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