C. Heidbreder - Frontiers in Addiction Research 2004 NIDA Mini-Convention The Dopamine D 3 Receptor System: New Possibilities for Dopamine-Based Reward

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.


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)


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)


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)


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


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


Efficacy Against Nicotine Dependence


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


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)


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)


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


Efficacy Against Cocaine Dependence


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


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


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)


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)


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)


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)


Effect of SB-277011-A (3-12 mg/kg i.p.) onStress-Triggered Relapse to Cocaine-Seeking

Xi et al. (2003)


Effect of Intracerebral Administration of SB-277011-Aon Stress-Triggered Relapse to Cocaine-Seeking

Xi et al. (2003)


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;


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.


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)


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

Documents

C. Heidbreder - Frontiers in Addiction Research 2004 NIDA Mini-Convention The Dopamine D 3 Receptor System: New Possibilities for Dopamine-Based Reward