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 M 5 - 95 10 – 15 % 43 / 5.3M Coût Social (USA, 1998) Age 1er épisode Risque 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 Répétition (deuil, divorce, chomage, alcoolisme, précarité …) Répétition Sujet résistant "Coping" ("fait face") Sujet vulnérable Dépression Prise en charge causes génétiques causes biologiques (gènes candidats) (périodes critiques du développement) Stress d’intensité varié

Behavioral testing of antidepressants stressful conditions Forced swimming test (“Porsolt”) Tail suspension test Learned helplessness (escape failures) Separation-induced ultrasonic vocalization Chronic mild stress

The genetic mouse model of helplessness The tail suspension test Immobility score 50 100 150 200 250 300 Helpless Immobility (s) Non-Helpless Generations 2 4 6 8 10 12 14 HELPLESS NON-HELPLESS duration of immobility (out of 6 min)  115s  35s

SWS2 bouts duration (min) REM sleep latency (min) Non-Helpless Helpless Number of awakenings SWS1 107.9 ±15.5 151.2 * ±8.3 * 200 100 SWS2 bouts duration (min) 2.29 ±0.26 1.36 * ±0.14 min per 24h REM * REM sleep latency (min) 80 31.5 ±11.6 15.4 * ±8.7 40

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 —CH2—CH—NH2 TRYPTOPHANE COOH para-Chlorophényl alanine (pCPA) N H —CH2—C00H HO ACIDE 5-HYDROXY INDOLE ACÉTIQUE (5-HIAA) 1/2 O2 Tryptophane Hydroxylase 5-HYDROXY TRYPTOPHANE (5-HTP) —CH2—CH—NH2 COOH HO N H Acétaldéhyde Déshydrogénase a-méthyl DOPA 5-HTP/DOPA Décarboxylase CO2 N H —CH2—CH2—NH2 HO N H —CH2—CHO HO Monoamine Oxydase A (MAOA) 5-HYDROXYTRYPTAMINE (5-HT) = SÉROTONINE 5-HYDROXYINDOLE ACÉTALDÉHYDE IMAOA

The serotonin system 5-HT 5-HT TRYPTOPHAN TRYPTOPHAN intron intron 7 (A779 C) 7 (A779 C) Alcoholism Alcoholism & Suicide & Suicide TRYPTOPHAN HYDROXYLASE TRYPTOPHAN HYDROXYLASE (L & U alleles) 5-HTP 5-HTP Low Low CSF 5-HIAA CSF 5-HIAA A.A. DECARBOXYLASE High ethanol tolerance High ethanol tolerance A.A. DECARBOXYLASE Suicide Suicide Severe ethanol dependence Severe ethanol dependence 5-HT 5-HT 5-HTTP — S 5-HTTP — S 5-HT1A,1B 5-HT 5-HT TRANSPORTER 5-HT TRANSPORTER 5-HTTP — L 5-HTTP — L 5-HT 5-HT2 5-HT3 5-HT 5-HT1B 5-HT 5-HT4 5-HT 5-HT1A 5-HT 5- 5- HTn HT HTR1B-2 HTR1B-2 allele allele (RFLP) (RFLP) HTR2C (C 23 S) The serotonin system HTR2C (C 23 S) Alcoholism Alcoholism Reward dependence Reward dependence

CNS 5-HT tone and depression/suicide 5-HT neurone Tryptophan depressed patients (suicide) n normal controls 5-HTP 10-15 20-30 5-HIAA (ng/ml) Serotonin (5-HT) CSF 5-HIAA

Decreased 5-HTT density in the brain stem of depressed patients [123I]-CIT binding Malison et al., 1998

Rechute induite par la déplétion en tryptophane chez des déprimés répondeurs aux ISRS Delgado et al., 1999

Implication of 5-HT system in 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 system in 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 Arg 441 His 441 TPH activity 100 20 (-80%) Depressed patients (A/A; G/A) 78/87 9/87 10.3% * Control subjects (A/A; G/A) 216/219 (mild depression) (generalized anxiety) 3/219 1.3% * p<0.001 Zhang et al., 2005 mainly non responsive to SSRIs

Pro447 (129Sv, C57BL/6) Arg447 (BALB/cJ, DBA/2) C G C G C G C G [C1473G] polymorphism of neuronal tryptophan hydroxylase (TPH2) in mice Pro447 (129Sv, C57BL/6) Arg447 (BALB/cJ, DBA/2) C G C G C G C G Zhang et al., 2004

Discovery of antidepressant drugs 1952-1953 - Isoniazid (anti-tuberculosis) 1957 - Iproniazid MAOIs 1957 - Imipramine 1960 - Amitriptyline Tricyclics

Increased monoaminergic tone by currently used antidepressants Autoreceptors (2, 5-HT1A, 1B...) 5-HT NA (DA) MAO A Transporter (5-HTT, NAT) Antidepressants

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®

Neurobiology of depression and antidepressants Where are we?  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?  Monoaminergic (serotoninergic) neurotransmission  Hypothalamo-hypophyso-adrenocortical (stress) axis  Hippocampal cells  Growth factors  Other perspectives (melatonin, substance P)

SUPERPOSITION DES VOIES MONOAMINERGIQUES INNERVATION INTENSE DES STRUCTURES IMPLIQUEES DANS LES DESORDRES PSYCHIATIQUES PARIETAL CORTEX FRONTAL CORTEX STRIATUM SEPTUM THALAMUS HIPPOCAMPUS SNPC ACCUMBENS VTA LOCUS COERULEUS DOPAMINE SEROTONINE RAPHE NORADRENALINE

DA 5-HT NA Cibles : Sites de recapture ( 5-HT et NA ) LES MECANISMES MONOAMINERGIQUES COMME CIBLES DANS LE TRAITEMENT DES MALADIES PSYCHIATRIQUES DA Cortex Frontal Système Limbique Ganglions de la Base Cognition Motricité Humeur 5-HT NA Cibles : Sites de recapture ( 5-HT et NA ) : Récepteurs ( 5-HT = 15, DA = 5, NA = 9) : Enzymes de dégradation (MAO A et B)

Functional connectivity 5-HT2A for NE neurons 5-HT2C for DA neurons

5-HT Serotoninergic nerve ending transporter ANTIDEPRESSANTS inhibition of serotonin/noradrenaline reuptake selective serotonin reuptake inhibitors (SSRI) tricyclic reuptake inhibitors blockade of receptors: ANTIDEPRESSANTS serotonin receptors ’ stimulation muscarinic a1-adrenergic histaminergic side effects - sedation - cardiovascular effects (orthostatic hypotension) - anticholinergic effects (alteration of cognitive functions) - peripheral effects (constipation, dry mouth, etc…) - increase in body weight -arousal -cognitive functions -body weight 0 or  : 0 or 

Immunogold-silver localization of 5-HTT Terminal (raphe nucleus) Terminal (raphe nucleus) Asymmetric synapse (hippocampus, granular cell region) Symmetric synapse

in the dorsal raphe nucleus Expression of 5-HTT in the dorsal raphe nucleus 5-HTT immunoreactivity mRNA expression

Variants of the serotonin transporter

5-HTT gene polymorphism Controls 5 10 15 +1 S 5-HTT gene promoter L luciferase -1800pb Luciferase activity S L

Interactions gène (5-HTT) / évènements de vie et dépression Génotype "s" Génotype ”l" Caspi et al., 2003

Évènement de vie négatif Répétition (deuil, divorce, chomage, alcoolisme, précarité …) Répétition Sujet résistant "Coping" ("fait face") Sujet vulnérable Dépression Prise en charge causes génétiques causes biologiques (gènes candidats) (périodes critiques du développement) Stress d’intensité varié

Réponse à la paroxétine (Deroxat®) et polymorphisme du gène du transporteur 5-HTT Zanardi et al., 2000

central serotoninergic system 5-HTT 5-HT1A 5-HTT transporter 5-HT receptors 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-HT1B 5-HTT 5-HT

? cAMP - cAMP + cAMP - DAG IP3 + Na+ K+ SEROTONIN 5-HT1A 5-HT1B 5-HT7 5-HT1D cAMP + 5-HT6 5-HT1E SEROTONIN CH2 -CH2 -NH2 HO N H 5-HT1F 5-HT4(L,S) 5-HT2A 5-HT5(A,B) 5-HT2B cAMP - ? 5-HT3A(L,S) 5-HT2C DAG IP3 + Na+ K+

} ? ? 5-HT1A 5-HT5A,B 5-HT1B 5-HT6 5-HT1D 5-HT7 5-HT1E 5-HT4(L,S) Depression Anxiety Sexual behavior Food intake Cognition Vasomotricity } Migraine 5-HT1A Nociception Food intake Vasomotricity Sleep/wakefulness Thermoregulation 5-HT5A,B 5-HT1B 5-HT6 5-HT7 5-HT1D Gastro-intestinal motility Cognition (?) SEROTONIN CH2-CH2-NH2 HO H N 5-HT1E ? 5-HT4(L,S) ? Migraine 5-HT1F Nausea, emesis Gastro-intestinal motility Cognition (?) Nociception (periphery) 5-HT3 (A,B) 5-HT2A 5-HT2C 5-HT2B Schizophrenia Anxiety Vasomotricity Sexual behavior Food intake Sleep/wakefulness Nociception (periphery) Smooth muscles (gastro-intestinal tract) Migraine (long term)

5-HT1A-mediated antidepressant-like effect of SSRI Mayorga et al., J. Pharmacol. Exp.Ther., 2001

Rat 5-HT1A receptor sequence Y Y Y 1 NH2 K D F Q N A I C T G M L P W V Y S E H R * * R R COOH 422 * Y: N-glycosylation *: Phosphorylation

Molecular organization of brain 5-HT1A receptor K+ 5-HT1A Adenylyl cyclase Ga Gg Gb RGS ? CAM? GIRK PSD95 ? Notion de transductosome : Rôle prot à domaine PDZ ? Ex R 5-HT2C : prot associée à l’ext C term des R (PSD95, SAP1, Veli3, dynamine, calmoduline, actine PSD95 : rôle dans la resensibilisation, maintien du R à la membrane homer Filamin ? Actin ?

récepteurs 5-HT1A marquage autoradiographique

Récepteurs 5-HT1A - cerveau humain ([11C]WAY 100635) Pike et al.

"Pre" and postsynaptic 5-HT1A – Experimental approaches dorsal raphe neurones hippocampal neurones K+ K+ 5-HT1A Ca++ 5-HT1A GABA B GABA B Gg Gg Gb Gb Gai3 Gao1 GIRK GIRK RGS ?? [35S]GTP-g-S RGS ?? [35S]GTP-g-S

Chronic SSRIs and 5-HT1A autoreceptors in the dorsal raphe nucleus 8-OH-DPAT (nM) 10 vehicle 30 fluoxetine action potentials / 10 sec 2 min vehicle 100 80 60 Inhibition of firing (% of baseline) fluoxetine 21 d 40 20 -9 -8 -7 -6 log [ 8-OH-DPAT] M

Chronic SSRIs and postsynaptic 5-HT1A receptors in the hippocampus 5-CT (nM) 3 10 30 100 300 saline-treated rat -67 mV fluoxetine-treated rat 10 mV 2 min -65 mV wash 2 4 6 8 10 fluoxetine 21 d Hyperpolarization (mV) vehicle -9 -8 -7 -6 log [ 5-CT] M

5-HTT binding sites labeled by [3H]citalopram DRN 5-HTT+/- DRN 5-HTT-/-

5-HT1A autoreceptor desensitization in 5-HTT -/- knock-out mice -4 log [ipsapirone] M Inhibition of firing (%) -9 -8 -7 -6 -5 25 50 75 100 5-HTT (+/+) 5-HTT (-/-) DRN 20 3 µM 10 µM Ipsapirone 1 µM Ipsapirone 300 nM Firing rate (spikes / 10s) WAY 100635 2 nM 5-HTT (-/-) DRN Ipsapirone 3 µM 5-HTT (+/+) - 9 8 7 6 2 4 Hyperpolarization (mv) log [5-CT] M 5-HTT (-/-) 5-HTT (+/+) CA1

"Pre" and postsynaptic 5-HT1A – Experimental approaches dorsal raphe neurones hippocampal neurones K+ K+ 5-HT1A Ca++ 5-HT1A GABA B GABA B Gg Gg Gb Gb Gai3 Gao1 GIRK GIRK RGS ?? [35S]GTP-g-S RGS ?? [35S]GTP-g-S

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-g-S binding (%) 5-HTT + / + + / - - / - dorsal raphe nucleus 150 ± 8 101 ± 8 * 51 ± 1 ** (-33%) (- 66%) hippocampus 460 ± 18 474 ± 38 NS 446 ± 49 NS (+3%) (-3%)

5-HT1A receptors 5-HTT + / + + / - - / - dorsal raphe nucleus +/+ +/- -/- [3H]alnespirone fmol / mg tissue + / + + / - - / - dorsal raphe nucleus 77 ± 1 71 ± 3 NS 41 ± 3** (- 8%) (- 48%) hippocampus 93 ± 1 109 ± 1** 117 ± 6 * (+17%) (+26%)

Fluoxetine-induced internalization Of DRN 5-HT1A autoreceptors Dendrites Control Fluoxetine WAY + fluoxetine

Both 5-HT1A and GABAB receptors might be implicated in antidepressants ’ action dorsal raphe neurones hippocampal neurones K+ K+ 5-HT1A Ca++ 5-HT1A GABA B GABA B Gg Gg Gb Gb Gai3 Gao1 GIRK GIRK RGS ?? [35S]GTP-g-S RGS ?? [35S]GTP-g-S

5-HT1A autoreceptors and serotoninergic tone Serotonin (5-HT) H n d 5-HT1A = inhibitory autoreceptor raphé area H n d Hypersensitivity : Cocaine (chronic) Alcohol (chronic) Depression Desensitization : Antidepressants Limbic structures (postsynaptic) [5-HT]  (H) [5-HT] (n) [5-HT]  (d)

5-HT1A receptor changes by chronic alcoholisation Control Alcohol

- tolerance to delayed reward  CB1 antagonist - tolerance to delayed reward  - self-control  - (mood)  reward system 5-HT - antidepressant drugs (SSRI) - physical exercise - cannabis - alcohol - cocaine - ecstasy - opioid - food 5-HT1A - impulsive behavior  - aggressiveness  - craving 

SSRI and 5-HT neurotransmission acute treatment chronic treatment [5-HT] 5-HT1A [5-HT] 5-HT1A SSRI SSRI raphe area pindolol 5-HT neuron [5-HT] [5-HT] SSRI SSRI 5-HT1B/1D 5-HT1B/1D [5-HT] = [5-HT] Target areas 5-HTn 5-HTn postsynaptic neuron

} ? ? 5-HT1A 5-HT5A,B 5-HT1B 5-HT6 5-HT1D 5-HT7 5-HT1E 5-HT4(L,S) Depression Anxiety Sexual behavior Food intake Cognition Vasomotricity } Migraine 5-HT1A Nociception Food intake Vasomotricity Sleep/wakefulness Thermoregulation 5-HT5A,B 5-HT1B 5-HT6 5-HT7 5-HT1D Gastro-intestinal motility Cognition (?) SEROTONIN CH2-CH2-NH2 HO H N 5-HT1E ? 5-HT4(L,S) ? Migraine 5-HT1F Nausea, emesis Gastro-intestinal motility Cognition (?) Nociception (periphery) 5-HT3 (A,B) 5-HT2A 5-HT2C 5-HT2B Schizophrenia Anxiety Depression Vasomotricity Sleep/wakefulness Sexual behavior Food intake Nociception (periphery) Smooth muscles (gastro-intestinal tract) Migraine (long term)

Disrupted activation of Rho GTPases by 5-HT2C mRNA editing McGrew et al., 2004

Edition sites of 5-HT2C receptor mRNA Ile Asn Val Asp Val Ser Met Gly B Wang et al., 2000

Phosphoinositid hydrolysis activities of RNA editing isoforms and splicing variants of 5-HT2C receptor Wang et al., 2000

Effect of stress and/or fluoxetine on 5-HT2C edited mRNA isoforms in mice cerebral cortex - forced swimming Englander et al., 2005

Novel perspectives in 5-HT-related treatment of affective disorders 5-HT1A agonists antagonists 5-HT1B/1D antagonists (+ SSRI) (+ SSRI) Depression 5-HT2B agonists 5-HT7 antagonists 5-HT2C antagonists (+ MTR agonists - agomelatine)

Neurobiology of depression and antidepressants Where are we?  Monoaminergic (serotoninergic) neurotransmission  Hypothalamo-hypophyso-adrenocortical (stress) axis  Hippocampal cells  Growth factors  Other perspectives (melatonin, substance P)

FEED BACK INHIBITORY CONTROL OF STRESS AXIS (HPA) 50 depression, aging cortisol (ng/ml) Alcoholisation + antidepressants Controls 10 stress recovery 1 2 3 4 Time (h)

Hippocampus GR Hypothalamus CRH GR Pituitary gland ACTH Adrenal gland Cortisol Target organs

DEXAMETHASONE TEST CRF Dexamethasone Hippocampus GR Hypothalamus CRH Pituitary gland ACTH Dexamethasone Adrenal gland Cortisol [Cortisol]? Target organs

DEXAMETHASONE TEST CONTROL DEPRESSION ALCOHOLISATION Cortisol (ng/ml) (250-300 g ethanol/day) Cortisol (ng/ml) 10 80 A B C A B C A B C A : basal B : CRH (0.1 mg i.v.) C : dexamethasone (1.5 mg p.o.) + CRH

Axe du stress, dépression et antidépresseurs Antidepressants - tricyclics - MAOIs - SSRIs - chronic stress - depression Axe du stress, dépression et antidépresseurs Hippocampus GR Hypothalamus (PVN) CRH, AVP GR Pituitary gland ACTH Adrenal gland Cortisol Target organs

Antidepressant-induced up regulation rat hippocampal neurones of GRmRNA in cultured rat hippocampal neurones 14 day-exposure Okugawa et al., 1999

CRH1 receptor antagonists

Antidepressant-like effect of CRH1R blockade by CP-154,526 in rats Learned helplessness procedure Mansberget al., 1997

Anxiolytic and antidepressant effects of CRH1R blockade by R 121919 Zobel et al., 2000

Neurobiology of depression and antidepressants Where are we?  Monoaminergic (serotoninergic) neurotransmission  Hypothalamo-hypophyso-adrenocortical (stress) axis  Hippocampal cells  Growth factors  Other perspectives (melatonin, substance P)

Hippocampus involution in depressed patients Sheline et al., 1996

Correlations between plasma cortisol and hippocampus volume Lupien et al., 1998

Glucocorticoid-induced neurodegeneration in the hippocampus

Neurogenesis of granule cells in 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 gyrus Helpless vs Non-Helpless mice 10 * BrdU labelled cells / section 5 Non- Helpless Helpless Age: 9 weeks * p<0.05

Granule cell proliferation in the dentate gyrus Effects of in Helpless mice fluoxetine 200 * * 150 100 BrdU labeled cells / hippo 50 none veh Fluoxetine NH Helpless * p<0.05

5-HT1A-mediated increase in granule cell proliferation by d-fenfluramine Jacobs et al., 2000

5-HT1A-dependent granule cell proliferation in the mouse dentate gyrus F = fluoxetine I = imipramine Li et al., 2003

Antidepressants (SSRI, NK1 ) Electroconvulsive shocks Granule cell proliferation (dentate gyrus - hippocampus) Opiates (morphine, heroin) Nicotine Psychostimulants (cocaine) (Cannabis)

ANTIDEPRESSANTS AND NEURONAL PLASTICITY chronic stress (sensitization) 5-HT, NA, etc… CRH BDNF GR HPA chronic NGF NT-3 Cortisol GR Cognitive and psychoaffective disorders Cell death hippocampus Neurogenesis

Neurobiology of depression and antidepressants Where are we?  Monoaminergic (serotoninergic) neurotransmission  Hypothalamo-hypophyso-adreno-cortical (stress) axis  Hippocampal cells  Growth factors  Other perspectives (melatonin, substance P)

Structures chimiques d’antidépresseurs mixtes

Effets a2-antagonistes de la mirtazapine NA 5-HT a2 a2 Effet antidépresseur Mirtazapine NA 5-HT3 5-HT2c 5-HT1A 5-HT2A Effet anxiogène << Effet anxiolytique

Spontaneous circadian rhythms Locomotor activity * * * * 60 50 40 Locomotor activity (counts per 5 min) 30 20 10 19:00 07:00 19:00 Helpless Non helpless

S 20098 (Agomelatine) MT1 MT2 Gi/o Gi/o 4q35-1 11q21-22 h350aa h363aa CH 3 N H MT1 MT2 Gi/o Gi/o 4q35-1 11q21-22 h350aa h363aa

Granule cell proliferation in the dentate gyrus Effects of agomelatine in Helpless mice H NH 50 100 150 200 * none veh Agomelatine BrdU labeled cells / hippo * 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). Supraspinal structures Bulbo-mesencephalic region Descending controls (5-HT, NA, CCK, SP…) Interneurones (ME, CCK, SP…) Dorsal root ganglia Primary afferent fibres (SP,CGRP,ME, Excitatory AA…) Periphery Spinal cord

Arg-Pro-Lys-Pro-Gln-Gln-Phe-Phe-Gly-Leu-Met-NH2 Selective antagonists Substance P Arg-Pro-Lys-Pro-Gln-Gln-Phe-Phe-Gly-Leu-Met-NH2 NK1 NK2 NK3 Selective antagonists Antidepressants -animal models -humans

Effect of NK1R knock-out and NK1R blockade on mouse behavior in the forced swim test Rupniak et al., 2001

Antidepressant (A) and anxiolytic (B) effects of NK1R blockade in human MK-869 paroxetine placebo Kramer et al., 1998

Up-regulation of GR-mRNA in NK1-/- knock-out mice Cerebral cortex Hippocampus Ant. Raphe area 80 ** 80 80 60 60 60 GR-mRNA (amol)/total RNA (µg) * GR-mRNA (amol)/total RNA (µg) GR-mRNA (amol)/total RNA (µg) * 40 40 40 20 20 20 Wild – type (C57BL/6J) NK1-/-

5-HT1A autoreceptor desensitization in NK1 -/- knock-out mice ipsapirone 1000 nM 1000 30 60 100 300 ipsapirone (nM) WAY 100635 (1 nM) 20 3 min NK1+/+ 10 ipsapirone 100 nM Spikes per 10 sec Inhibition of firing (%) log [ipsapirone] M NK1+/+ NK1-/- *

Chronic NK1 receptor blockade desensitizes DRN 5-HT1A autoreceptors DRN-5-HT1A-evoked [35S]GTP-g-S binding DRN-5-HT neuron firing 20 60 100 ipsapirone (nM) 3 min 50 100 150 Vehicle ** * Vehicle Spikes per 10 sec Percentage over baseline (%) GR 205171 (10 mg/kg/d) ipsapirone (nM) 60 100 300 20 -9 -8 -7 -6 -5 Log [5-CT] M GR 205171 10 mg/kg/d (21 days) Froger et al. 2003

5-HT1A receptor adaptation to chronic antidepressant treatments Tricyclics  "presynaptic " 5-HT1A autoreceptors (DRN)  "postsynaptic " 5-HT1A heteroreceptors (hippocampus) SSRIs NK1 antagonists MAOIs

Neurobiology of depression and antidepressants Current questions Monoaminergic neurotransmission hypothalamo-hypophyso- Adrenocortical axis  DEPRESSION ANTIDEPRESSANTS hippocampal granule cell proliferation growth factors (BDNF)