LES ETATS DEPRESSIFS: ELEMENTS CLES Episode dépressif majeur: Mélancholie/Anhédonie: absence de...
-
Upload
lula-caillaud -
Category
Documents
-
view
103 -
download
0
Transcript of LES ETATS DEPRESSIFS: ELEMENTS CLES Episode dépressif majeur: Mélancholie/Anhédonie: absence de...
LES ETATS DEPRESSIFS: ELEMENTS CLES
Episode dépressif majeur:
Mélancholie/Anhédonie: absence de plaisir pour toute activité.
Perte d’espoir, idées de culpabilité et de dévalorisation de soi. Perte d’appétit, trouble du sommeil et perturbation de l’activité psychomotrice (agitation ou ralentissement). Idées morbides, suicidaires. Difficultés pour se concentrer, penser et prendre des décisions. Anergie, asthénie.
Symptômes : TLJ/TLJ pendant au moins deux semaines consécutives.
~ $ 55 M5 - 9510 – 15 %43 / 5.3M
Coût Social
(USA, 1998)
Age
1er épisodeRisque à vie
Patients
USA-Europe
/France
The symptoms of major depression• Depressed mood most of the day (in children
and adolescents, irritability may signify a depressed mood).
• Markedly diminished interest or pleasure in all or most activities most of the day.
• Large increase or decrease in appetite.
• Insomnia or excessive sleeping.
• Restlessness (evident by hand wringing and such) or slowness of movement.
• Fatigue or loss of energy.
• Feelings of worthlessness or excessive or inappropriate guilt.
• Indecisiveness or diminished ability to think or concentrate.
• Recurrent thoughts of death or of suicide.
Évènement de vie négatif(deuil, divorce, chomage, alcoolisme, précarité …)
Répétition
Sujet résistant
"Coping"("fait face")
Sujet vulnérable
DépressionPrise en charge
causes génétiques causes biologiques
causes génétiques(gènes candidats)
causes biologiques(périodes critiques du développement)
Stress d’intensité
varié
Forced swimming test (“Porsolt”)Tail suspension test
Learned helplessness (escape failures)Separation-induced ultrasonic vocalizationChronic mild stress
Behavioral testing of antidepressants
stressful conditions
The tail suspension test
HELPLESS NON-HELPLESS
duration of immobility (out of 6 min)
115s 35s
Immobility score
Imm
ob
ilit
y (
s)
Generations
0 2 4 6 8 10 12 14
Helpless
Non-Helpless
0
50
100
150
200
250
300
The genetic mouse model of helplessness
SWS2 bouts duration (min)
2.29±0.26
1.36 *±0.14
Number of awakenings
107.9±15.5
151.2 *
±8.3
REM sleep latency (min)
31.5±11.6
15.4 *±8.7
Non-Helpless
Helpless
0
40
80
REM
*
0
100
200
SWS1
*
min
per
24
h
Helpless model of depression
(females/males) Helplessness in several paradigms
Alterations in circadian rhythms
Sleep alterations
Failure to cope with stress (HPA axis)
Anhedonia (sucrose intake)
Decreased 5-HT tone (supersensitive DRN 5-HT1A autoreceptors)
Reversal by antidepressant drugs
Biosynthèse et Catabolisme de la Sérotonine
CO2
N
H
—CH2—CH2—NH2HO
5-HTP/DOPA Décarboxylase
5-HYDROXYTRYPTAMINE
(5-HT) = SÉROTONINE
N
H
—CH2—CH—NH2
COOH
N
H
—CH2—CH—NH2
COOH
HO
Tryptophane Hydroxylase
TRYPTOPHANE
5-HYDROXYTRYPTOPHAN
E(5-HTP)
1/2 O2
N
H
—CH2—CHOHO
5-HYDROXYINDOLEACÉTALDÉHYDE
Monoamine
Oxydase A
(MAOA)
N
H
—CH2—C00HHO
ACIDE 5-HYDROXYINDOLE ACÉTIQUE (5-HIAA)
Acétaldéhyde Déshydrogénase
para-Chlorophénylalanine (pCPA)
-méthylDOPA
IMAOA
5-HT5-HT35-HT5-HT1B5-HT5-HT2 5-HT5-HT45-HT5-HT1A 5-5-HTHTn
5-HT TRANSPORTER5-HT TRANSPORTER
TRYPTOPHANTRYPTOPHAN
TRYPTOPHAN HYDROXYLASETRYPTOPHAN HYDROXYLASE
5-HT5-HT
A.A. DECARBOXYLASEA.A. DECARBOXYLASE
5-HTP5-HTP
intronintron 7 (A779 C) 7 (A779 C) AlcoholismAlcoholism & Suicide & Suicide(L & U alleles)(L & U alleles)
LowLow CSF 5-HIAA CSF 5-HIAA
High ethanol toleranceHigh ethanol toleranceSuicideSuicide
Severe ethanol dependenceSevere ethanol dependence
5-HTTP — S5-HTTP — S
5-HTTP — L5-HTTP — L
AlcoholismAlcoholism
5-HT5-HT1A,1B
HTR1B-2HTR1B-2 allele allele (RFLP) (RFLP) HTR2C (C 23 S)HTR2C (C 23 S)
Reward dependenceReward dependence
The serotonin system
n
5-HIAA(ng/ml)
10-15 20-30
Tryptophan
5-HTP
Serotonin (5-HT)
5-HT neurone5-HT neurone
CSFCSF
normalcontrols
depressedpatients(suicide)
CNS 5-HT tone and depression/suicide
5-HIAA
Decreased 5-HTT densityin the brain stem of depressed patients
Malison et al., 1998
[123I]-CIT binding
Rechute induite par la déplétion en tryptophane
chez des déprimés répondeurs aux ISRS
Delgado et al., 1999
Implication of 5-HT systemin depression and antidepressant
action (1)
Reduced CSF 5-HIAA.
Blunted neuroendocrine and temperature responses to 5-HT agonists.
Reduced [3H]imipramine binding in platelets and postmortem brain (depressed suicided subjects).
Reduced 5-HT1A receptor binding (postsynaptic sites) in living brain and postmortem brain tissues.
Increased 5-HT2A receptor binding in frontal/temporal cortex (postmortem brain tissues).
Implication of 5-HT systemin depression and antidepressant
action (2)
Antidepressant efficacy of agents which increase extracellular 5–HT (SSRIs).
Depressogenic effects of Trp depletion in antidepressant-treated patients.
Antidepressants decrease 5-HT2A receptor density (but ECS increases) and 5-HT1A autoreceptor functioning.
Serotonin synthesis pathway
TPH1 (periphery)
TPH2 (CNS)
TPH2 gene polymorphism and depression(12q21.1)
G1463A
CGT CAT
His 441Arg 441
TPH activity 100 20
Depressed patients(A/A; G/A)
78/87 9/87
Control subjects(A/A; G/A)
216/219(mild depression)
(generalized anxiety)
3/219
10.3% *
1.3%
p<0.001*mainly non responsive to SSRIs Zhang et al., 2005
(-80%)
[C1473G] polymorphism of neuronal tryptophan hydroxylase (TPH2) in mice
Zhang et al., 2004
C
CC
C G
G
G
G
Pro447 (129Sv, C57BL/6)
Arg447 (BALB/cJ, DBA/2)
Discovery of antidepressant drugs
1952-1953- Isoniazid (anti-tuberculosis)
1957 - Iproniazid
1957 - Imipramine
1960 - Amitriptyline
MAOIs
Tricyclics
Increased monoaminergic tone
by currently used antidepressants
5-HTNA
(DA)
Antidepressants
Transporter(5-HTT, NAT)
MAO AAutoreceptors
(2, 5-HT1A, 1B...)
Les antidépresseurs aujourd’hui (1) Inhibiteurs de recapture de la sérotonine (5-HT;
ISRS): Fluoxétine - Prozac®
Paroxétine - Déroxat®
Fluvoxamine - Floxyfral®
Sertraline - Zoloft®
Citalopram - Séropram®
Escitalopram - Cipralex®
Monoaminergic (serotoninergic) neurotransmission
Hypothalamo-hypophyso-adrenocortical (stress) axis
Neurobiology of depression and antidepressants
Where are we?
Hippocampal cells
Growth factors
Other perspectives (melatonin, substance P)
Monoaminergic (serotoninergic) neurotransmission
Hypothalamo-hypophyso-adrenocortical (stress) axis
Hippocampal cells
Growth factors
Other perspectives (melatonin, substance P)
Neurobiology of depression and antidepressants
Where are we?
ACCUMBENS
FRONTALCORTEX
SEPTUM
STRIATUM
PARIETALCORTEX
HIPPOCAMPUSTHALAMUS
SNPC
LOCUSCOERULEUS
VTA
RAPHE
NORADRENALINE
SEROTONINE
DOPAMINE
SUPERPOSITION DES VOIES MONOAMINERGIQUESINNERVATION INTENSE DES STRUCTURES IMPLIQUEES
DANS LES DESORDRES PSYCHIATIQUES
LES MECANISMES MONOAMINERGIQUES COMME CIBLES DANS LE TRAITEMENT DES MALADIES PSYCHIATRIQUES
Cibles : Sites de recapture ( 5-HT et NA ): Récepteurs ( 5-HT = 15, DA = 5, NA = 9): Enzymes de dégradation (MAO A et B)
Humeur
Cognition Motricité
DA
NA5-HT
Cortex FrontalSystème LimbiqueGanglions de la Base
Functionalconnectivity
5-HT2A for NE neurons5-HT2C for DA neurons
5-HT
Serotoninergic nerve ending transporter
ANTIDEPRESSANTSserotonin receptors ’
stimulation
-arousal-cognitive functions
-body weight
0 or
: 0 or
inhibition ofserotonin/noradrenaline
reuptake
- sedation- cardiovascular effects (orthostatic hypotension) - anticholinergic effects (alteration of cognitive functions)
- peripheral effects (constipation, dry mouth, etc…)
- increase in body weight
side effects
muscarinic 1-adrenergic histaminergic
blockade of receptors:
tricyclicreuptake inhibitors
selective serotoninreuptake inhibitors
(SSRI)
Immunogold-silver localization of 5-HTT
Terminal (raphe
nucleus)
Terminal(raphe nucleus)
Asymmetric synapse(hippocampus,granular cell region)
Symmetric synapse
Expression of 5-HTT
in the dorsal raphe nucleus
5-HTT immunoreactivity
mRNA expression
Variants of the serotonin transporter
Controls
0
5
10
15
S LLu
cif
era
se a
cti
vity
5-HTT gene polymorphism
+1
S
+1
5-HTT gene promoter
L
luciferase
-1800pb
Interactions gène (5-HTT) / évènements de vie et dépression
Caspi et al., 2003
Génotype "s" Génotype ”l"
Évènement de vie négatif(deuil, divorce, chomage, alcoolisme, précarité …)
Répétition
Sujet résistant
"Coping"("fait face")
Sujet vulnérable
DépressionPrise en charge
causes génétiques causes biologiques
causes génétiques(gènes candidats)
causes biologiques(périodes critiques du développement)
Stress d’intensité
varié
Zanardi et al., 2000
Réponse à la paroxétine (Deroxat®)et polymorphisme du gène du transporteur
5-HTT
central serotoninergic system
5-HT
5-HT1A
5-HT1B
5-HTT
5-HTT
5-HT 1 A,B,D,E,F [AMPc] gK+ gCa2+ 5-HT 2 A,B,C[IP3 ,DAG ] gK+
5-HT 3As,l, 3B Na+/ K+ GMPc 5-HT 4,6,7 [AMPc] 5-HT 5 A, B [AMPc]
5-HT receptors
5-HTT transporter
cAMP -
DAG
IP 3 +
?cAMP -
Na+
K+
5-HT5-HT66
5-HT5-HT1A1A
5-HT5-HT1E1E
5-HT5-HT3A(L,S)3A(L,S)
5-HT5-HT5(A,B)5(A,B)
5-HT5-HT77
5-HT5-HT4(L,S)4(L,S)
5-HT5-HT2A2A
cAM
P +
5-HT5-HT1B1B
5-HT5-HT1D1D
5-HT5-HT1F1F
5-HT5-HT2C2C
5-HT5-HT2B2B
SEROTONIN
CH2 -CH2 -NH2 HO
NH
5-HT5-HT1B1B
5-HT5-HT1D1D
5-HT5-HT1E1E
5-HT5-HT1F1F
5-HT5-HT2A2A
5-HT5-HT2B2B
5-HT5-HT2C2C
5-HT5-HT3 (A,B)3 (A,B)
5-HT5-HT4(L,S)4(L,S)
5-HT5-HT77
5-HT5-HT66
5-HT5-HT1A 1A 5-HT5-HT5A,B5A,B
DepressionDepressionAnxietyAnxiety
Sexual behaviorSexual behavior
VasomotricityVasomotricityNociceptionNociceptionFood intakeFood intake
}} MigraineMigraine
??
Gastro-intestinalGastro-intestinalmotilitymotility
Cognition (?)Cognition (?)
Nausea, emesisNausea, emesisGastro-intestinal motilityGastro-intestinal motility
Cognition (?)Cognition (?)Nociception (periphery)Nociception (periphery)
AnxietyAnxietySexual behaviorSexual behavior
Food intake Food intake Smooth musclesSmooth muscles
(gastro-intestinal tract)(gastro-intestinal tract)Migraine (long term)Migraine (long term)
SchizophreniaSchizophreniaVasomotricityVasomotricitySleep/wakefulnessSleep/wakefulnessNociception (periphery)Nociception (periphery)
MigraineMigraine??SEROTONINSEROTONIN
CHCH22-CH-CH22-NH-NH22 HOHO
HH
NN
VasomotricityVasomotricitySleep/wakefulnessSleep/wakefulnessThermoregulationThermoregulation
Food intakeFood intakeCognitionCognition
Mayorga et al., J. Pharmacol. Exp.Ther., 2001
5-HT1A-mediated antidepressant-like effect of SSRI
Rat 5-HT1A receptor sequence
YY
RR
Y 1
COOH422
K
D
FQN
AF
KK
KI
I
C KFC
IT G M I
L I F
P L W C
F FIV L A V
F P L L L GA I I NW L G
Y S SNL NL
P V I YA Y
NF
C
ES
S C HMP
AV
T
S
YQ
F
NV G E Q T G MDVFSFGQTASPFGTGTSISDV N N
A
IGS
L
ER
SL Q N V
AN
Y
T V A L
M L D
L V VSVP L
LNK
WT L G
QV
TC
G YH
YI STF GT
A F Y I
LLLP
L M
R
PE
S
D
D P D A CT
IS
K
D
ISLT
I L W
I GL FP I S
G L M P
T R W
AL A A
I L H
C T S S
Y
T
D
WA
I
PI D Y V
N K
R
R
PR
T
T SI
GL L LL IT
L G N
F C VA
C VVA
IA A
V Q YL A A M
D L FI A L D
CV L
L C IAL DA
R
V
KT
LG
E
KM
A
AL
R
R
KT
V
R
R
F
A
AR
RF
IRKTVRK E V KT KGAGSLG
TS
S
E NAAKR
KN
ER
SSE
GNSY
AP
A
C L ER
S
A
SKPP P K
LNGQP
SG
DG
W
RR
C AP
H L
LP
R VQ G DD EA T LE I E VV H R G N S K EVAGVA G T PE TC NRN
I
L Y GL
NH2
* *
*Y: N-glycosylation
*: Phosphorylation
Molecular organization of brain 5-HT1A receptor
G
5-HT1A
G
RGS ?CAM?
G
Actin ?
Filamin ?
K+
Adenylyl cyclase
GIRKPSD95 ?PSD95 ?
récepteurs 5-HT1A marquage
autoradiographique
Récepteurs 5-HT1A - cerveau humain([11C]WAY 100635)
Pike et al.
hippocampal neurones
K+
GIRKRGS ??
GG
5-HT1AGABA B
Go1
dorsal raphe neurones
K+
GIRKRGS ??
GG
5-HT1AGABA B
Gi3
Ca++
[35S]GTP--S
[35S]GTP--S
""PrePre"" and postsynaptic 5-HT and postsynaptic 5-HT1A1A – Experimental – Experimental approachesapproaches
Chronic SSRIs and 5-HT1A autoreceptorsin the dorsal raphe nucleus
-9 -8 -7 -60
20
40
60
80
100
log [ 8-OH-DPAT] M
vehicle
fluoxetine 21 d
Inh
ibit
ion
of
firi
ng
(%
of
base
lin
e)
8-OH-DPAT (nM)
0
10
10
vehicle
0
10
8-OH-DPAT (nM)
10 30
fluoxetineacti
on
pote
nti
als
/ 1
0 s
ec
2 min
Chronic SSRIs and postsynaptic 5-HT1A receptors in the hippocampus
5-CT (nM)
3 10 30 100 300
saline-treated rat
-67 mV
5-CT (nM)
3 10 30 100 300
fluoxetine-treated rat
10 mV
2 min
-65 mV
wash
wash
-9 -8 -7 -60
2
4
6
8
10
fluoxetine 21 d
vehicle
log [ 5-CT] M
Hyp
erp
ola
riza
tion
(m
V)
5-HTT binding siteslabeled by
[3H]citalopram
DRN
DRN
5-HTT +/+
5-HTT+/-
5-HTT-/-
5-HT1A autoreceptor desensitization
in 5-HTT -/- knock-out mice
-9 -8 -7 -6
2
4
6
8
Hyp
erp
ola
riza
tion
(m
v)
log [5-CT] M
5-HTT (-/-)
5-HTT (+/+)
CA1
0
-4
log [ipsapirone] M
Inh
ibit
ion
of
firi
ng
(%
)
-9 -8 -7 -6 -50
25
50
75
100 5-HTT (+/+)
5-HTT (-/-)
DRN
20
0
3 µM 10 µMIpsapirone 1 µM
Ipsapirone 300 nM
20
0
Fir
ing
rate
(sp
ikes
/ 1
0s)
WAY 100635 2 nM5-HTT (-/-)
DRN
20
0
Ipsapirone 3 µM
5-HTT (+/+)
hippocampal neurones
K+
GIRKRGS ??
GG
5-HT1AGABA B
Go1
dorsal raphe neurones
K+
GIRKRGS ??
GG
5-HT1AGABA B
Gi3
Ca++
[35S]GTP--S
[35S]GTP--S
""PrePre"" and postsynaptic 5-HT and postsynaptic 5-HT1A1A – Experimental – Experimental approachesapproaches
5-HT1A-G protein coupling in 5-HTT-/- knock-out mice
Hip
DRN
5-CT
+/- -/-+/+
BASAL
5-HTT
+ / + - / -
5-CT (10 µM)-evoked [35S]GTP--S binding (%)
+ / -
hippocampus 460 ± 18 446 ± 49 NS
(-3%)474 ± 38 NS
(+3%)
dorsal raphe nucleus 150 ± 8 101 ± 8 *(-33%)
51 ± 1 **(- 66%)
5-HTT
5-HT1A receptors
+ / ++ / + + / -+ / - - / -- / -
dorsal raphe nucleus dorsal raphe nucleus 77 ± 177 ± 1 71 ± 3 71 ± 3 NSNS
(- 8%)(- 8%)41 ± 341 ± 3**** (- 48%)(- 48%)
fmol / mg tissuefmol / mg tissue
hippocampushippocampus 93 ± 193 ± 1(+17%)(+17%) 117 ± 6 117 ± 6 ** (+26%)(+26%)109 ± 1109 ± 1****
[3H]alnespirone
+/+ +/- -/-5-HTT
DendritesControl Fluoxetine WAY + fluoxetine
Fluoxetine-induced internalization
Of DRN 5-HT1A autoreceptors
hippocampal neurones
K+
GIRKRGS ??
GG
5-HT1AGABA B
Go1
dorsal raphe neurones
K+
GIRKRGS ??
GG
5-HT1AGABA B
Gi3
Ca++
[35S]GTP--S
[35S]GTP--S
Both 5-HTBoth 5-HT1A1A and GABA and GABABB receptors might be receptors might be implicatedimplicated
in antidepressants ’ actionin antidepressants ’ action
[5-HT] (n)[5-HT] (H)
[5-HT] (d)
Serotonin (5-HT)
5-HT1A autoreceptors and serotoninergic tone
5-HT1A = inhibitory
autoreceptor
raphéarea
Limbicstructures(postsynaptic)
H
H n
dn
d
Desensitization :Desensitization :
Hypersensitivity :Hypersensitivity :Cocaine (chronic)Alcohol (chronic)Depression
Antidepressants
5-HT1A receptor changes by chronic alcoholisationControl Alcohol
5-HT
5-HT1A
- antidepressant drugs (SSRI)
- physical exercise
- impulsive behavior - aggressiveness
- craving
- tolerance to delayed reward - self-control
- (mood)
- cannabis- alcohol- cocaine- ecstasy- opioid- food
reward system
CB1 antagonist
5-HT neuron
postsynaptic neuron
raphe area
Target areas
chronic treatment
[5-HT]
0
acute treatment
5-HTn5-HTn
SSRI
SSRI and 5-HT neurotransmission
[5-HT] =
SSRI [5-HT]5-HT1A
[5-HT]5-HT1A
SSRI
SSRI[5-HT]
5-HT1B/1D
pindolol
[5-HT]
5-HT1B/1D0
5-HT5-HT1B1B
5-HT5-HT1D1D
5-HT5-HT1E1E
5-HT5-HT1F1F
5-HT5-HT2A2A
5-HT5-HT2B2B
5-HT5-HT2C2C
5-HT5-HT3 (A,B)3 (A,B)
5-HT5-HT4(L,S)4(L,S)
5-HT5-HT77
5-HT5-HT66
5-HT5-HT1A 1A 5-HT5-HT5A,B5A,B
DepressionDepressionAnxietyAnxiety
Sexual behaviorSexual behavior
VasomotricityVasomotricityNociceptionNociceptionFood intakeFood intake
}} MigraineMigraine
??
Gastro-intestinalGastro-intestinalmotilitymotility
Cognition (?)Cognition (?)
Nausea, emesisNausea, emesisGastro-intestinal motilityGastro-intestinal motility
Cognition (?)Cognition (?)Nociception (periphery)Nociception (periphery)
AnxietyAnxietyDepressionDepression
Sexual behaviorSexual behaviorFood intake Food intake Smooth musclesSmooth muscles
(gastro-intestinal tract)(gastro-intestinal tract)Migraine (long term)Migraine (long term)
SchizophreniaSchizophreniaVasomotricityVasomotricitySleep/wakefulnessSleep/wakefulnessNociception (periphery)Nociception (periphery)
MigraineMigraine??SEROTONINSEROTONIN
CHCH22-CH-CH22-NH-NH22 HOHO
HH
NN
VasomotricityVasomotricitySleep/wakefulnessSleep/wakefulnessThermoregulationThermoregulation
Food intakeFood intakeCognitionCognition
Disrupted activation of Rho GTPasesby 5-HT2C mRNA editing
McGrew et al.,2004
Wang et al., 2000
Edition sites of 5-HT2C receptor mRNA
A
B
Ile Asn Ile
Val Asp
Met
Val
Ser
Gly
Phosphoinositid hydrolysis activities of RNA editing isoforms and splicing variants of 5-HT2C
receptor
Wang et al., 2000
Effect of stress and/or fluoxetineon 5-HT2C edited mRNA isoforms in mice
Englander et al., 2005cerebral cortex - forced swimming
Novel perspectives in 5-HT-related treatment of affective disorders
Depression
5-HT2Cantagonists
5-HT1A
agonists
antagonists5-HT1B/1D
antagonists
5-HT2Bagonists5-HT7
antagonists
(+ MTR agonists - agomelatine)
(+ SSRI)(+ SSRI)
Monoaminergic (serotoninergic) neurotransmission
Hypothalamo-hypophyso-adrenocortical (stress) axis
Hippocampal cells
Growth factors
Other perspectives (melatonin, substance P)
Neurobiology of depression and antidepressants
Where are we?
FEED BACK INHIBITORY CONTROLOF STRESS AXIS (HPA)
depression,aging
stress recovery
0 1 2 3 4 Time (h)
cort
isol
(ng
/ml)
Controls
Alcoholisation
+ antidepressants
10
50
GR
GR
Hippocampus
HypothalamusCRH
Pituitary gland ACTH
Adrenal glandCortisol
Target organs
Hippocampus
HypothalamusCRH
Pituitary gland ACTH
Adrenal glandCortisol
Target organs
GR
GR
[Cortisol]?
CRF
Dexamethasone
DEXAMETHASONE TEST
DEXAMETHASONE TESTC
ort
isol
(ng
/ml)
10
80
CONTROL
A B C
DEPRESSION
A B C
ALCOHOLISATION(250-300 g ethanol/day)
A B C
A : basal
B : CRH (0.1 mg i.v.)
C : dexamethasone (1.5 mg p.o.) + CRH
Hippocampus
Hypothalamus (PVN)CRH, AVP
Pituitary glandACTH
Adrenal glandCortisol
Target organs
GR
GR
- chronic stress- depression
Antidepressants - tricyclics - MAOIs - SSRIs
Axe du stress, dépression et antidépresse
urs
Okugawa et al., 1999
Antidepressant-induced up regulation
of GRmRNA in cultured
rat hippocampal neurones
14 day-exposure
CRH1 receptor antagonists
Mansberget al., 1997
Antidepressant-like effect of CRH1R blockade by CP-154,526 in rats
Learned helplessness procedure
Zobel et al., 2000
Anxiolytic and antidepressant effects of CRH1R blockade
by R 121919
Monoaminergic (serotoninergic) neurotransmission
Hypothalamo-hypophyso-adrenocortical (stress) axis
Hippocampal cells
Growth factors
Other perspectives (melatonin, substance P)
Neurobiology of depression and antidepressants
Where are we?
Sheline et al., 1996
Hippocampus involution in depressed patients
Lupien et al., 1998
Correlations between plasma cortisol and hippocampus volume
Glucocorticoid-induced
neurodegeneration in the hippocampus
Neurogenesis of granule cellsin the hippocampus
Marquage de la prolifération cellulaire par le BrdU au sein du gyrus denté
Lignée DBA/2J Lignée C57BL/6J
Granule cell proliferation in the dentate gyrusHelpless vs Non-Helpless mice
Brd
U lab
elled
cells /
secti
on
0
5
10
Non- Helpless Helpless
Age: 9 weeks* p<0.05
*
Granule cell proliferation in the dentate gyrusEffects of in Helpless mice
Helpless
NH
0
50
100
150
200
**
none veh Fluoxetine
Brd
U lab
ele
d c
ells /
hip
po
* p<0.05
fluoxetinefluoxetine
Jacobs et al., 2000
5-HT1A-mediated increase in granule cell proliferation
by d-fenfluramine
Li et al., 2003
5-HT1A-dependent granule cell proliferationin the mouse dentate gyrus
F = fluoxetineI = imipramine
Antidepressants (SSRI, NK1 )
Electroconvulsive shocks
Granule cell proliferation (dentate gyrus - hippocampus)
Opiates (morphine, heroin)NicotinePsychostimulants (cocaine)(Cannabis)
ANTIDEPRESSANTS AND NEURONAL PLASTICITY
chronic stress (sensitization)
CRH
Cognitive andpsychoaffectivedisorders
Cortisol GR
chronicHPA
hippocampusCell death
Neurogenesis
Antidepressants
5-HT, NA, etc…
NGF
NT-3
GRBDNF
Monoaminergic (serotoninergic) neurotransmission
Hypothalamo-hypophyso-adreno-cortical (stress) axis
Hippocampal cells
Growth factors
Other perspectives (melatonin, substance P)
Neurobiology of depression and antidepressants
Where are we?
Structures chimiques d’antidépresseurs mixtes
Mirtazapine
NA
Effet antidépress
eur
Effet anxiogène << Effet anxiolytique
NA
5-HT
5-HT2A
5-HT2c
5-HT35-HT1A
2 2
Effets 2-antagonistes de la mirtazapine
Locom
oto
r acti
vit
y (
cou
nts
per
5 m
in)
0
10
20
30
40
50
60
19:00 07:00 19:00
* * * *
Spontaneous circadian rhythms
Locomotor activity
Non helplessHelpless
MT2
Gi/o
11q21-22
h363aa
MT1
Gi/o
4q35-1
h350aa
O
O
CH3NH
CH 3
S 20098(Agomelatin
e)
Granule cell proliferation in the dentate gyrusEffects of agomelatine in Helpless mice
H
NH
0
50
100
150
200
**
none veh Agomelatine
Brd
U lab
ele
d c
ells /
hip
po
* p<0.05
Monoaminergic and peptidergic control of nociception
Most previous studies were performed at the level of the first relay of pain pathways, the dorsal horn of the spinal cord.
Peptide release (in vitro and in vivo).
Pain-associated alterations in peptidergic neurotransmission.
Chronic pain models :
Inflammatory pain (poly-arthritic rat).
Neuropathic pain (sciatic nerve section).
PeripheryPeriphery
Dorsal root gangliaDorsal root ganglia
Bulbo-mesencephalicBulbo-mesencephalicregionregion
SupraspinalSupraspinalstructuresstructures
Spinal cordSpinal cord
Descending controlsDescending controls(5-HT, NA, CCK, SP…)(5-HT, NA, CCK, SP…)
InterneuronesInterneurones(ME, CCK, SP…)(ME, CCK, SP…)
PrimaryPrimaryafferent fibresafferent fibres((SPSP,CGRP,ME,,CGRP,ME,Excitatory AA…)Excitatory AA…)
Substance P
Arg-Pro-Lys-Pro-Gln-Gln-Phe-Phe-Gly-Leu-Met-NH2
Selective antagonists
Antidepressants-animal models
-humans
NK1 NK2 NK3
Rupniak et al., 2001
Effect of NK1R knock-out and NK1R blockadeon mouse behavior in the forced swim test
Kramer et al., 1998
Antidepressant (A) and anxiolytic (B) effects of NK1R
blockade in human
placebo
MK-869
paroxetine
Up-regulation of GR-mRNAin NK1-/- knock-out mice
0
20
40
60
80
**
Cerebral cortex
GR
-mR
NA
(am
ol)
/to
tal
RN
A (
µg
)
0
20
40
60
80
*
Hippocampus
GR
-mR
NA
(am
ol)
/to
tal
RN
A (
µg
)
0
20
40
60
80
*
Ant. Raphe area
GR
-mR
NA
(am
ol)
/to
tal
RN
A (
µg
)
Wild – type (C57BL/6J)NK1-/-
NK1-/-
ipsapirone 1000 nM
100030 60 100 300ipsapirone (nM)
WAY 100635 (1 nM)
20
0
3 min
20
0
NK1+/+
20
0
ipsapirone (nM)
30 60 100 30010
ipsapirone 100 nM
WAY 100635 (1 nM)
20
0
3 min
Sp
ike
s p
er
10
se
c
-9 -8 -7 -6 -5 -40
25
50
75
100
Inhi
bitio
n of
fir
ing
(%)
log [ipsapirone] M
NK1+/+
NK1-/-***
**
**
**
**
5-HT1A autoreceptor desensitization in NK1 -/- knock-out mice
Froger et al. 2003
Sp
ikes p
er
10 s
ec
20
0
ipsapirone (nM)60 100 300
GR 205171 10 mg/kg/d (21 days)GR 205171 10 mg/kg/d (21 days)
VehicleVehicle
20
0
60 100 ipsapirone (nM)
3 min
Log [5-CT] M
Perc
en
tag
e o
ver
baselin
e (
%)
-9 -8 -7 -6 -50
50
100
150
**
**
* *
Vehicle
GR 205171 (10 mg/kg/d)
DRN-5-HT neuron firingDRN-5-HT1A-evoked
[35S]GTP--S binding
Chronic NK1 receptor blockadedesensitizes DRN 5-HT1A
autoreceptors
5-HT1A receptor adaptation
to chronic antidepressant
treatments
"presynaptic " 5-HT1A
autoreceptors(DRN)
"postsynaptic " 5-HT1A
heteroreceptors(hippocampus)
0
0
0
Tricyclics
MAOIs
SSRIsNK1 antagonists
DEPRESSION ANTIDEPRESSANTS
hypothalamo-hypophyso-Adrenocortical axis
hippocampal granulecell proliferation
growth factors(BDNF)
Monoaminergicneurotransmission
Neurobiology of depression and
antidepressants
Current questions