2004 NIDA Mini-Convention
Effect of SB-277011-A on Cocaine Self-administrationunder a 2nd Order Schedule of Reinforcement
First Interval Second Interval#
of
Ina
cti
ve
Re
sp
on
se
s
Dose of SB-277011-ADose of SB-277011-A
# o
f R
es
po
ns
es
0
50
100
150
200
250
300
veh 0.3 3 10 20 30
**
0
50
100
150
200
250
veh 0.3 3 10 20 30
* **
0
10
20
30
40
50
60
veh 0.3 3 10 20 300
10
20
30
40
50
60
veh 0.3 3 10 20 30
Active Lever
Inactive Lever
Di Ciano et al. (2003)
C. Heidbreder - Frontiers in Addiction Research 2004 NIDA Mini-Convention
Effect of SB-277011-A on Cocaine-InducedConditioned Place Preference
Tim
e S
pen
t in
Co
mp
artm
ents
on
Tes
t Day
10
Drug-Paired
Vehicle-Paired*SB277011A can block the acquisition ofcocaine-induced CPP
Tim
e S
pen
t in
Co
mp
artm
ents
on
Tes
t Day
10
Drug-Paired
Vehicle-Paired
* *
SB277011A can block the expression ofcocaine-induced CPP
Vorel et al. (2003)
C. Heidbreder - Frontiers in Addiction Research 2004 NIDA Mini-Convention
SB-277011-A Inhibits Cocaine SA Behaviorunder FR-10 Reinforcement
(Representative cocaine infusions, 3 hrs)
Vehicle + Cocaine (0.5 mg/kg, FR10)
SB + Cocaine (0.5 mg/kg, FR10)
0.125 0.25 0.5
Infu
sion
s / 3 hrs
0
20
40
60
80
100 Vehicle
SB-277011A (24 mg/kg)
(Mean +/- S.E.M.)
Cocaine (mg/kg/infusion)
***
*
Xi et al. (2004)
SB-277011A (mg/kg, i.p.)
0 3 6 12 24
Tim
e (m
in)
to 2
0 L
ever
Pre
sses
0
20
40
60
80
100
120
140 Cocaine (0.75 mg/kg/infusion)
C. Heidbreder - Frontiers in Addiction Research 2004 NIDA Mini-Convention
SB-277011-A Inhibits Cocaine SA Behaviorunder PR Reinforcement
After SB-277011A (24 mg/kg)
Time (min)
0 20 40 60 80 100 120 140 160 180 200
Cu
mu
lative
Le
ve
r Pre
sse
s 0
20
40
60
80
Break-Point =15}
Cocaine = 0.5 mg/kg/infusion
0 20 40 60 80 100 120 140 160 180 200
Cu
mu
lative
Le
ve
r Pre
sse
s 0
200
400
600
800
}Break-Point =145
After Vehicle
Cocaine = 0.5 mg/kg/infusion
Time (min)
SB-277011A (mg/kg)
Veh 6 12 24
Bre
ak
-Po
int
0
20
40
60
80
100
120
*
***
Xi et al. (2004)
C. Heidbreder - Frontiers in Addiction Research 2004 NIDA Mini-Convention
Effect of SB-277011-A (3-12 mg/kg i.p.) onStress-Triggered Relapse to Cocaine-Seeking
Xi et al. (2003)
C. Heidbreder - Frontiers in Addiction Research 2004 NIDA Mini-Convention
Effect of Intracerebral Administration of SB-277011-Aon Stress-Triggered Relapse to Cocaine-Seeking
Xi et al. (2003)
C. Heidbreder - Frontiers in Addiction Research 2004 NIDA Mini-Convention
Why are the Effects Observed with SB-277011-AD3- rather than D2- mediated? (I)
• In contrast with DA D2 antagonists, SB-277011-A does not produce any significant effect on spontaneous locomotion;
• In contrast with DA D2 receptor antagonists, SB-277011-A is not cataleptogenic at doses up to 78.8 mg/kg;
• In contrast with DA D2 receptor antagonists, SB-277011-A does not increase serum prolactin levels (hyperprolactinaemia);
• SB-277011-A can reverse the DA D3 preferring agonist quinelorane-induced decrease in extracellular DA levels in the NAc. In contrast, the effects of quinelorane in the dorsal striatum are not reversed even by doses of SB-277011-A up to 93 mg/kg, thus further reflecting regional differences in DA D3 receptor regulation of DA outflow;
C. Heidbreder - Frontiers in Addiction Research 2004 NIDA Mini-Convention
Why are the Effects Observed with SB-277011-AD3- rather than D2- mediated? (II)
• In contrast with DA D2 antagonists, SB-277011-A does not produce a significant right-shift along the pulse frequency axis in the rate-frequency curve paradigm of the intracranial self-stimulation behavior;
• SB-277011-A does not produce conditioned place aversion in contrast with both the DA D3 agonists 7-OH-DPAT and PD-128907 and the partial D3 agonist BP-897;
• SB-277011-A does not alter nicotine or cocaine self-administration under an FR-1 schedule of reinforcement
• SB-277011-A does not alter natural reinforcers: sucrose (2nd order schedule and oral ethanol self-administration, food self-administration, and food CPP.
C. Heidbreder - Frontiers in Addiction Research 2004 NIDA Mini-Convention
Why Selective DA D3 Receptor AntagonistsMight be Promising for the treatment of Drug Addiction?
• Higher efficacy than gold standards• Immediate effect• No side effects or drop outs due to adverse/aversive effects• No abuse liability• No tolerance to efficacy following long-term treatment• Treatment of multiple dependencies (nicotine, alcohol, cocaine, heroin)• Potential of treatment of psychiatric co-morbidities (e.g. schizophrenia)
C. Heidbreder - Frontiers in Addiction Research 2004 NIDA Mini-Convention
Acknowledgements
Dr. Eliot L. Gardner, NIDA/NIH, Baltimore, USADr. Charles R. Ashby, Saint John’s University, New York, USA
Prof. Barry J. Everitt, University of Cambridge, UKDr. Luigi Cervo, Mario Negri Research Institute, Milano, Italy
Dr. Peter K. Thanos, Brookhaven National Labs, Upton, New York, USA
Drs Maria Pilla, Michela Andreoli, Michela Tessari, Dan Hutcheson