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LES ETATS DEPRESSIFS: ELEMENTS CLES Episode dépressif majeur: Mélancholie/Anhédonie: absence de plaisir pour toute activité. Perte despoir, idées de culpabilité

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Présentation au sujet: "LES ETATS DEPRESSIFS: ELEMENTS CLES Episode dépressif majeur: Mélancholie/Anhédonie: absence de plaisir pour toute activité. Perte despoir, idées de culpabilité"— Transcription de la présentation:

1 LES ETATS DEPRESSIFS: ELEMENTS CLES Episode dépressif majeur: Mélancholie/Anhédonie: absence de plaisir pour toute activité. Perte despoir, idées de culpabilité et de dévalorisation de soi. Perte dappétit, trouble du sommeil et perturbation de lactivité 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 – 15 %43 / 5.3M Coût Social (USA, 1998) Age 1er épisode Risque à vie Patients USA-Europe /France

2 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.

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

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

5 The tail suspension test HELPLESSNON-HELPLESS duration of immobility (out of 6 min) 115s 35s Immobility score Immobility (s) Generations Helpless Non-Helpless The genetic mouse model of helplessness

6 SWS 2 bouts duration (min) 2.29 ± * ±0.14 Number of awakenings ± * ±8.3 REM sleep latency (min) 31.5 ± * ±8.7 Non-Helpless Helpless REM * SWS 1 * min per 24h

7 Helpless model of depression (females/males) l Helplessness in several paradigms l Alterations in circadian rhythms l Sleep alterations l Failure to cope with stress (HPA axis) l Anhedonia (sucrose intake) l Decreased 5-HT tone (supersensitive DRN 5-HT 1A autoreceptors) l Reversal by antidepressant drugs

8 Biosynthèse et Catabolisme de la Sérotonine CO 2 N H CH 2 CH 2 NH 2 HO 5-HTP/DOPA Décarboxylase 5-HYDROXYTRYPTAMINE (5-HT) = SÉROTONINE N H CH 2 CHNH 2 COOH N H CH 2 CHNH 2 COOH HO Tryptophane Hydroxylase TRYPTOPHANE 5-HYDROXY TRYPTOPHANE (5-HTP) 1/2 O 2 N H CH 2 CHO HO 5-HYDROXYINDOLE ACÉTALDÉHYDE Monoamine Oxydase A (MAO A ) N H CH 2 C00H HO ACIDE 5-HYDROXY INDOLE ACÉTIQUE (5-HIAA) Acétaldéhyde Déshydrogénase para- Chlorophényl alanine (pCPA) -méthyl DOPA IMAO A

9 5-HT 5-HT 3 5-HT 5-HT 1B 5-HT 5-HT 2 5-HT 5-HT 4 5-HT 5-HT 1A 5- HT HT n 5-HT TRANSPORTER TRYPTOPHAN TRYPTOPHAN HYDROXYLASE 5-HT A.A. DECARBOXYLASE 5-HTP intron 7 (A779 C) Alcoholism & Suicide (L & U alleles) Low CSF 5-HIAA High ethanol tolerance Suicide Severe ethanol dependence 5-HTTP S 5-HTTP L Alcoholism 5-HT 5-HT 1A, 1B HTR1B-2 allele (RFLP) HTR2C (C 23 S) Reward dependence The serotonin system

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

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

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

13 Implication of 5-HT system in depression and antidepressant action (1) l Reduced CSF 5-HIAA. l Blunted neuroendocrine and temperature responses to 5-HT agonists. l Reduced [ 3 H]imipramine binding in platelets and postmortem brain (depressed suicided subjects). l Reduced 5-HT 1A receptor binding (postsynaptic sites) in living brain and postmortem brain tissues. l Increased 5-HT 2A receptor binding in frontal/temporal cortex (postmortem brain tissues).

14 Implication of 5-HT system in depression and antidepressant action (2) l Antidepressant efficacy of agents which increase extracellular 5–HT (SSRIs). l Depressogenic effects of Trp depletion in antidepressant-treated patients. l Antidepressants decrease 5-HT 2A receptor density (but ECS increases) and 5-HT 1A autoreceptor functioning.

15 Serotonin synthesis pathway TPH1 (periphery) TPH2 (CNS)

16 TPH2 gene polymorphism and depression (12q21.1) G1463A CGT CAT His 441 Arg 441 TPH activity Depressed patients (A/A; G/A) 78/87 9/87 Control subjects (A/A; G/A) 216/219 (mild depression) (generalized anxiety) 3/ % * 1.3% p<0.001 * mainly non responsive to SSRIs Zhang et al., 2005 (-80%)

17 [C1473G] polymorphism of neuronal tryptophan hydroxylase (TPH2) in mice Zhang et al., 2004 C CC CG G G G Pro 447 (129Sv, C57BL/6) Arg 447 (BALB/cJ, DBA/2)

18 Discovery of antidepressant drugs Isoniazid (anti-tuberculosis) Iproniazid Imipramine Amitriptyline MAOIs Tricyclics

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

20

21 Les antidépresseurs aujourdhui (1) Inhibiteurs de recapture de la sérotonine (5-HT; ISRS): Fluoxétine - Prozac® Paroxétine - Déroxat® Fluvoxamine - Floxyfral® Sertraline - Zoloft® Citalopram - Séropram® Escitalopram - Cipralex®

22 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)

23 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?

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

25

26 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 CognitionMotricité DA NA 5-HT Cortex Frontal Système Limbique Ganglions de la Base

27 Functional connectivity 5-HT 2A for NE neurons 5-HT 2C for DA neurons

28 5-HT Serotoninergic nerve ending transporter ANTIDEPRESSANTS serotonin receptors stimulation -arousal -cognitive functions -body weight 0 or : 0 or inhibition of serotonin/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: tricyclic reuptake inhibitors selective serotonin reuptake inhibitors (SSRI)

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

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

31 Variants of the serotonin transporter

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

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

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

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

36 central serotoninergic system 5-HT 5-HT 1A 5-HT 1B 5-HTT 5-HT 1 A,B,D,E,F [AMPc] gK + gCa 2+ 5-HT 2 A,B,C [IP 3, 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

37 cAMP - DAG IP 3 + ? cAMP - Na + K + 5-HT 6 5-HT 1A 5-HT 1E 5-HT 3A(L,S) 5-HT 5(A,B) 5-HT 7 5-HT 4(L,S) 5-HT 2A cAMP + 5-HT 1B 5-HT 1D 5-HT 1F 5-HT 2C 5-HT 2B SEROTONIN CH 2 -CH 2 -NH 2 HO N H

38 5-HT 1B 5-HT 1D 5-HT 1E 5-HT 1F 5-HT 2A 5-HT 2B 5-HT 2C 5-HT 3 (A,B) 5-HT 4(L,S) 5-HT 7 5-HT 6 5-HT 1A 5-HT 5A,B Depression Anxiety Sexual behavior Vasomotricity Nociception Food intake } Migraine Migraine ? Gastro-intestinalmotility Cognition (?) Nausea, emesis Gastro-intestinal motility Cognition (?) Nociception (periphery) Anxiety Sexual behavior Food intake Smooth muscles (gastro-intestinal tract) Migraine (long term) Schizophrenia Vasomotricity Sleep/wakefulness Nociception (periphery) Migraine Migraine ? SEROTONIN CH 2 -CH 2 -NH 2 HOH N VasomotricitySleep/wakefulnessThermoregulation Food intake Cognition

39 Mayorga et al., J. Pharmacol. Exp.Ther., HT 1A -mediated antidepressant-like effect of SSRI

40 Rat 5-HT 1A receptor sequence YY R R Y 1 COOH 422 NH 2 * * * Y: N-glycosylation * : Phosphorylation

41 Molecular organization of brain 5-HT 1A receptor G 5-HT 1A G RGS ? CAM? G Actin ? Filamin ? K+K+ Adenylyl cyclase GIRK PSD95 ?

42 récepteurs 5-HT 1A marquage autoradiographique

43 Récepteurs 5-HT 1A - cerveau humain ([ 11 C]WAY ) Pike et al.

44 hippocampal neurones K+K+ GIRK RGS ?? G G 5-HT 1A GABA B G o1 dorsal raphe neurones K+K+ GIRK RGS ?? G G 5-HT 1A GABA B G i3 Ca ++ [ 35 S]GTP- -S "Pre" and postsynaptic 5-HT 1A – Experimental approaches

45 Chronic SSRIs and 5-HT 1A autoreceptors in the dorsal raphe nucleus log [ 8-OH-DPAT] M vehicle fluoxetine 21 d Inhibition of firing (% of baseline) 8-OH-DPAT (nM) 0 10 vehicle OH-DPAT (nM) fluoxetine action potentials / 10 sec 2 min

46 Chronic SSRIs and postsynaptic 5-HT 1A receptors in the hippocampus 5-CT (nM) saline-treated rat -67 mV 5-CT (nM) fluoxetine-treated rat 10 mV 2 min -65 mV wash fluoxetine 21 d vehicle log [ 5-CT] M Hyperpolarization (mV)

47 5-HTT binding sites labeled by [ 3 H]citalopram DRN 5-HTT +/+ 5-HTT+/- 5-HTT-/-

48 5-HT 1A autoreceptor desensitization in 5-HTT -/- knock-out mice Hyperpolarization (mv) log [5-CT] M 5-HTT (-/-) 5-HTT (+/+) CA log [ipsapirone] M Inhibition of firing (%) HTT (+/+) 5-HTT (-/-) DRN µM10 µMIpsapirone 1 µM Ipsapirone 300 nM 20 0 Firing rate (spikes / 10s) WAY nM 5-HTT (-/-) DRN 20 0 Ipsapirone 3 µM 5-HTT (+/+)

49 hippocampal neurones K+K+ GIRK RGS ?? G G 5-HT 1A GABA B G o1 dorsal raphe neurones K+K+ GIRK RGS ?? G G 5-HT 1A GABA B G i3 Ca ++ [ 35 S]GTP- -S "Pre" and postsynaptic 5-HT 1A – Experimental approaches

50 5-HT 1A -G protein coupling in 5-HTT-/- knock-out mice Hip DRN 5-CT +/--/-+/+ BASAL 5-HTT + / +- / - 5-CT (10 µM)-evoked [ 35 S]GTP- -S binding (%) + / - hippocampus 460 ± ± 49 NS (-3%) 474 ± 38 NS (+3%) dorsal raphe nucleus 150 ± ± 8 * (-33%) 51 ± 1 ** (- 66%) 5-HTT

51 5-HT 1A receptors + / + + / + + / - - / - dorsal raphe nucleus 77 ± 1 71 ± 3 NS (- 8%) (- 8%) 41 ± 3 ** (- 48%) (- 48%) fmol / mg tissue hippocampus 93 ± 1 (+17%) 117 ± 6 * (+26%) (+26%) 109 ± 1 ** [ 3 H]alnespirone +/++/--/- 5-HTT

52 Dendrites Control FluoxetineWAY + fluoxetine Fluoxetine-induced internalization Of DRN 5-HT 1A autoreceptors

53 hippocampal neurones K+K+ GIRK RGS ?? G G 5-HT 1A GABA B G o1 dorsal raphe neurones K+K+ GIRK RGS ?? G G 5-HT 1A GABA B G i3 Ca ++ [ 35 S]GTP- -S Both 5-HT 1A and GABA B receptors might be implicated in antidepressants action

54 [5-HT] (n) [5-HT] (H) [5-HT] (d) Serotonin (5-HT) 5-HT 1A autoreceptors and serotoninergic tone 5-HT 1A = inhibitory autoreceptor raphé area Limbic structures ( postsynaptic) H Hn d n d Desensitization : Hypersensitivity : Cocaine (chronic) Alcohol (chronic) Depression Antidepressants

55 5-HT 1A receptor changes by chronic alcoholisation Control Alcohol

56 5-HT 5-HT 1A - antidepressant drugs (SSRI) - physical exercise - impulsive behavior - aggressiveness - craving - tolerance to delayed reward - self-control - (mood) - cannabis - alcohol - cocaine - ecstasy - opioid - food reward system CB 1 antagonist

57 5-HTneuron postsynaptic neuron raphearea Target areas chronic treatment [5-HT] 0 acute treatment 5-HT n SSRI SSRI and 5-HT neurotransmission [5-HT] = SSRI [5-HT] 5-HT 1A [5-HT] 5-HT 1A SSRI [5-HT] 5-HT 1B/1D pindolol [5-HT] 5-HT 1B/1D 0

58 5-HT 1B 5-HT 1D 5-HT 1E 5-HT 1F 5-HT 2A 5-HT 2B 5-HT 2C 5-HT 3 (A,B) 5-HT 4(L,S) 5-HT 7 5-HT 6 5-HT 1A 5-HT 5A,B Depression Anxiety Sexual behavior Vasomotricity Nociception Food intake } Migraine Migraine ? Gastro-intestinalmotility Cognition (?) Nausea, emesis Gastro-intestinal motility Cognition (?) Nociception (periphery) AnxietyDepression Sexual behavior Food intake Smooth muscles (gastro-intestinal tract) Migraine (long term) Schizophrenia Vasomotricity Sleep/wakefulness Nociception (periphery) Migraine Migraine ? SEROTONIN CH 2 -CH 2 -NH 2 HOH N VasomotricitySleep/wakefulnessThermoregulation Food intake Cognition

59 Disrupted activation of Rho GTPases by 5-HT 2C mRNA editing McGrew et al., 2004

60 Wang et al., 2000 Edition sites of 5-HT 2C receptor mRNA A B IleAsnIle Val Asp Met Val Ser Gly

61 Phosphoinositid hydrolysis activities of RNA editing isoforms and splicing variants of 5-HT 2C receptor Wang et al., 2000

62 Effect of stress and/or fluoxetine on 5-HT 2C edited mRNA isoforms in mice Englander et al., 2005 cerebral cortex - forced swimming

63 Novel perspectives in 5-HT-related treatment of affective disorders Depression 5-HT 2C antagonists 5-HT 1A agonists antagonists 5-HT 1B/1D antagonists 5-HT 2B agonists 5-HT 7 antagonists (+ MTR agonists - agomelatine) (+ SSRI)

64 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?

65 FEED BACK INHIBITORY CONTROL OF STRESS AXIS (HPA) depression, aging stressrecovery Time (h) cortisol (ng/ml) Controls Alcoholisation + antidepressants 10 50

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

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

68 Cortisol (ng/ml) CONTROL ABC DEPRESSION ABC ALCOHOLISATION ( g ethanol/day) ABC A : basal B : CRH (0.1 mg i.v.) C : dexamethasone (1.5 mg p.o.) + CRH

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

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

71 CRH 1 receptor antagonists

72 Mansberget al., 1997 Antidepressant-like effect of CRH 1 R blockade by CP-154,526 in rats Learned helplessness procedure

73 Zobel et al., 2000 Anxiolytic and antidepressant effects of CRH 1 R blockade by R

74 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?

75 Sheline et al., 1996 Hippocampus involution in depressed patients

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

77 Glucocorticoid- induced neurodegeneration in the hippocampus

78 Neurogenesis of granule cells in the hippocampus

79 Marquage de la prolifération cellulaire par le BrdU au sein du gyrus denté Lignée DBA/2JLignée C57BL/6J

80 Granule cell proliferation in the dentate gyrus Helpless vs Non-Helpless mice BrdU labelled cells / section Non- HelplessHelpless Age: 9 weeks * p<0.05 *

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

82 Jacobs et al., HT 1A -mediated increase in granule cell proliferation by d-fenfluramine

83 Li et al., HT 1A -dependent granule cell proliferation in the mouse dentate gyrus F = fluoxetine I = imipramine

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

85 ANTIDEPRESSANTS AND NEURONAL PLASTICITY chronic stress (sensitization) CRH Cognitive and psychoaffective disorders CortisolGR chronicHPA hippocampus Cell death Neurogenesis Antidepressants 5-HT, NA, etc… NGF NT-3 GRBDNF

86 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?

87 Structures chimiques dantidépresseurs mixtes

88 Mirtazapine NA Effet antidépresseu r Effet anxiogène <

89

90 Locomotor activity (counts per 5 min) :0007:0019:00 ** * * Spontaneous circadian rhythms Locomotor activity Non helplessHelpless

91

92 MT 2 Gi/o 11q21-22 h363aa MT 1 Gi/o 4q35-1 h350aa O O CH 3 N H 3 S (Agomelatine)

93 Granule cell proliferation in the dentate gyrus Effects of agomelatine in Helpless mice H NH * * none veh Agomelatine BrdU labeled cells / hippo * p<0.05

94 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). Periphery Dorsal root ganglia Bulbo-mesencephalicregion Supraspinalstructures Spinal cord Descending controls (5-HT, NA, CCK, SP…) Interneurones (ME, CCK, SP…) Primary afferent fibres ( SP,CGRP,ME, Excitatory AA…)

95 Substance P Arg-Pro-Lys-Pro-Gln-Gln-Phe-Phe-Gly-Leu-Met-NH 2 Selective antagonists Antidepressants -animal models -humans NK 1 NK 2 NK 3

96 Rupniak et al., 2001 Effect of NK 1 R knock-out and NK 1 R blockade on mouse behavior in the forced swim test

97 Kramer et al., 1998 Antidepressant (A) and anxiolytic (B) effects of NK 1 R blockade in human placebo MK-869 paroxetine

98 Up-regulation of GR-mRNA in NK 1 -/- knock-out mice ** Cerebral cortex GR-mRNA (amol)/total RNA (µg) * Hippocampus GR-mRNA (amol)/total RNA (µg) * Ant. Raphe area GR-mRNA (amol)/total RNA (µg) Wild – type (C57BL/6J) NK1-/-

99 ipsapirone 1000 nM ipsapirone (nM) WAY (1 nM) min 20 0 NK1+/ ipsapirone (nM) ipsapirone 100 nM WAY (1 nM) min Spikes per 10 sec Inhibition of firing (%) log [ipsapirone] M NK1+/+ NK1-/- ****** **** **** **** **** 5-HT 1A autoreceptor desensitization in NK 1 -/- knock-out mice

100 Froger et al Spikes per 10 sec 20 0 ipsapirone (nM) GR mg/kg/d (21 days) Vehicle ipsapirone (nM) 3 min Log [5-CT] M Percentage over baseline (%) ** * * Vehicle GR (10 mg/kg/d) DRN-5-HT neuron firing DRN-5-HT 1A -evoked [ 35 S]GTP- -S binding Chronic NK1 receptor blockade desensitizes DRN 5-HT 1A autoreceptors

101 5-HT 1A receptor adaptation to chronic antidepressant treatments "presynaptic " 5-HT 1A autoreceptors (DRN) "postsynaptic " 5-HT 1A heteroreceptors (hippocampus) Tricyclics MAOIs SSRIs NK 1 antagonists

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


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