, Volume 213, Issue 2–3, pp 265–287 | Cite as

The role of serotonin receptor subtypes in treating depression: a review of animal studies

  • Gregory V. Carr
  • Irwin LuckiEmail author



Serotonin reuptake inhibitors (SSRIs) are effective in treating depression. Given the existence of different families and subtypes of 5-HT receptors, multiple 5-HT receptors may be involved in the antidepressant-like behavioral effects of SSRIs.


Behavioral pharmacology studies investigating the role of 5-HT receptor subtypes in producing or blocking the effects of SSRIs were reviewed.


Few animal behavior tests were available to support the original development of SSRIs. Since their development, a number of behavioral tests and models of depression have been developed that are sensitive to the effects of SSRIs, as well as to other types of antidepressant treatments. The rationale for the development and use of these tests is reviewed. Behavioral effects similar to those of SSRIs (antidepressant-like) have been produced by agonists at 5-HT1A, 5-HT1B, 5-HT2C, 5-HT4, and 5-HT6 receptors. Also, antagonists at 5-HT2A, 5-HT2C, 5-HT3, 5-HT6, and 5-HT7 receptors have been reported to produce antidepressant-like responses. Although it seems paradoxical that both agonists and antagonists at particular 5-HT receptors can produce antidepressant-like effects, they probably involve diverse neurochemical mechanisms. The behavioral effects of SSRIs and other antidepressants may also be augmented when 5-HT receptor agonists or antagonists are given in combination.


The involvement of 5-HT receptors in the antidepressant-like effects of SSRIs is complex and involves the orchestration of stimulation and blockade at different 5-HT receptor subtypes. Individual 5-HT receptors provide opportunities for the development of a newer generation of antidepressants that may be more beneficial and effective than SSRIs.


Serotonin Receptors Antidepressant Anxiety Depression 


  1. Abbas AI, Hedlund PB, Huang XP, Tran TB, Meltzer HY, Roth BL (2009) Amisulpride is a potent 5-HT7 antagonist: relevance for antidepressant actions in vivo. Psychopharmacology (Berl) 205:119–128Google Scholar
  2. Airan RD, Meltzer LA, Roy M, Gong Y, Chen H, Deisseroth K (2007) High-speed imaging reveals neurophysiological links to behavior in an animal model of depression. Science 317:819–823PubMedGoogle Scholar
  3. Albinsson A, Bjork A, Svartengren J, Klint T, Andersson G (1994) Preclinical pharmacology of FG5893: a potential anxiolytic drug with high affinity for both 5-HT1A and 5-HT2A receptors. Eur J Pharmacol 261:285–294PubMedGoogle Scholar
  4. Alexander B, Warner-Schmidt J, Eriksson T, Tamminga C, Arango-Llievano M, Ghose S, Vernov M, Stavarche M, Musatov S, Flajolet M, Svenningsson P, Greengard P, Kaplitt MG (2010) Reversal of depressed behaviors in mice by p11 gene therapy in the nucleus accumbens. Sci Transl Med 2:54ra76PubMedGoogle Scholar
  5. Ansorge MS, Morelli E, Gingrich JA (2008) Inhibition of serotonin but not norepinephrine transport during development produces delayed, persistent perturbations of emotional behaviors in mice. J Neurosci 28:199–207PubMedGoogle Scholar
  6. Anthony JP, Sexton TJ, Neumaier JF (2000) Antidepressant-induced regulation of 5-HT(1b) mRNA in rat dorsal raphe nucleus reverses rapidly after drug discontinuation. J Neurosci Res 61:82–87PubMedGoogle Scholar
  7. Artigas F, Romero L, de Montigny C, Blier P (1996) Acceleration of the effect of selected antidepressant drugs in major depression by 5-HT1A antagonists. Trends Neurosci 19:378–383PubMedGoogle Scholar
  8. Artigas F, Celada P, Laruelle M, Adell A (2001) How does pindolol improve antidepressant action? Trends Pharmacol Sci 22:224–228PubMedGoogle Scholar
  9. Bai F, Li X, Clay M, Lindstrom T, Skolnick P (2001) Intra- and interstrain differences in models of “behavioral despair”. Pharmacol Biochem Behav 70:187–192PubMedGoogle Scholar
  10. Balu DT, Lucki I (2009) Adult hippocampal neurogenesis: regulation, functional implications, and contribution to disease pathology. Neurosci Biobehav Rev 33:232–252PubMedGoogle Scholar
  11. Balu DT, Hodes GE, Anderson BT, Lucki I (2009) Enhanced sensitivity of the MRL/MpJ mouse to the neuroplastic and behavioral effects of chronic antidepressant treatments. Neuropsychopharmacology 34:1764–1773PubMedGoogle Scholar
  12. Banasr M, Hery M, Printemps R, Daszuta A (2004) Serotonin-induced increases in adult cell proliferation and neurogenesis are mediated through different and common 5-HT receptor subtypes in the dentate gyrus and the subventricular zone. Neuropsychopharmacology 29:450–460PubMedGoogle Scholar
  13. Barnes NM, Sharp T (1999) A review of central 5-HT receptors and their function. Neuropharmacology 38:1083–1152PubMedGoogle Scholar
  14. Beaulieu JM, Zhang X, Rodriguiz RM, Sotnikova TD, Cools MJ, Wetsel WC, Gainetdinov RR, Caron MG (2008) Role of GSK3 beta in behavioral abnormalities induced by serotonin deficiency. Proc Natl Acad Sci U S A 105:1333–1338PubMedGoogle Scholar
  15. Bechtholt AJ, Valentino RJ, Lucki I (2008) Overlapping and distinct brain regions associated with the anxiolytic effects of chlordiazepoxide and chronic fluoxetine. Neuropsychopharmacology 33:2117–2130PubMedGoogle Scholar
  16. Berg KA, Harvey JA, Spampinato U, Clarke WP (2008) Physiological and therapeutic relevance of constitutive activity of 5-HT 2A and 5-HT 2 C receptors for the treatment of depression. Prog Brain Res 172:287–305PubMedGoogle Scholar
  17. Berton O, McClung CA, Dileone RJ, Krishnan V, Renthal W, Russo SJ, Graham D, Tsankova NM, Bolanos CA, Rios M, Monteggia LM, Self DW, Nestler EJ (2006) Essential role of BDNF in the mesolimbic dopamine pathway in social defeat stress. Science 311:864–868PubMedGoogle Scholar
  18. Beyer CE, Lin Q, Rosenzweig-Lipson S, Schechter LE (2006) Alpha 2A-adrenoceptors enhance the serotonergic effects of fluoxetine. Eur J Pharmacol 539:164–167PubMedGoogle Scholar
  19. Bhatnagar S, Nowak N, Babich L, Bok L (2004) Deletion of the 5-HT3 receptor differentially affects behavior of males and females in the Porsolt forced swim and defensive withdrawal tests. Behav Brain Res 153:527–535PubMedGoogle Scholar
  20. Blier P, Szabo ST (2005) Potential mechanisms of action of atypical antipsychotic medications in treatment-resistant depression and anxiety. J Clin Psychiatry 66(Suppl 8):30–40PubMedGoogle Scholar
  21. Blier P, Ward NM (2003) Is there a role for 5-HT1A agonists in the treatment of depression? Biol Psychiatry 53:193–203PubMedGoogle Scholar
  22. Bodnoff SR, Suranyi-Cadotte B, Aitken DH, Quirion R, Meaney MJ (1988) The effects of chronic antidepressant treatment in an animal model of anxiety. Psychopharmacology (Berl) 95:298–302Google Scholar
  23. Bodnoff SR, Suranyi-Cadotte B, Quirion R, Meaney MJ (1989) A comparison of the effects of diazepam versus several typical and atypical anti-depressant drugs in an animal model of anxiety. Psychopharmacology (Berl) 97:277–279Google Scholar
  24. Bonaventure P, Kelly L, Aluisio L, Shelton J, Lord B, Galici R, Miller K, Atack J, Lovenberg TW, Dugovic C (2007) Selective blockade of 5-hydroxytryptamine (5-HT)7 receptors enhances 5-HT transmission, antidepressant-like behavior, and rapid eye movement sleep suppression induced by citalopram in rodents. J Pharmacol Exp Ther 321:690–698PubMedGoogle Scholar
  25. Bonnavion P, Bernard JF, Hamon M, Adrien J, Fabre V (2010) Heterogeneous distribution of the serotonin 5-HT(1A) receptor mRNA in chemically identified neurons of the mouse rostral brainstem: implications for the role of serotonin in the regulation of wakefulness and REM sleep. J Comp Neurol 518:2744–2770PubMedGoogle Scholar
  26. Boothman LJ, Mitchell SN, Sharp T (2006) Investigation of the SSRI augmentation properties of 5-HT(2) receptor antagonists using in vivo microdialysis. Neuropharmacology 50:726–732PubMedGoogle Scholar
  27. Borsini F (1995) Role of the serotonergic system in the forced swimming test. Neurosci Biobehav Rev 19:377–395PubMedGoogle Scholar
  28. Borsini F, Meli A (1988) Is the forced swimming test a suitable model for revealing antidepressant activity? Psychopharmacology (Berl) 94:147–160Google Scholar
  29. Borsini F, Podhorna J, Marazziti D (2002) Do animal models of anxiety predict anxiolytic-like effects of antidepressants? Psychopharmacology (Berl) 163:121–141Google Scholar
  30. Bortolozzi A, Diaz-Mataix L, Scorza MC, Celada P, Artigas F (2005) The activation of 5-HT receptors in prefrontal cortex enhances dopaminergic activity. J Neurochem 95:1597–1607PubMedGoogle Scholar
  31. Bravo G, Maswood S (2006) Acute treatment with 5-HT3 receptor antagonist, tropisetron, reduces immobility in intact female rats exposed to the forced swim test. Pharmacol Biochem Behav 85:362–368PubMedGoogle Scholar
  32. Burnet PW, Mead A, Eastwood SL, Lacey K, Harrison PJ, Sharp T (1995) Repeated ECS differentially affects rat brain 5-HT1A and 5-HT2A receptor expression. Neuroreport 6:901–904PubMedGoogle Scholar
  33. Calcagnetti DJ, Quatrella LA, Schechter MD (1996) Olfactory bulbectomy disrupts the expression of cocaine-induced conditioned place preference. Physiol Behav 59:597–604PubMedGoogle Scholar
  34. Caldecott-Hazard S, Schneider LS (1992) Clinical and biochemical aspects of depressive disorders: III. Treatment and controversies. Synapse 10:141–168PubMedGoogle Scholar
  35. Carlsen J, De Olmos J, Heimer L (1982) Tracing of two-neuron pathways in the olfactory system by the aid of transneuronal degeneration: projections to the amygdaloid body and hippocampal formation. J Comp Neurol 208:196–208PubMedGoogle Scholar
  36. Carr GV, Schechter LE, Lucki I (2011) Antidepressant and anxiolytic effects of selective 5-HT(6) receptor agonists in rats. Psychopharmacology (in press)Google Scholar
  37. Ceglia I, Acconcia S, Fracasso C, Colovic M, Caccia S, Invernizzi RW (2004) Effects of chronic treatment with escitalopram or citalopram on extracellular 5-HT in the prefrontal cortex of rats: role of 5-HT1A receptors. Br J Pharmacol 142:469–478PubMedGoogle Scholar
  38. Cervo L, Grignaschi G, Samanin R (1988) 8-Hydroxy-2-(di-n-propylamino)tetralin, a selective serotonin1A receptor agonist, reduces the immobility of rats in the forced swimming test by acting on the nucleus raphe dorsalis. Eur J Pharmacol 158:53–59PubMedGoogle Scholar
  39. Cervo L, Canetta A, Calcagno E, Burbassi S, Sacchetti G, Caccia S, Fracasso C, Albani D, Forloni G, Invernizzi RW (2005) Genotype-dependent activity of tryptophan hydroxylase-2 determines the response to citalopram in a mouse model of depression. J Neurosci 25:8165–8172PubMedGoogle Scholar
  40. Cesana R, Ceci A, Ciprandi C, Borsini F (1993) Mesulergine antagonism towards the fluoxetine anti-immobility effect in the forced swimming test in mice. J Pharm Pharmacol 45:473–475PubMedGoogle Scholar
  41. Chaput Y, de Montigny C, Blier P (1991) Presynaptic and postsynaptic modifications of the serotonin system by long-term administration of antidepressant treatments. An in vivo electrophysiologic study in the rat. Neuropsychopharmacology 5:219–229PubMedGoogle Scholar
  42. Chenu F, David DJ, Leroux-Nicollet I, Le Maitre E, Gardier AM, Bourin M (2008) Serotonin1B heteroreceptor activation induces an antidepressant-like effect in mice with an alteration of the serotonergic system. J Psychiatry Neurosci 33:541–550PubMedGoogle Scholar
  43. Chou-Green JM, Holscher TD, Dallman MF, Akana SF (2003) Repeated stress in young and old 5-HT(2 C) receptor knockout mice. Physiol Behav 79:217–226PubMedGoogle Scholar
  44. Clenet F, De Vos A, Bourin M (2001) Involvement of 5-HT(2 C) receptors in the anti-immobility effects of antidepressants in the forced swimming test in mice. Eur Neuropsychopharmacol 11:145–152PubMedGoogle Scholar
  45. Compan V, Zhou M, Grailhe R, Gazzara RA, Martin R, Gingrich J, Dumuis A, Brunner D, Bockaert J, Hen R (2004) Attenuated response to stress and novelty and hypersensitivity to seizures in 5-HT4 receptor knock-out mice. J Neurosci 24:412–419PubMedGoogle Scholar
  46. Conductier G, Dusticier N, Lucas G, Cote F, Debonnel G, Daszuta A, Dumuis A, Nieoullon A, Hen R, Bockaert J, Compan V (2006) Adaptive changes in serotonin neurons of the raphe nuclei in 5-HT(4) receptor knock-out mouse. Eur J Neurosci 24:1053–1062PubMedGoogle Scholar
  47. Cousins MS, Seiden LS (2000) The serotonin-1A receptor antagonist WAY-100635 modifies fluoxetine’s antidepressant-like profile on the differential reinforcement of low rates 72-s schedule in rats. Psychopharmacology (Berl) 148:438–442Google Scholar
  48. Cremers TI, Rea K, Bosker FJ, Wikstrom HV, Hogg S, Mork A, Westerink BH (2007) Augmentation of SSRI effects on serotonin by 5-HT2C antagonists: mechanistic studies. Neuropsychopharmacology 32:1550–1557PubMedGoogle Scholar
  49. Crowley JJ, Blendy JA, Lucki I (2005) Strain-dependent antidepressant-like effects of citalopram in the mouse tail suspension test. Psychopharmacology (Berl) 183:257–264Google Scholar
  50. Crowley JJ, Brodkin ES, Blendy JA, Berrettini WH, Lucki I (2006) Pharmacogenomic evaluation of the antidepressant citalopram in the mouse tail suspension test. Neuropsychopharmacology 31:2433–2442PubMedGoogle Scholar
  51. Cryan JF, Lucki I (2000a) 5-HT4 receptors do not mediate the antidepressant-like behavioral effects of fluoxetine in a modified forced swim test. Eur J Pharmacol 409:295–299PubMedGoogle Scholar
  52. Cryan JF, Lucki I (2000b) Antidepressant-like behavioral effects mediated by 5-Hydroxytryptamine(2 C) receptors. J Pharmacol Exp Ther 295:1120–1126PubMedGoogle Scholar
  53. Cryan JF, Slattery DA (2007) Animal models of mood disorders: recent developments. Curr Opin Psychiatry 20:1–7PubMedGoogle Scholar
  54. Cryan JF, Redmond AM, Kelly JP, Leonard BE (1997) The effects of the 5-HT1A agonist flesinoxan, in three paradigms for assessing antidepressant potential in the rat. Eur Neuropsychopharmacol 7:109–114PubMedGoogle Scholar
  55. Cryan JF, Mombereau C, Vassout A (2005a) The tail suspension test as a model for assessing antidepressant activity: review of pharmacological and genetic studies in mice. Neurosci Biobehav Rev 29:571–625PubMedGoogle Scholar
  56. Cryan JF, Page ME, Lucki I (2005b) Differential behavioral effects of the antidepressants reboxetine, fluoxetine, and moclobemide in a modified forced swim test following chronic treatment. Psychopharmacology (Berl) 182:335–344Google Scholar
  57. Cryan JF, Valentino RJ, Lucki I (2005c) Assessing substrates underlying the behavioral effects of antidepressants using the modified rat forced swimming test. Neurosci Biobehav Rev 29:547–569PubMedGoogle Scholar
  58. David DJ, Renard CE, Jolliet P, Hascoet M, Bourin M (2003) Antidepressant-like effects in various mice strains in the forced swimming test. Psychopharmacology (Berl) 166:373–382Google Scholar
  59. David DJ, Samuels BA, Rainer Q, Wang JW, Marsteller D, Mendez I, Drew M, Craig DA, Guiard BP, Guilloux JP, Artymyshyn RP, Gardier AM, Gerald C, Antonijevic IA, Leonardo ED, Hen R (2009) Neurogenesis-dependent and -independent effects of fluoxetine in an animal model of anxiety/depression. Neuron 62:479–493PubMedGoogle Scholar
  60. Dawson LA, Watson JM (2009) Vilazodone: a 5-HT1A receptor agonist/serotonin transporter inhibitor for the treatment of affective disorders. CNS Neurosci Ther 15:107–117PubMedGoogle Scholar
  61. Dawson LA, Hughes ZA, Starr KR, Storey JD, Bettelini L, Bacchi F, Arban R, Poffe A, Melotto S, Hagan JJ, Price GW (2006) Characterisation of the selective 5-HT1B receptor antagonist SB-616234-A (1-[6-(cis-3, 5-dimethylpiperazin-1-yl)-2, 3-dihydro-5-methoxyindol-1-yl]-1- [2′-methyl-4′-(5-methyl-1, 2, 4-oxadiazol-3-yl)biphenyl-4-yl]methanone hydrochloride): in vivo neurochemical and behavioural evidence of anxiolytic/antidepressant activity. Neuropharmacology 50:975–983PubMedGoogle Scholar
  62. de Bodinat C, Guardiola-Lemaitre B, Mocaer E, Renard P, Munoz C, Millan MJ (2010) Agomelatine, the first melatonergic antidepressant: discovery, characterization and development. Nat Rev Drug Discov 9:628–642PubMedGoogle Scholar
  63. De Vry J (1995) 5-HT1A receptor agonists: recent developments and controversial issues. Psychopharmacology (Berl) 121:1–26Google Scholar
  64. Dekeyne A, Millan MJ (2003) Discriminative stimulus properties of antidepressant agents: a review. Behav Pharmacol 14:391–407PubMedGoogle Scholar
  65. Dekeyne A, Mannoury la Cour C, Gobert A, Brocco M, Lejeune F, Serres F, Sharp T, Daszuta A, Soumier A, Papp M, Rivet JM, Flik G, Cremers TI, Muller O, Lavielle G, Millan MJ (2008) S32006, a novel 5-HT2C receptor antagonist displaying broad-based antidepressant and anxiolytic properties in rodent models. Psychopharmacology (Berl) 199:549–568Google Scholar
  66. Delgado PL (2004) How antidepressants help depression: mechanisms of action and clinical response. J Clin Psychiatry 65(Suppl 4):25–30PubMedGoogle Scholar
  67. Delgado PL, Price LH, Miller HL, Salomon RM, Licinio J, Krystal JH, Heninger GR, Charney DS (1991) Rapid serotonin depletion as a provocative challenge test for patients with major depression: relevance to antidepressant action and the neurobiology of depression. Psychopharmacol Bull 27:321–330PubMedGoogle Scholar
  68. Detke MJ, Lucki I (1996) Detection of serotonergic and noradrenergic antidepressants in the rat forced swimming test: the effects of water depth. Behav Brain Res 73:43–46PubMedGoogle Scholar
  69. Detke MJ, Rickels M, Lucki I (1995a) Active behaviors in the rat forced swimming test differentially produced by serotonergic and noradrenergic antidepressants. Psychopharmacology (Berl) 121:66–72Google Scholar
  70. Detke MJ, Wieland S, Lucki I (1995b) Blockade of the antidepressant-like effects of 8-OH-DPAT, buspirone and desipramine in the rat forced swim test by 5HT1A receptor antagonists. Psychopharmacology (Berl) 119:47–54Google Scholar
  71. Detke MJ, Johnson J, Lucki I (1997) Acute and chronic antidepressant drug treatment in the rat forced swimming test model of depression. Exp Clin Psychopharmacol 5:107–112PubMedGoogle Scholar
  72. Di Matteo V, Di Giovanni G, Pierucci M, Esposito E (2008) Serotonin control of central dopaminergic function: focus on in vivo microdialysis studies. Prog Brain Res 172:7–44PubMedGoogle Scholar
  73. Dremencov E, Newman ME, Kinor N, Blatman-Jan G, Schindler CJ, Overstreet DH, Yadid G (2005) Hyperfunctionality of serotonin-2 C receptor-mediated inhibition of accumbal dopamine release in an animal model of depression is reversed by antidepressant treatment. Neuropharmacology 48:34–42PubMedGoogle Scholar
  74. Dremencov E, Weizmann Y, Kinor N, Gispan-Herman I, Yadid G (2006) Modulation of dopamine transmission by 5HT2C and 5HT3 receptors: a role in the antidepressant response. Curr Drug Targets 7:165–175PubMedGoogle Scholar
  75. Dremencov E, El Mansari M, Blier P (2007) Noradrenergic augmentation of escitalopram response by risperidone: electrophysiologic studies in the rat brain. Biol Psychiatry 61:671–678PubMedGoogle Scholar
  76. Dulawa SC, Hen R (2005) Recent advances in animal models of chronic antidepressant effects: the novelty-induced hypophagia test. Neurosci Biobehav Rev 29:771–783PubMedGoogle Scholar
  77. Dulawa SC, Holick KA, Gundersen B, Hen R (2004) Effects of chronic fluoxetine in animal models of anxiety and depression. Neuropsychopharmacology 29:1321–1330PubMedGoogle Scholar
  78. Duman RS, Monteggia LM (2006) A neurotrophic model for stress-related mood disorders. Biol Psychiatry 59:1116–1127PubMedGoogle Scholar
  79. Edwards E, Harkins K, Wright G, Henn FA (1991) 5-HT1b receptors in an animal model of depression. Neuropharmacology 30:101–105PubMedGoogle Scholar
  80. Eisensamer B, Rammes G, Gimpl G, Shapa M, Ferrari U, Hapfelmeier G, Bondy B, Parsons C, Gilling K, Zieglgansberger W, Holsboer F, Rupprecht R (2003) Antidepressants are functional antagonists at the serotonin type 3 (5-HT3) receptor. Mol Psychiatry 8:994–1007PubMedGoogle Scholar
  81. Esposito E (2006) Serotonin-dopamine interaction as a focus of novel antidepressant drugs. Curr Drug Targets 7:177–185PubMedGoogle Scholar
  82. Fabre V, Beaufour C, Evrard A, Rioux A, Hanoun N, Lesch KP, Murphy DL, Lanfumey L, Hamon M, Martres MP (2000) Altered expression and functions of serotonin 5-HT1A and 5-HT1B receptors in knock-out mice lacking the 5-HT transporter. Eur J Neurosci 12:2299–2310PubMedGoogle Scholar
  83. Fone KC (2008) An update on the role of the 5-hydroxytryptamine6 receptor in cognitive function. Neuropharmacology 55:1015–1022PubMedGoogle Scholar
  84. Fox MA, Andrews AM, Wendland JR, Lesch KP, Holmes A, Murphy DL (2007) A pharmacological analysis of mice with a targeted disruption of the serotonin transporter. Psychopharmacology (Berl) 195:147–166Google Scholar
  85. Frazer A, Benmansour S (2002) Delayed pharmacological effects of antidepressants. Mol Psychiatry 7(Suppl 1):S23–S28PubMedGoogle Scholar
  86. Gaddum JH, Picarelli ZP (1957) Two kinds of tryptamine receptor. Br J Pharmacol Chemother 12:323–328PubMedGoogle Scholar
  87. Gavioli EC, Vaughan CW, Marzola G, Guerrini R, Mitchell VA, Zucchini S, De Lima TC, Rae GA, Salvadori S, Regoli D, Calo G (2004) Antidepressant-like effects of the nociceptin/orphanin FQ receptor antagonist UFP-101: new evidence from rats and mice. Naunyn Schmiedebergs Arch Pharmacol 369:547–553PubMedGoogle Scholar
  88. Gobbi G, Murphy DL, Lesch K, Blier P (2001) Modifications of the serotonergic system in mice lacking serotonin transporters: an in vivo electrophysiological study. J Pharmacol Exp Ther 296:987–995PubMedGoogle Scholar
  89. Gross C, Zhuang X, Stark K, Ramboz S, Oosting R, Kirby L, Santarelli L, Beck S, Hen R (2002) Serotonin1A receptor acts during development to establish normal anxiety-like behaviour in the adult. Nature 416:396–400PubMedGoogle Scholar
  90. Gur E, Lerer B, Dremencov E, Newman ME (2000) Chronic repetitive transcranial magnetic stimulation induces subsensitivity of presynaptic serotonergic autoreceptor activity in rat brain. Neuroreport 11:2925–2929PubMedGoogle Scholar
  91. Guscott M, Bristow LJ, Hadingham K, Rosahl TW, Beer MS, Stanton JA, Bromidge F, Owens AP, Huscroft I, Myers J, Rupniak NM, Patel S, Whiting PJ, Hutson PH, Fone KC, Biello SM, Kulagowski JJ, McAllister G (2005) Genetic knockout and pharmacological blockade studies of the 5-HT7 receptor suggest therapeutic potential in depression. Neuropharmacology 48:492–502PubMedGoogle Scholar
  92. Guzzetti S, Calcagno E, Canetta A, Sacchetti G, Fracasso C, Caccia S, Cervo L, Invernizzi RW (2008) Strain differences in paroxetine-induced reduction of immobility time in the forced swimming test in mice: role of serotonin. Eur J Pharmacol 594:117–124PubMedGoogle Scholar
  93. Haddjeri N, Blier P, de Montigny C (1998) Long-term antidepressant treatments result in a tonic activation of forebrain 5-HT1A receptors. J Neurosci 18:10150–10156PubMedGoogle Scholar
  94. Hall RD, Macrides F (1983) Olfactory bulbectomy impairs the rat’s radial-maze behavior. Physiol Behav 30:797–803PubMedGoogle Scholar
  95. Hannon J, Hoyer D (2008) Molecular biology of 5-HT receptors. Behav Brain Res 195:198–213PubMedGoogle Scholar
  96. Harkin A, Connor TJ, Walsh M, St John N, Kelly JP (2003) Serotonergic mediation of the antidepressant-like effects of nitric oxide synthase inhibitors. Neuropharmacology 44:616–623PubMedGoogle Scholar
  97. Hedlund PB, Huitron-Resendiz S, Henriksen SJ, Sutcliffe JG (2005) 5-HT7 receptor inhibition and inactivation induce antidepressantlike behavior and sleep pattern. Biol Psychiatry 58:831–837PubMedGoogle Scholar
  98. Heisler LK, Chu HM, Brennan TJ, Danao JA, Bajwa P, Parsons LH, Tecott LH (1998) Elevated anxiety and antidepressant-like responses in serotonin 5-HT1A receptor mutant mice. Proc Natl Acad Sci U S A 95:15049–15054PubMedGoogle Scholar
  99. Heisler LK, Zhou L, Bajwa P, Hsu J, Tecott LH (2007) Serotonin 5-HT(2 C) receptors regulate anxiety-like behavior. Genes Brain Behav 6:491–496PubMedGoogle Scholar
  100. Hodes GE, Hill-Smith TE, Lucki I (2010) Fluoxetine treatment induces dose-dependent alterations in depression associated behavior and neural plasticity in female mice. Neurosci Lett 484:12–16PubMedGoogle Scholar
  101. Hogg S, Dalvi A (2004) Acceleration of onset of action in schedule-induced polydipsia: combinations of SSRI and 5-HT1A and 5-HT1B receptor antagonists. Pharmacol Biochem Behav 77:69–75PubMedGoogle Scholar
  102. Holick KA, Lee DC, Hen R, Dulawa SC (2008) Behavioral effects of chronic fluoxetine in BALB/cJ mice do not require adult hippocampal neurogenesis or the serotonin 1A receptor. Neuropsychopharmacology 33:406–417PubMedGoogle Scholar
  103. Holmes A, Yang RJ, Murphy DL, Crawley JN (2002) Evaluation of antidepressant-related behavioral responses in mice lacking the serotonin transporter. Neuropsychopharmacology 27:914–923PubMedGoogle Scholar
  104. Jans LA, Riedel WJ, Markus CR, Blokland A (2007) Serotonergic vulnerability and depression: assumptions, experimental evidence and implications. Mol Psychiatry 12:522–543PubMedGoogle Scholar
  105. Jayatissa MN, Bisgaard C, Tingstrom A, Papp M, Wiborg O (2006) Hippocampal cytogenesis correlates to escitalopram-mediated recovery in a chronic mild stress rat model of depression. Neuropsychopharmacology 31:2395–2404PubMedGoogle Scholar
  106. Jeltsch-David H, Koenig J, Cassel JC (2008) Modulation of cholinergic functions by serotonin and possible implications in memory: general data and focus on 5-HT(1A) receptors of the medial septum. Behav Brain Res 195:86–97PubMedGoogle Scholar
  107. Jolly DC, Richards JB, Seiden LS (1999) Serotonergic mediation of DRL 72 s behavior: receptor subtype involvement in a behavioral screen for antidepressant drugs. Biol Psychiatry 45:1151–1162PubMedGoogle Scholar
  108. Jones MD, Lucki I (2005) Sex differences in the regulation of serotonergic transmission and behavior in 5-HT receptor knockout mice. Neuropsychopharmacology 30:1039–1047PubMedGoogle Scholar
  109. Kendler KS, Kuhn J, Prescott CA (2004) The interrelationship of neuroticism, sex, and stressful life events in the prediction of episodes of major depression. Am J Psychiatry 161:631–636PubMedGoogle Scholar
  110. Kim SW, Shin IS, Kim JM, Lee SH, Lee JH, Yoon BH, Yang SJ, Hwang MY, Yoon JS (2007) Amisulpride versus risperidone in the treatment of depression in patients with schizophrenia: a randomized, open-label, controlled trial. Prog Neuropsychopharmacol Biol Psychiatry 31:1504–1509PubMedGoogle Scholar
  111. Knobelman DA, Hen R, Lucki I (2001) Genetic regulation of extracellular serotonin by 5-hydroxytryptamine(1A) and 5-hydroxytryptamine(1B) autoreceptors in different brain regions of the mouse. J Pharmacol Exp Ther 298:1083–1091PubMedGoogle Scholar
  112. Kostowski W, Dyr W, Krzascik P, Jarbe T, Archer T (1992) 5-Hydroxytryptamine1A receptor agonists in animal models of depression and anxiety. Pharmacol Toxicol 71:24–30PubMedGoogle Scholar
  113. Kreiss DS, Lucki I (1994) Discriminative stimulus properties of the serotonin uptake inhibitor sertraline. Experimental and Clinical Psychopharmacology 2:25–36Google Scholar
  114. Kroczka B, Zieba A, Dudek D, Pilc A, Nowak G (2000) Zinc exhibits an antidepressant-like effect in the forced swimming test in mice. Pol J Pharmacol 52:403–406PubMedGoogle Scholar
  115. Le Francois B, Czesak M, Steubl D, Albert PR (2008) Transcriptional regulation at a HTR1A polymorphism associated with mental illness. Neuropharmacology 55:977–985PubMedGoogle Scholar
  116. Lira A, Zhou M, Castanon N, Ansorge MS, Gordon JA, Francis JH, Bradley-Moore M, Lira J, Underwood MD, Arango V, Kung HF, Hofer MA, Hen R, Gingrich JA (2003) Altered depression-related behaviors and functional changes in the dorsal raphe nucleus of serotonin transporter-deficient mice. Biol Psychiatry 54:960–971PubMedGoogle Scholar
  117. Lopez-Gil X, Artigas F, Adell A (2010) Unraveling monoamine receptors involved in the action of typical and atypical antipsychotics on glutamatergic and serotonergic transmission in prefrontal cortex. Curr Pharm Des 16:502–515PubMedGoogle Scholar
  118. Lucas G, Rymar VV, Du J, Mnie-Filali O, Bisgaard C, Manta S, Lambas-Senas L, Wiborg O, Haddjeri N, Pineyro G, Sadikot AF, Debonnel G (2007) Serotonin(4) (5-HT(4)) receptor agonists are putative antidepressants with a rapid onset of action. Neuron 55:712–725PubMedGoogle Scholar
  119. Lucas G, Du J, Romeas T, Mnie-Filali O, Haddjeri N, Pineyro G, Debonnel G (2010) Selective serotonin reuptake inhibitors potentiate the rapid antidepressant-like effects of serotonin4 receptor agonists in the rat. PLoS One 5:e9253PubMedGoogle Scholar
  120. Lucassen PJ, Meerlo P, Naylor AS, van Dam AM, Dayer AG, Fuchs E, Oomen CA, Czeh B (2010) Regulation of adult neurogenesis by stress, sleep disruption, exercise and inflammation: implications for depression and antidepressant action. Eur Neuropsychopharmacol 20:1–17PubMedGoogle Scholar
  121. Lucki I, Singh A, Kreiss DS (1994) Antidepressant-like behavioral effects of serotonin receptor agonists. Neurosci Biobehav Rev 18:85–95PubMedGoogle Scholar
  122. Lucki I, Dalvi A, Mayorga AJ (2001) Sensitivity to the effects of pharmacologically selective antidepressants in different strains of mice. Psychopharmacology (Berl) 155:315–322Google Scholar
  123. Mac Sweeney CP, Lesourd M, Gandon JM (1998) Antidepressant-like effects of alnespirone (S 20499) in the learned helplessness test in rats. Eur J Pharmacol 345:133–137PubMedGoogle Scholar
  124. Maes M, Meltzer HY (1995) The serotonin hypothesis of major depression. In: Bloom F, Kupfer D (eds) Psychopharmacology: the fourth generation of progress. Raven, New York, pp 933–944Google Scholar
  125. Mahesh R, Rajkumar R, Minasri B, Venkatesha Perumal R (2007) Potential antidepressants: pharmacology of 2-(4-methyl piperazin-1-yl)-1, 8-naphthyridine-3-carbonitrile in rodent behavioural models. Pharmazie 62:919–924PubMedGoogle Scholar
  126. Maier S, Seligman M (1976) Learned helplessness: theory and evidence. J Experimental Psychology: General 105:3–46Google Scholar
  127. Malatynska E, Knapp RJ (2005) Dominant-submissive behavior as models of mania and depression. Neurosci Biobehav Rev 29:715–737PubMedGoogle Scholar
  128. Malberg JE, Eisch AJ, Nestler EJ, Duman RS (2000) Chronic antidepressant treatment increases neurogenesis in adult rat hippocampus. J Neurosci 20:9104–9110PubMedGoogle Scholar
  129. Mann J (2003) Neurobiology of suicidal behaviour. Nature Reviews 4:819–828PubMedGoogle Scholar
  130. Marek GJ, Carpenter LL, McDougle CJ, Price LH (2003) Synergistic action of 5-HT2A antagonists and selective serotonin reuptake inhibitors in neuropsychiatric disorders. Neuropsychopharmacology 28:402–412PubMedGoogle Scholar
  131. Marek GJ, Martin-Ruiz R, Abo A, Artigas F (2005) The selective 5-HT2A receptor antagonist M100907 enhances antidepressant-like behavioral effects of the SSRI fluoxetine. Neuropsychopharmacology 30:2205–2215PubMedGoogle Scholar
  132. Marona-Lewicka D, Nichols DE (1997) The effect of selective serotonin releasing agents in the chronic mild stress model of depression in rats. Stress 2:91–100PubMedGoogle Scholar
  133. Marona-Lewicka D, Nichols DE (1998) Drug discrimination studies of the interoceptive cues produced by selective serotonin uptake inhibitors and selective serotonin releasing agents. Psychopharmacology (Berl) 138:67–75Google Scholar
  134. Martin P, Gozlan H, Puech AJ (1992) 5-HT3 receptor antagonists reverse helpless behaviour in rats. Eur J Pharmacol 212:73–78PubMedGoogle Scholar
  135. Matsuda T, Somboonthum P, Suzuki M, Asano S, Baba A (1995) Antidepressant-like effect by postsynaptic 5-HT1A receptor activation in mice. Eur J Pharmacol 280:235–238PubMedGoogle Scholar
  136. Mayorga AJ, Dalvi A, Page ME, Zimov-Levinson S, Hen R, Lucki I (2001) Antidepressant-like behavioral effects in 5-hydroxytryptamine(1A) and 5-hydroxytryptamine(1B) receptor mutant mice. J Pharmacol Exp Ther 298:1101–1107PubMedGoogle Scholar
  137. McMahon FJ, Buervenich S, Charney D, Lipsky R, Rush AJ, Wilson AF, Sorant AJ, Papanicolaou GJ, Laje G, Fava M, Trivedi MH, Wisniewski SR, Manji H (2006) Variation in the gene encoding the serotonin 2A receptor is associated with outcome of antidepressant treatment. Am J Hum Genet 78:804–814PubMedGoogle Scholar
  138. Meneses A (2007) Stimulation of 5-HT1A, 5-HT1B, 5-HT2A/2 C, 5-HT3 and 5-HT4 receptors or 5-HT uptake inhibition: short- and long-term memory. Behav Brain Res 184:81–90PubMedGoogle Scholar
  139. Merali Z, Levac C, Anisman H (2003) Validation of a simple, ethologically relevant paradigm for assessing anxiety in mice. Biol Psychiatry 54:552–565PubMedGoogle Scholar
  140. Meyer JH, McMain S, Kennedy SH, Korman L, Brown GM, DaSilva JN, Wilson AA, Blak T, Eynan-Harvey R, Goulding VS, Houle S, Links P (2003) Dysfunctional attitudes and 5-HT2 receptors during depression and self-harm. Am J Psychiatry 160:90–99PubMedGoogle Scholar
  141. Millan MJ (2006) Multi-target strategies for the improved treatment of depressive states: conceptual foundations and neuronal substrates, drug discovery and therapeutic application. Pharmacol Ther 110:135–370PubMedGoogle Scholar
  142. Millan MJ, Brocco M, Veiga S, Cistarelli L, Melon C, Gobert A (1998) WAY 100, 635 enhances both the ‘antidepressant’ actions of duloxetine and its influence on dialysate levels of serotonin in frontal cortex. Eur J Pharmacol 341:165–167PubMedGoogle Scholar
  143. Millan MJ, Gobert A, Girardon S, Dekeyne A (1999) Citalopram elicits a discriminative stimulus in rats at a dose selectively increasing extracellular levels of serotonin vs. dopamine and noradrenaline. Eur J Pharmacol 364:147–150PubMedGoogle Scholar
  144. Miller BH, Schultz LE, Gulati A, Cameron MD, Pletcher MT (2008) Genetic regulation of behavioral and neuronal responses to fluoxetine. Neuropsychopharmacology 33:1312–1322PubMedGoogle Scholar
  145. Murphy DL, Fox MA, Timpano KR, Moya PR, Ren-Patterson R, Andrews AM, Holmes A, Lesch KP, Wendland JR (2008) How the serotonin story is being rewritten by new gene-based discoveries principally related to SLC6A4, the serotonin transporter gene, which functions to influence all cellular serotonin systems. Neuropharmacology 55:932–960PubMedGoogle Scholar
  146. Muscat R, Papp M, Willner P (1992) Reversal of stress-induced anhedonia by the atypical antidepressants, fluoxetine and maprotiline. Psychopharmacology (Berl) 109:433–438Google Scholar
  147. Nakagawa Y, Ishima T, Takashima T (1998) The 5-HT3 receptor agonist attenuates the action of antidepressants in the forced swim test in rats. Brain Res 786:189–193PubMedGoogle Scholar
  148. Nelson JC, Papakostas GI (2009) Atypical antipsychotic augmentation in major depressive disorder: a meta-analysis of placebo-controlled randomized trials. Am J Psychiatry 166:980–991PubMedGoogle Scholar
  149. Nesterova IV, Gurevich EV, Nesterov VI, Otmakhova NA, Bobkova NV (1997) Bulbectomy-induced loss of raphe neurons is counteracted by antidepressant treatment. Prog Neuropsychopharmacol Biol Psychiatry 21:127–140PubMedGoogle Scholar
  150. Neumaier JF, Root DC, Hamblin MW (1996) Chronic fluoxetine reduces serotonin transporter mRNA and 5-HT1B mRNA in a sequential manner in the rat dorsal raphe nucleus. Neuropsychopharmacology 15:515–522PubMedGoogle Scholar
  151. Neumaier JF, Petty F, Kramer GL, Szot P, Hamblin MW (1997) Learned helplessness increases 5-hydroxytryptamine1B receptor mRNA levels in the rat dorsal raphe nucleus. Biol Psychiatry 41:668–674PubMedGoogle Scholar
  152. Nibuya M, Morinobu S, Duman RS (1995) Regulation of BDNF and trkB mRNA in rat brain by chronic electroconvulsive seizure and antidepressant drug treatments. J Neurosci 15:7539–7547PubMedGoogle Scholar
  153. Nowak G, Siwek M, Dudek D, Zieba A, Pilc A (2003a) Effect of zinc supplementation on antidepressant therapy in unipolar depression: a preliminary placebo-controlled study. Pol J Pharmacol 55:1143–1147PubMedGoogle Scholar
  154. Nowak G, Szewczyk B, Wieronska JM, Branski P, Palucha A, Pilc A, Sadlik K, Piekoszewski W (2003b) Antidepressant-like effects of acute and chronic treatment with zinc in forced swim test and olfactory bulbectomy model in rats. Brain Res Bull 61:159–164PubMedGoogle Scholar
  155. O’Donnell JM, Marek GJ, Seiden LS (2005) Antidepressant effects assessed using behavior maintained under a differential-reinforcement-of-low-rate (DRL) operant schedule. Neurosci Biobehav Rev 29:785–798PubMedGoogle Scholar
  156. O’Leary OF, Bechtholt AJ, Crowley JJ, Hill TE, Page ME, Lucki I (2007) Depletion of serotonin and catecholamines block the acute behavioral response to different classes of antidepressant drugs in the mouse tail suspension test. Psychopharmacology (Berl) 192:357–371Google Scholar
  157. Page ME, Detke MJ, Dalvi A, Kirby LG, Lucki I (1999) Serotonergic mediation of the effects of fluoxetine, but not desipramine, in the rat forced swimming test. Psychopharmacology (Berl) 147:162–167Google Scholar
  158. Page ME, Cryan JF, Sullivan A, Dalvi A, Saucy B, Manning DR, Lucki I (2002) Behavioral and neurochemical effects of 5-(4-[4-(5-Cyano-3-indolyl)-butyl)-butyl]-1-piperazinyl)-benzofuran-2-carb oxamide (EMD 68843): a combined selective inhibitor of serotonin reuptake and 5-hydroxytryptamine(1A) receptor partial agonist. J Pharmacol Exp Ther 302:1220–1227PubMedGoogle Scholar
  159. Pandey DK, Mahesh R, Kumar AA, Rao VS, Arjun M, Rajkumar R (2010) A novel 5-HT(2A) receptor antagonist exhibits antidepressant-like effects in a battery of rodent behavioural assays: approaching early-onset antidepressants. Pharmacol Biochem Behav 94:363–373PubMedGoogle Scholar
  160. Parks CL, Robinson PS, Sibille E, Shenk T, Toth M (1998) Increased anxiety of mice lacking the serotonin1A receptor. Proc Natl Acad Sci U S A 95:10734–10739PubMedGoogle Scholar
  161. Patel JG, Bartoszyk GD, Edwards E, Ashby CR Jr (2004) The highly selective 5-hydroxytryptamine (5-HT)2A receptor antagonist, EMD 281014, significantly increases swimming and decreases immobility in male congenital learned helpless rats in the forced swim test. Synapse 52:73–75PubMedGoogle Scholar
  162. Pause BM, Miranda A, Goder R, Aldenhoff JB, Ferstl R (2001) Reduced olfactory performance in patients with major depression. J Psychiatr Res 35:271–277PubMedGoogle Scholar
  163. Pehek EA, Nocjar C, Roth BL, Byrd TA, Mabrouk OS (2006) Evidence for the preferential involvement of 5-HT2A serotonin receptors in stress- and drug-induced dopamine release in the rat medial prefrontal cortex. Neuropsychopharmacology 31:265–277PubMedGoogle Scholar
  164. Peroutka SJ, Snyder SH (1980) Long-term antidepressant treatment decreases spiroperidol-labeled serotonin receptor binding. Science 210:88–90PubMedGoogle Scholar
  165. Petit-Demouliere B, Chenu F, Bourin M (2005) Forced swimming test in mice: a review of antidepressant activity. Psychopharmacology (Berl) 177:245–255Google Scholar
  166. Petty F, Davis LL, Kabel D, Kramer GL (1996) Serotonin dysfunction disorders: a behavioral neurochemistry perspective. J Clin Psychiatry 57(Suppl 8):11–16PubMedGoogle Scholar
  167. Philip NS, Carpenter LL, Tyrka AR, Price LH (2008) Augmentation of antidepressants with atypical antipsychotics: a review of the current literature. J Psychiatr Pract 14:34–44PubMedGoogle Scholar
  168. Pineyro G, Blier P (1999) Autoregulation of serotonin neurons: role in antidepressant drug action. Pharmacol Rev 51:533–591PubMedGoogle Scholar
  169. Porsolt RD, Bertin A, Blavet N, Deniel M, Jalfre M (1979) Immobility induced by forced swimming in rats: effects of agents which modify central catecholamine and serotonin activity. Eur J Pharmacol 57:201–210PubMedGoogle Scholar
  170. Porsolt RD, Bertin A, Jalfre M (1977a) Behavioral despair in mice: a primary screening test for antidepressants. Arch Int Pharmacodyn Ther 229:327–336PubMedGoogle Scholar
  171. Porsolt RD, Le Pichon M, Jalfre M (1977b) Depression: a new animal model sensitive to antidepressant treatments. Nature 266:730–732PubMedGoogle Scholar
  172. Przegalinski E, Moryl E, Papp M (1995) The effect of 5-HT1A receptor ligands in a chronic mild stress model of depression. Neuropharmacology 34:1305–1310PubMedGoogle Scholar
  173. Rakjumar R, Mahesh R (2010) The auspicious role of the 5-HT3 receptor in depression: a probable neuronal target? J Psychopharmacol 24:455–469Google Scholar
  174. Ramamoorthy R, Radhakrishnan M, Borah M (2008) Antidepressant-like effects of serotonin type-3 antagonist, ondansetron: an investigation in behaviour-based rodent models. Behav Pharmacol 19:29–40PubMedGoogle Scholar
  175. Redrobe JP, Bourin M (1997) Partial role of 5-HT2 and 5-HT3 receptors in the activity of antidepressants in the mouse forced swimming test. Eur J Pharmacol 325:129–135PubMedGoogle Scholar
  176. Reneric JP, Lucki I (1998) Antidepressant behavioral effects by dual inhibition of monoamine reuptake in the rat forced swimming test. Psychopharmacology (Berl) 136:190–197Google Scholar
  177. Richardson-Jones JW, Craige CP, Guiard BP, Stephen A, Metzger KL, Kung HF, Gardier AM, Dranovsky A, David DJ, Beck SG, Hen R, Leonardo ED (2010) 5-HT1A autoreceptor levels determine vulnerability to stress and response to antidepressants. Neuron 65:40–52PubMedGoogle Scholar
  178. Rickels K, Athanasiou M, Robinson DS, Gibertini M, Whalen H, Reed CR (2009) Evidence for efficacy and tolerability of vilazodone in the treatment of major depressive disorder: a randomized, double-blind, placebo-controlled trial. J Clin Psychiatry 70:326–333PubMedGoogle Scholar
  179. Ripoll N, David DJ, Dailly E, Hascoet M, Bourin M (2003) Antidepressant-like effects in various mice strains in the tail suspension test. Behav Brain Res 143:193–200PubMedGoogle Scholar
  180. Rosa AO, Lin J, Calixto JB, Santos AR, Rodrigues AL (2003) Involvement of NMDA receptors and L-arginine-nitric oxide pathway in the antidepressant-like effects of zinc in mice. Behav Brain Res 144:87–93PubMedGoogle Scholar
  181. Rosenzweig-Lipson S, Sabb A, Stack G, Mitchell P, Lucki I, Malberg JE, Grauer S, Brennan J, Cryan JF, Sukoff Rizzo SJ, Dunlop J, Barrett JE, Marquis KL (2007) Antidepressant-like effects of the novel, selective, 5-HT2C receptor agonist WAY-163909 in rodents. Psychopharmacology (Berl) 192:159–170Google Scholar
  182. Ruf BM, Bhagwagar Z (2009) The 5-HT1B receptor: a novel target for the pathophysiology of depression. Curr Drug Targets 10:1118–1138PubMedGoogle Scholar
  183. Rush AJ, Trivedi MH, Wisniewski SR, Stewart JW, Nierenberg AA, Thase ME, Ritz L, Biggs MM, Warden D, Luther JF, Shores-Wilson K, Niederehe G, Fava M (2006) Bupropion-SR, sertraline, or venlafaxine-XR after failure of SSRIs for depression. N Engl J Med 354:1231–1242PubMedGoogle Scholar
  184. Rygula R, Abumaria N, Flugge G, Fuchs E, Ruther E, Havemann-Reinecke U (2005) Anhedonia and motivational deficits in rats: impact of chronic social stress. Behav Brain Res 162:127–134PubMedGoogle Scholar
  185. Rygula R, Abumaria N, Flugge G, Hiemke C, Fuchs E, Ruther E, Havemann-Reinecke U (2006) Citalopram counteracts depressive-like symptoms evoked by chronic social stress in rats. Behav Pharmacol 17:19–29PubMedGoogle Scholar
  186. Sahay A, Drew MR, Hen R (2007) Dentate gyrus neurogenesis and depression. Prog Brain Res 163:697–722PubMedGoogle Scholar
  187. Sahay A, Hen R (2007) Adult hippocampal neurogenesis in depression. Nat Neurosci 10:1110–1115PubMedGoogle Scholar
  188. Sanchez C, Hyttel J (1999) Comparison of the effects of antidepressants and their metabolites on reuptake of biogenic amines and on receptor binding. Cell Mol Neurobiol 19:467–489PubMedGoogle Scholar
  189. Santarelli L, Saxe M, Gross C, Surget A, Battaglia F, Dulawa S, Weisstaub N, Lee J, Duman R, Arancio O, Belzung C, Hen R (2003) Requirement of hippocampal neurogenesis for the behavioral effects of antidepressants. Science 301:805–809PubMedGoogle Scholar
  190. Sari Y (2004) Serotonin1B receptors: from protein to physiological function and behavior. Neurosci Biobehav Rev 28:565–582PubMedGoogle Scholar
  191. Savelieva KV, Zhao S, Pogorelov VM, Rajan I, Yang Q, Cullinan E, Lanthorn TH (2008) Genetic disruption of both tryptophan hydroxylase genes dramatically reduces serotonin and affects behavior in models sensitive to antidepressants. PLoS ONE 3:e3301PubMedGoogle Scholar
  192. Savitz J, Lucki I, Drevets WC (2009) 5-HT(1A) receptor function in major depressive disorder. Prog Neurobiol 88:17–31PubMedGoogle Scholar
  193. Schechter LE, Lin Q, Smith DL, Zhang G, Shan Q, Platt B, Brandt MR, Dawson LA, Cole D, Bernotas R, Robichaud A, Rosenzweig-Lipson S, Beyer CE (2008) Neuropharmacological profile of novel and selective 5-HT6 receptor agonists: WAY-181187 and WAY-208466. Neuropsychopharmacology 33:1323–1335PubMedGoogle Scholar
  194. Schreiber R, De Vry J (1993) Neuroanatomical basis for the antidepressant-like effects of the 5-HT(1A) receptor agonists 8-OH-DPAT and ipsapirone in the rat forced swimming test. Behav Pharmacol 4:625–636PubMedGoogle Scholar
  195. Scruggs JL, Schmidt D, Deutch AY (2003) The hallucinogen 1-[2, 5-dimethoxy-4-iodophenyl]-2-aminopropane (DOI) increases cortical extracellular glutamate levels in rats. Neurosci Lett 346:137–140PubMedGoogle Scholar
  196. Shelton RC, Sanders-Bush E, Manier DH, Lewis DA (2009) Elevated 5-HT 2A receptors in postmortem prefrontal cortex in major depression is associated with reduced activity of protein kinase A. Neuroscience 158:1406–1415PubMedGoogle Scholar
  197. Shen C, Li H, Meller E (2002) Repeated treatment with antidepressants differentially alters 5-HT1A agonist-stimulated [35 S]GTP gamma S binding in rat brain regions. Neuropharmacology 42:1031–1038PubMedGoogle Scholar
  198. Shephard RA, Broadhurst PL (1982) Effects of diazepam and picrotoxin on hyponeophagia in rats. Neuropharmacology 21:771–773PubMedGoogle Scholar
  199. Siesser WB, Zhang X, Jacobsen JP, Sotnikova TD, Gainetdinov RR, Caron MG (2010) Tryptophan hydroxylase 2 genotype determines brain serotonin synthesis but not tissue content in C57Bl/6 and BALB/c congenic mice. Neurosci Lett 481:6–11PubMedGoogle Scholar
  200. Singh A, Lucki I (1993) Antidepressant-like activity of compounds with varying efficacy at 5-HT1A receptors. Neuropharmacology 32:331–340PubMedGoogle Scholar
  201. Smriga M, Torii K (2003) L-Lysine acts like a partial serotonin receptor 4 antagonist and inhibits serotonin-mediated intestinal pathologies and anxiety in rats. Proc Natl Acad Sci U S A 100:15370–15375PubMedGoogle Scholar
  202. Song C, Leonard BE (2005) The olfactory bulbectomised rat as a model of depression. Neurosci Biobehav Rev 29:627–647PubMedGoogle Scholar
  203. Steru L, Chermat R, Thierry B, Simon P (1985) The tail suspension test: a new method for screening antidepressants in mice. Psychopharmacology (Berl) 85:367–370Google Scholar
  204. Stockmeier CA, DiCarlo JJ, Zhang Y, Thompson P, Meltzer HY (1993) Characterization of typical and atypical antipsychotic drugs based on in vivo occupancy of serotonin2 and dopamine2 receptors. J Pharmacol Exp Ther 266:1374–1384PubMedGoogle Scholar
  205. Svenningsson P, Chergui K, Rachleff I, Flajolet M, Zhang X, El Yacoubi M, Vaugeois JM, Nomikos GG, Greengard P (2006) Alterations in 5-HT1B receptor function by p11 in depression-like states. Science 311:77–80PubMedGoogle Scholar
  206. Svenningsson P, Tzavara ET, Qi H, Carruthers R, Witkin JM, Nomikos GG, Greengard P (2007) Biochemical and behavioral evidence for antidepressant-like effects of 5-HT6 receptor stimulation. J Neurosci 27:4201–4209PubMedGoogle Scholar
  207. Szewczyk B, Poleszak E, Wlaz P, Wrobel A, Blicharska E, Cichy A, Dybala M, Siwek A, Pomierny-Chamiolo L, Piotrowska A, Branski P, Pilc A, Nowak G (2009) The involvement of serotonergic system in the antidepressant effect of zinc in the forced swim test. Prog Neuropsychopharmacol Biol Psychiatry 33:323–329PubMedGoogle Scholar
  208. Tardito D, Perez J, Tiraboschi E, Musazzi L, Racagni G, Popoli M (2006) Signaling pathways regulating gene expression, neuroplasticity, and neurotrophic mechanisms in the action of antidepressants: a critical overview. Pharmacol Rev 58:115–134PubMedGoogle Scholar
  209. Tatarczynska E, Klodzinska A, Chojnacka-Wojcik E (2002) Effects of combined administration of 5-HT1A and/or 5-HT1B receptor antagonists and paroxetine or fluoxetine in the forced swimming test in rats. Pol J Pharmacol 54:615–623PubMedGoogle Scholar
  210. Tatarczynska E, Klodzinska A, Stachowicz K, Chojnacka-Wojcik E (2004) Effect of combined administration of 5-HT1A or 5-HT1B/1D receptor antagonists and antidepressants in the forced swimming test. Eur J Pharmacol 487:133–142PubMedGoogle Scholar
  211. Tatarczynska E, Antkiewicz-Michaluk L, Klodzinska A, Stachowicz K, Chojnacka-Wojcik E (2005) Antidepressant-like effect of the selective 5-HT1B receptor agonist CP 94253: a possible mechanism of action. Eur J Pharmacol 516:46–50PubMedGoogle Scholar
  212. Tordera RM, Monge A, Del Rio J, Lasheras B (2002) Antidepressant-like activity of VN2222, a serotonin reuptake inhibitor with high affinity at 5-HT1A receptors. Eur J Pharmacol 442:63–71PubMedGoogle Scholar
  213. Trillat AC, Malagie I, Scearce K, Pons D, Anmella MC, Jacquot C, Hen R, Gardier AM (1997) Regulation of serotonin release in the frontal cortex and ventral hippocampus of homozygous mice lacking 5-HT1B receptors: in vivo microdialysis studies. J Neurochem 69:2019–2025PubMedGoogle Scholar
  214. Ulak G, Mutlu O, Tanyeri P, Komsuoglu FI, Akar FY, Erden BF (2010) Involvement of serotonin receptor subtypes in the antidepressant-like effect of trim in the rat forced swimming test. Pharmacol Biochem Behav 95:308–314PubMedGoogle Scholar
  215. Valentine G, Dow A, Banasr M, Pittman B, Duman R (2008) Differential effects of chronic antidepressant treatment on shuttle box escape deficits induced by uncontrollable stress. Psychopharmacology (Berl) 200:585–596Google Scholar
  216. van der Heyden JA, Molewijk E, Olivier B (1987) Strain differences in response to drugs in the tail suspension test for antidepressant activity. Psychopharmacology (Berl) 92:127–130Google Scholar
  217. Vieyra-Reyes P, Mineur YS, Picciotto MR, Tunez I, Vidaltamayo R, Drucker-Colin R (2008) Antidepressant-like effects of nicotine and transcranial magnetic stimulation in the olfactory bulbectomy rat model of depression. Brain Res Bull 77:13–18PubMedGoogle Scholar
  218. Walther DJ, Bader M (2003) A unique central tryptophan hydroxylase isoform. Biochem Pharmacol 66:1673–1680PubMedGoogle Scholar
  219. Walther DJ, Peter JU, Bashammakh S, Hortnagl H, Voits M, Fink H, Bader M (2003) Synthesis of serotonin by a second tryptophan hydroxylase isoform. Science 299:76PubMedGoogle Scholar
  220. Warner-Schmidt JL, Flajolet M, Maller A, Chen EY, Qi H, Svenningsson P, Greengard P (2009) Role of p11 in cellular and behavioral effects of 5-HT4 receptor stimulation. J Neurosci 29:1937–1946PubMedGoogle Scholar
  221. Weiss J, Goodman P, Losito B, Corrigan S, Charry J, Bailey W (1981) Behavioral depression produced by and uncontrollable stressor: relationship to norepinephrine, dopamine and serotonin levels in various regions of the rat brain. Brain Res Rev 3:167–205Google Scholar
  222. Welch WM (1995) Discovery and preclinical development of the serotonin reuptake inhibitor sertraline. Adv Med Chem 3:113–148Google Scholar
  223. Wesolowska A (2007) Study into a possible mechanism responsible for the antidepressant-like activity of the selective 5-HT6 receptor antagonist SB-399885 in rats. Pharmacol Rep 59:664–671PubMedGoogle Scholar
  224. Wesolowska A (2010) Potential role of the 5-HT6 receptor in depression and anxiety: an overview of preclinical data. Pharmacol Rep 62:564–577PubMedGoogle Scholar
  225. Wesolowska A, Nikiforuk A (2007) Effects of the brain-penetrant and selective 5-HT6 receptor antagonist SB-399885 in animal models of anxiety and depression. Neuropharmacology 52:1274–1283PubMedGoogle Scholar
  226. Wesolowska A, Nikiforuk A (2008) The selective 5-HT(6) receptor antagonist SB-399885 enhances anti-immobility action of antidepressants in rats. Eur J Pharmacol 582:88–93PubMedGoogle Scholar
  227. Wesolowska A, Nikiforuk A, Stachowicz K, Tatarczynska E (2006) Effect of the selective 5-HT7 receptor antagonist SB 269970 in animal models of anxiety and depression. Neuropharmacology 51:578–586PubMedGoogle Scholar
  228. Willner P (1997) Validity, reliability and utility of the chronic mild stress model of depression: a 10-year review and evaluation. Psychopharmacology (Berl) 134:319–329Google Scholar
  229. Willner P (2005) Chronic mild stress (CMS) revisited: consistency and behavioural-neurobiological concordance in the effects of CMS. Neuropsychobiology 52:90–110PubMedGoogle Scholar
  230. Wolff MC, Leander JD (1999) The discriminative stimulus properties of LY233708, a selective serotonin reuptake inhibitor, in the pigeon. Psychopharmacology (Berl) 146:275–279Google Scholar
  231. Wong DT, Perry KW, Bymaster FP (2005) Case history: the discovery of fluoxetine hydrochloride (Prozac). Nat Rev Drug Discov 4:764–774PubMedGoogle Scholar
  232. Wood MD, Scott C, Clarke K, Cato KJ, Patel N, Heath J, Worby A, Gordon L, Campbell L, Riley G, Davies CH, Gribble A, Jones DN (2006) Pharmacological profile of antipsychotics at monoamine receptors: atypicality beyond 5-HT2A receptor blockade. CNS Neurol Disord Drug Targets 5:445–452PubMedGoogle Scholar
  233. Yalcin I, Belzung C, Surget A (2008) Mouse strain differences in the unpredictable chronic mild stress: a four-antidepressant survey. Behav Brain Res 193:140–143PubMedGoogle Scholar
  234. Zazpe A, Artaiz I, Labeaga L, Lucero ML, Orjales A (2007) Reversal of learned helplessness by selective serotonin reuptake inhibitors in rats is not dependent on 5-HT availability. Neuropharmacology 52:975–984PubMedGoogle Scholar
  235. Zhang X, Beaulieu JM, Sotnikova TD, Gainetdinov RR, Caron MG (2004) Tryptophan hydroxylase-2 controls brain serotonin synthesis. Science 305:217PubMedGoogle Scholar
  236. Zhuang X, Gross C, Santarelli L, Compan V, Trillat AC, Hen R (1999) Altered emotional states in knockout mice lacking 5-HT1A or 5-HT1B receptors. Neuropsychopharmacology 21:52S–60SPubMedGoogle Scholar

Copyright information

© Springer-Verlag 2010

Authors and Affiliations

  1. 1.Department of PsychiatryUniversity of PennsylvaniaPhiladelphiaUSA

Personalised recommendations