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Psychiatric Drug Discovery and DevelopmentPrinceton, June 23-24, 2003
The Vasopressin V1b Receptoras a Therapeutic Target in Stress-Related Disorders
Guy Griebel
Psychiatric Drug Discovery and DevelopmentPrinceton, June 23-24, 2003
Schematic representation of the endocrine, behavioral and autonomic responses to stress mediated by vasopressin (AVP), and the
consequences of repeated stress
The blockade of V1b receptors in the hypothalamus may prevent the
deleterious effects of an hyperactive HPA (stress) axis
Psychiatric Drug Discovery and DevelopmentPrinceton, June 23-24, 2003
The vasopressin pathways in the brain• • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • •
Psychiatric Drug Discovery and DevelopmentPrinceton, June 23-24, 2003
Immunohistochemical localization of the V1b receptor in the rat brain
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Psychiatric Drug Discovery and DevelopmentPrinceton, June 23-24, 2003
Immunohistochemical localization of V1b receptors in brainareas known to modulate anxiety behaviors in rats
Bed Nucleus of theStria Terminalis
Lateral Septum Amygdala Dendate Gyrus
Control
V1bR
Psychiatric Drug Discovery and DevelopmentPrinceton, June 23-24, 2003
The V1b receptor and stress
Rabadan-Diehl et al., J. Neuroendocrinol. 7 : 903-10, 1995
Immo
V 1b
rece
ptor
mR
NA
(per
cent
of c
ontr
ol)
0
50
100
150
200
250
Control8 days14 days
i.p. HS
**
*
*
Eight or 14 days immobilization stress or hypertonic saline injection (ip HS) increases V1b receptor mRNA
Psychiatric Drug Discovery and DevelopmentPrinceton, June 23-24, 2003
SSR149415 : Chemical Structure
Chemical name : : (2S, 4R)-1-[5-chloro-1-[(2,4-dimethoxyphenyl)sulfonyl]-3-(2-methoxyphenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-hydroxy-N,N-dimethyl-2-pyrrolidinecarboxamide, isomer(-)
N
NO
O
S
Cl N
O
OH
OO
O
O
C30 H32 Cl N3 O8 SMW = 630.12
Psychiatric Drug Discovery and DevelopmentPrinceton, June 23-24, 2003
Selectivity profile of SSR149415 for vasopressin andoxytocin receptors
SSR149415 is selective for the rat and human V1b receptor
• • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • •
Mammary270 ± 39
Kidney2897 ± 509
Liver1050 ± 112
CHO1.3 ± 0.9
Hypophysis3.3
Rat
Itk174 ± 35
CHO1412 ± 214
CHO91 ± 23
CHO1.5 ± 0.8
Hypophysis6.0
Human
OTV2V1aV1bKi (nM)
Psychiatric Drug Discovery and DevelopmentPrinceton, June 23-24, 2003
Efficacy of SSR149415 at the human V1b receptor
Inhibition by SSR149415 of AVP-induced Ca2+
increase in CHO cells transfected with the human V1b receptor.
SSR149415 is a competitive antagonist
10-10 10-9 10-8 10-7
SSR 149415 (M)
0
20
40
60
80
100
IC 50 = 3.8 nMIn
hibi
tion
(% o
f Con
trol
)
ICIC5050 = 3.8 = 3.8 nMnM
Psychiatric Drug Discovery and DevelopmentPrinceton, June 23-24, 2003
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Effects of SSR149415 on vasopressin-induced ACTHsecretion in conscious rats
Basal
AC
TH (
pg/m
l)
AVP + SSR149415 (mg/kg p.o., 2 h)
AVP 1 3 10 300
50
100
150
200
250
300
350
AC
TH (p
g/m
l)
**
**
**
AVP + SSR149415 (mg/kg p.o. 2 h)
Basal
SSR149415 decreased in a dose-dependent manner vasopressin-induced secretion of ACTH
Psychiatric Drug Discovery and DevelopmentPrinceton, June 23-24, 2003
Animal models used and psychiatric conditions* modeled to investigate the effects of SSR149415 on emotional processes
• 4-Plate• Light/dark
• Social Interaction• Punished Drinking• Elevated Plus-Maze
Generalized Anxiety Disorder
• Mouse Defense Test Battery
• Forced Swimming• Chronic Mild Stress
• Chronic social stress
PanicDisorder
AcuteStress
Disorder
Major Depressive
Disorder
*According to the DSM-IV classification (1994)
Risk Assessment
Flight Defensive Aggression
• Restraint stress-induced ACTH secretion and
physiological changes• Tail-pinch-induced NE
release• Social Defeat
• Conditioned fear• Distress vocalizations in
rats or guinea pigs
• • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • •
Psychiatric Drug Discovery and DevelopmentPrinceton, June 23-24, 2003
0 10 3 10 30
% T
IME
OPE
N A
RM
S
0
10
20
30
40
50
*
*
mg/kg, po
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Effects of SSR149415 in two classical models of anxiety: The elevated plus-maze and Vogel conflict tests in rats
SSR149415 produced weak anxiolytic-like activity in the elevated plus-maze and Vogel conflict tests in rats
mg/kg, ip0 .3 1 3 0 1 3 10
NU
MB
ER O
F PU
NIS
HED
R
ESPO
NSE
S
0
9
18
27
36
45
54
* **
* *
Diazepam SSR149415
Elevated Plus-maze Vogel Conflict
Psychiatric Drug Discovery and DevelopmentPrinceton, June 23-24, 2003
mg/kg p.o.0.1 0.3 1 3
TIM
E IN
OPE
N A
RM
S (%
)
0
10
20
30
40
50
60
70
80
90
100
**
$
****
**
$
$$
non stress control stress control stress + SSR149415
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Effects of SSR149415 in the elevated plus-maze test in mice following social defeat
SSR149415 antagonized the heightened emotionality in the elevated plus-maze produced by prior (stressful) exposure to an aggressive isolated resident
Psychiatric Drug Discovery and DevelopmentPrinceton, June 23-24, 2003
• • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • •
The mouse defense test battery
FLIGHT
RISK ASSESSMENT
DEFENSIVE AGGRESSION
Psychiatric Drug Discovery and DevelopmentPrinceton, June 23-24, 2003
Effects of SSR149415 in the mouse defense test battery
FLIGHT RISKASSESSMENT
DEFENSIVEATTACK
0 1 3 10 0 1 3 10 300
3
6
9
12
**
STO
PS
0 1 3 10 0 1 3 10 300
40
80
120
160
200
**
*
AVO
IDAN
CE D
ISTA
NCE
(cm
)
0 1 3 10 0 1 3 10 300.0
0.5
1.0
1.5
2.0
2.5
3.0
**
*
*
**
BITI
NG
S
SSR149415 reduced defensive aggression, but no other aspects of defensive behaviors
mg/kg, po
Diazepam SSR149415
Psychiatric Drug Discovery and DevelopmentPrinceton, June 23-24, 2003
0 1 10 30
Dur
atio
n (s
)
0
10
20
30
40
50
** **
0 1 10 300
5
10
15
20
25
30
* *
0 1 10 300
2
4
6
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10
12
14
**
**
Effects of SSR149415 on offensive aggression in hamsters
SSR149415, mg/kg, po
Olfactory Investigation Chase Flank Marking
SSR149415 reduced both conspecific offensive attack and olfactory investigation in hamsters
Psychiatric Drug Discovery and DevelopmentPrinceton, June 23-24, 2003
Effects of SSR149415 on maternal separation-induced distress vocalizations in rat or guinea pig pups
Rat Pups Guinea Pig Pups
SSR149415 produced a dose-dependent decrease in both sonic and ultrasonic distress vocalizations
0 3 10 30 0 3 10 30
ULT
RA
SON
IC D
ISTR
ESS
VOC
ALI
ZATI
ON
S (s
)
0
40
80
120
160
200
240
0 1 3 10 0 10 20 30 SO
NIC
DIS
TRES
SVO
CA
LIZA
TIO
NS
(s)
0
40
80
120
160
200
240
*
**
***
*
* *mg/kg, ip mg/kg, sc
Fluoxetine SSR149415
Psychiatric Drug Discovery and DevelopmentPrinceton, June 23-24, 2003
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Effects of SSR149415 on acute stress-induced ACTH or NE secretion in rats
Restraint Stress-induced increase in plasma ACTH levels
Tail Pinch Stress-induced release in NE in the prefrontal cortex
SSR149415 prevented both restraint and tail pinch stress-induced ACTH and NE releases, respectively
ACTH
(pg/
ml)
050
100150200250300350
* *
0 3 10 N
OR
ADR
ENAL
INE
( % b
asel
ine)
100
125
150
175
200
Basal 0 3 10 SSR149415, mg/kg, po SSR149415, mg/kg, ip
Psychiatric Drug Discovery and DevelopmentPrinceton, June 23-24, 2003
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Effects of SSR149415 in an animal model of depression: The forced-swimming test in rats
0 10 20 40 0 3 10 30 0 3 10 30
IMM
OB
ILIT
Y T
IME
(se
c)
0
50
100
150
200
250
300
mg/kg, PO
SR149415
***
*
*
*
IMIPRAMINE FLUOXETINE
SSR149415 produced dose-dependent antidepressant-like activity
Psychiatric Drug Discovery and DevelopmentPrinceton, June 23-24, 2003
Chronic sequential appplication of mild stressors*
1 2 3 4 5 6 7 8 9 weeks
Treatments
Tests
•Restraint
•Water and food deprivation
•Paired housing in damp sawdust
•Light/dark cycle modification
•Forced swimming
The Chronic Mild Stress Procedure in Mice :A model of depression
Non-stressedmouse Stressed mouse
*
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Psychiatric Drug Discovery and DevelopmentPrinceton, June 23-24, 2003
Effects of repeated treatment (39 days/once a day, ip) of SSR149415 in the chronic mild stress model in mice
Physical state
WEEKS
1 2 3 4 5 6 7
PH
YS
ICA
L S
TATE
SC
ALE
1.0
1.5
2.0
2.5
3.0STRESSED CONTROLSFLUOXETINE (10 mg/kg)SSR149415 (10 mg/kg)SSR149415 (30 mg/kg)
*
CMS CMS+TREAT
**
**
• • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • •
Repeated administration of SSR149415 reversed the degradation of the physical state produced by stress
Psychiatric Drug Discovery and DevelopmentPrinceton, June 23-24, 2003
Effects of 39-day treatment (once a day, ip) of SSR149415 in the chronic mild stress model in mice
Anxiety in the Elevated plus-maze
OPE
N A
RM
EN
TRIE
S
0
5
10
15
20
** *
( g g)
*
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NU
MB
ER O
F O
RIE
NTA
TIO
NS
0
1
2
3
4
5
6
** * *
Risk Assessment in the Mouse Defense Test Battery
Repeated administration of SSR149415 reversed anxiety produced by stress
SSR149415 (10 mg/kg)FLUOXETINE (10 mg/kg)
SSR149415 (30 mg/kg)
NON-STRESSED CONTROLSSTRESSED CONTROLS
Psychiatric Drug Discovery and DevelopmentPrinceton, June 23-24, 2003
No stress
Stress
24h post BrdU
Chronic mild stress decreases the number of BrdU-positive cells
Cell proliferation in the hippocampal dentate gyrus of stressed and non-stressed mice
Num
ber o
f Brd
U p
ositi
ve c
ells
per d
enta
te g
yrus
0
1000
2000
3000
4000
**
no stress stress
Psychiatric Drug Discovery and DevelopmentPrinceton, June 23-24, 2003
Repeated treatment with SSR149415 prevented stress-induced decrease of cell proliferation in the subgranular zone and neurogenesis in the granular cell layer of the dendate gyrus
Effect of SSR149415 on chronic mild stress-induced decrease in neurogenesis in the hippocampus of mice
Num
ber o
f Brd
U p
ositi
ve c
ells
per d
enta
te g
yrus
0
500
1000
1500
2000
t
*
t
no stress stress
vehicleSSR149415Fluoxetine
Num
ber o
f Brd
U p
ositi
ve c
ells
per d
enta
te g
yrus
0
500
1000
1500
2000
2500t
t
*
no stress stress
t
Cell proliferation (24 h post BrdU) Neurogenesis (30 days post BrdU)
Psychiatric Drug Discovery and DevelopmentPrinceton, June 23-24, 2003
Phenotype of BrdU-labeled cells 30 days after the end of stress exposure
Mature neuron
Glial cells 9%
73%
No difference in phenotypic expression patterns between groups
The population of surviving BrdU-positive cells essentially mature into neurons
0
25
50
75
100
Phen
otyp
es o
f Brd
U p
ositi
ve c
ells
(%)
0
25
50
75
100
no stress stress
stress +SSR149415 fluoxetine
NeuNGFAP
Psychiatric Drug Discovery and DevelopmentPrinceton, June 23-24, 2003
The Visible Burrow System: A Realistic Model of Depression in Rats
DOMINANT MALE RAT
FEMALE RATS
SUBORDINATE MALE RATS
Psychiatric Drug Discovery and DevelopmentPrinceton, June 23-24, 2003
Effects of repeated treatment with SSR149415 on agonistic behavior in socially stressed rats in a visible burrow system
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Fluoxetine and SSR149415-treated animals showed higher wound counts than did controls rats
DAY1 2 3 4 5 6 7 8 9 10 11 12 13 14
NU
MB
ER O
F W
OU
ND
S
0
10
20
30
40
50
60
**
***
SSR149415 (10 mg/kg)FLUOXETINE (10 mg/kg)CONTROLS
ACTH
(pg/
ml)
0
50
100
150
200
DOMINANTSNON-STRESSED CONTROLSSTRESSED CONTROLSFLUOXETINE (10 mg/kg po)SSR149415 (10 mg/kg po)
Fighting intensity with the dominant rat ACTH secretion following restraint stress
SSR149415-treated rats showed much higher plasma ACTH levels relative to vehicle subordinates, suggesting
normalization of this HPA axis parameter
Psychiatric Drug Discovery and DevelopmentPrinceton, June 23-24, 2003
Expected clinical spectrum of therapeutic activity of SSR149415 in anxiety/depressive disorders
Generalized Anxiety Disorder
Panic Disorder Acute Stress Disorder
Major Depressive Disorder
Benzodiazepines
Tricyclics, SSRIs and mixed 5HT/NARIs
SSR149415
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Psychiatric Drug Discovery and DevelopmentPrinceton, June 23-24, 2003
SSR149415 : Safety studies
Central depressant effects in mice : rotarod, traction test and spontaneous activity
No effect up to 100 mg/kg, p.o.
Sleep pattern in rats : EEGNo modification up to 30 mg/kg, p.o.
Food intake and weight gain : Obese (ob/ob) andLean female mice, normoglycemic mice and rats
No effect up to 30 mg/kg, p.o.
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Psychiatric Drug Discovery and DevelopmentPrinceton, June 23-24, 2003
Effects of SSR149415 on spatial memory in mice: TheMorris water maze
day1 2 3 4 5
late
ncy
(s)
0
10
20
30
40
50
60
visibleplatform
SALINESSR149415 30mg/kg
DIAZEPAM 3mg/kg
SSR149415 had no effect on either the acquisition of the test or on recalling the platform position after removal.
Psychiatric Drug Discovery and DevelopmentPrinceton, June 23-24, 2003
Effects of SSR149415 in the forced-swimming test in hypophysectomized rats
SSR149415 is still effective in hypophysectomized rats, indicating that the antidepressant-like effects do not depend on blocking only the hypothalamic V1b receptors
0 3 10 30
IMM
OB
ILIT
Y TI
ME
(sec
)
0
20
40
60
80
100
120
SSR149415 (mg/kg, po)
*
Psychiatric Drug Discovery and DevelopmentPrinceton, June 23-24, 2003
Effects of local infusions of SSR149415 in the forced-swimming test in rats
Lateral Septum Central Amygdala
The antidepressant-like effects of SSR149415 are mediated by the V1b receptors located in the lateral septum and the amygdala
Imm
obili
ty ti
me
(s)
0
50
100
150
Saline 0.10.01
**
SSR149415 (µg)
Saline
Imm
obili
ty ti
me
(s)
0
50
100
150
10.10.010.001
***
SSR149415 (µg)
Psychiatric Drug Discovery and DevelopmentPrinceton, June 23-24, 2003
Conclusion• • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • •
The V1b receptor antagonist SSR149415 is able to attenuate some but not all stress-related behaviors in rodents.
The V1b receptor antagonist showed clear effects only in particularly stressful situations, and in tests sensitive to social or aggression cues.
SSR149415 is devoid of central depressant effects, even at high doses, and does not affect cognitive processes or food intake, suggesting a large therapeutic window.
The lateral septum and the central nucleus of the amygdala participate in the antidepressant-like action of SSR149415
V1b receptor antagonists might be useful as a treatment for major depression and stress disorders that result from traumatic events
Psychiatric Drug Discovery and DevelopmentPrinceton, June 23-24, 2003
CHEMISTRY
ELECTROPHYSIOLOGICAL STUDIES
P. AVENETM. DECOBERTD. FRANCON
BEHAVIORAL STUDIES
NEUROCHEMICAL STUDIES
M. ARNONEO. BERGISD.C. BLANCHARDR.J. BLANCHARDE. DUCONSEILLEJ. SIMIANDP. SOUBRIEJ. STEMMELIN
R. ALONSOL. LUKOVICC. SERRADEIL-LE GALR. STEINBERG
Acknowledgments
J. WAGNON