Skip to main content
SpringerLink
Log in

Implication of 5-HT2 receptor subtypes in the mechanism of action of antidepressants in the four plates test

  • Original Investigation
  • Published:
Psychopharmacology Aims and scope Submit manuscript

Abstract

Rationale

The selective serotonin reuptake inhibitors (SSRIs) and the serotonin and noradrenaline reuptake inhibitors (SNRIs) increase synaptic levels of serotonin, leading to an increased activation of a multitude of specific postsynaptic 5-HT receptors. However, it is not yet known which 5-HT receptor subtypes mediate the therapeutic effects of antidepressants.

Methods

The effects of the SSRI, paroxetine and the SNRI, venlafaxine were evaluated in the mouse four plates test (FPT).

Results

Paroxetine administered intraperitoneally (IP) (0.5, 2–8 mg/kg) potently augmented the number of punished passages accepted by mice in this paradigm. The effects of paroxetine (8 mg/kg) were not reversed by the selective 5-HT2C receptor antagonist, RS 10-2221 (0.1 mg/kg and 1 mg/kg) or the selective 5-HT2B/2C receptor antagonist SB 206553 (0.1 mg/kg and 1 mg/kg), at doses which lack an effect when administered alone. In contrast, the selective 5-HT2A receptor antagonist, SR 46349B (0.1 mg/kg and 1 mg/kg) completely abolished the paroxetine-induced increase in punished passages. The acute administration of venlafaxine induced an anxiolytic-like effect in the FPT at the doses of 2–16 mg/kg. This effect was reversed by the 5-HT2B/2C receptor antagonist as did SR 46349B, for both doses administered. Our results strongly suggest that activation of 5-HT2A receptors is critically involved in the anxiolytic activity of paroxetine, whereas the 5-HT2A and 5-HT2B receptors are involved in the anti-punishment action of venlafaxine in the FPT. The co-administration of selective 5-HT2A, 2B, 2C receptor agonists (DOI, 0.06 mg/kg and 0.25 mg/kg; BW 723C86, 0.5 mg/kg and 2 mg/kg and RO 60-0175, 0.06 mg/kg and 0.25 mg/kg), respectively, was subsequently investigated. The effects of sub-active doses of paroxetine (0.25 mg/kg and 1 mg/kg) were augmented by BW 723C86 and RO 60-0175 receptor agonist challenge. The anti-punishment effects of venlafaxine (0.25 mg/kg and 1 mg/kg) were potentialised only by DOI co-administration.

Conclusion

These results indicate that the co-administration of 5-HT2 receptor agonists with paroxetine and venlafaxine may provide a powerful tool for enhancing the clinical efficacy of these antidepressants.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Subscribe and save

Springer+ Basic
$34.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or eBook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8
Fig. 9
Fig. 10

Similar content being viewed by others

References

  • Ables AZ, Baughman OL III (2003) Antidepressants: update on new agents and indications. Am Fam Phys 67:547–554

    Google Scholar 

  • Ardid D, Marty H, Fialip J, Privat AM, Eschalier A, Lavarenne J (1992) Comparative effects of different uptake inhibitor antidepressants in two pain tests in mice. Fundam Clin Pharmacol 6:75–82

    CAS  PubMed  Google Scholar 

  • Beijamini V, Andreatini R (2003) Effects of Hypericum perforatum and paroxetine on rat performance in the elevated T-maze. Pharmacol Res 48:199–207

    Article  CAS  PubMed  Google Scholar 

  • Besson A, Haddjeri N, Blier P, De Montigny C (2000) Effects of the co-administration of mirtazapine and paroxetine on serotonergic neurotransmission in the rat brain. Eur Neuropsychopharmacol 10:177–188

    Article  CAS  PubMed  Google Scholar 

  • Beyer CE, Boikess S, Luo B, Dawson LA (2002) Comparison of the effects of antidepressants on norepinephrine and serotonin concentrations in the rat frontal cortex: an in-vivo microdialysis study. J Psychopharmacol 16:297–304

    CAS  PubMed  Google Scholar 

  • Boissier JR, Simon P (1965) Action of caffeine on the spontaneous motility of the mouse. Arch Int Pharmacodyn Ther 158:212–221

    CAS  PubMed  Google Scholar 

  • Boissier JR, Simon P, Aron C (1968) A new method for rapid screening of minor tranquillizers in mice. Eur J Pharmacol 4:145–151

    Article  CAS  PubMed  Google Scholar 

  • Borsini F, Podhorna J, Marazziti D (2002) Do animal models of anxiety predict anxiety-like effects of antidepressants. Psychopharmacology 163:121–141

    Article  CAS  PubMed  Google Scholar 

  • Bourin M, Lambert O (2002) Pharmacotherapy of anxious disorders. Hum Psychopharmacol 17:383–400

    Article  CAS  PubMed  Google Scholar 

  • Bourin M, Chue P, Guillon Y (2001) Paroxetine: a review. CNS Drug Rev 7:25–47

    CAS  PubMed  Google Scholar 

  • Bourin M, David DJ, Jolliet P, Gardier A (2002) Mechanism of action of antidepressants and therapeutic perspectives. Therapie 57:385–396

    CAS  PubMed  Google Scholar 

  • Briley M (2003) New hope in the treatment of painful symptoms in depression. Curr Opin Invest Drugs 4:42–45

    CAS  Google Scholar 

  • Cusack B, Nelson A, Richelson E (1994) Binding of antidepressants to human brain receptors: focus on newer generation compounds. Psychopharmacology 114:559–565

    CAS  PubMed  Google Scholar 

  • Damjanoska KJ, Muma NA, Zhang Y, D’Souza DN, Garcia F, Carrasco GA, Kindel GH, Haskins KA, Shankaran M, Petersen BR, Van de Kar LD (2003) Neuroendocrine evidence that (S)-2-(chloro-5-fluoro-indol- l-yl)-1-methylethylamine fumarate (Ro 60-0175) is not a selective 5-hydroxytryptamine(2C) receptor agonist. J Pharmacol Exp Ther 304:1209–1216

    Article  CAS  PubMed  Google Scholar 

  • David DJ, Bourin M, Jego G, Przybylski C, Jolliet P, Gardier AM (2003) Effects of acute treatment with paroxetine, citalopram and venlafaxine in vivo on noradrenaline and serotonin outflow: a microdialysis study in Swiss mice. Br J Pharmacol 140:1128–1136

    Article  CAS  PubMed  Google Scholar 

  • Davidson JR, Dupont RL, Hedges D, Haskins JT (1999) Efficacy, safety, and tolerability of venlafaxine extended release and buspirone in outpatients with generalized anxiety disorder. J Clin Psychiatry 60:528–535

    CAS  PubMed  Google Scholar 

  • Deakin JF, Graeff FG, Guimaraes FS (1993) Clinical implication of microdialysis findings. Trends Pharmacol Sci 14:263

    Article  CAS  PubMed  Google Scholar 

  • Di Matteo V, Cacchio VM, Di Giulio C, Esposito E (2002) Role of serotonin 2C receptors in the control of brain dopaminergic function. Pharmacol Biochem Behav 71:727–734

    Article  PubMed  Google Scholar 

  • Duman EN, Kesim M, Kadioglu M, Yaris E, Kalyoncu NI, Erciyes N (2004) Possible involvement of opioide and serotonergic mechanisms in antinociceptive effect of paroxetine in acute pain. J Pharmacol Sci 94:161–165

    Article  CAS  PubMed  Google Scholar 

  • Duxon MS, Starr KR, Upton N (2000) Latency to paroxetine-induced anxiolysis in the rat is reduced by co-administration of the 5-HT1A receptor antagonist WAY100635. Br J Pharmacol 130:1713–1719

    CAS  PubMed  Google Scholar 

  • Fasmer OB, Hunskaar S, Hole K (1989) Antinociceptive effects of serotonergic reuptake inhibitors in mice. Neuropharmacology 28:1363–1366

    Google Scholar 

  • Felton TM, Kang TB, Hjorth S, Auerbach SB (2003) Effects of selective serotonin and serotonin/noradrenaline reuptake inhibitors on extracellular serotonin in rat diencephalon and frontal cortex. Naunyn Schmiedebergs Arch Pharmacol 367:297–305

    CAS  PubMed  Google Scholar 

  • Ferreri M, Lavergne F, Berlin I, Payan C, Puech AJ (2001) Benefits from mianserin augmentation of fluoxetine in patients with major depression non-responders to fluoxetine alone. Acta Psychiatr Scand 103:66–72

    Article  CAS  PubMed  Google Scholar 

  • Fuller RW (1994) Uptake inhibitors increase extracellular serotonin concentration measured by brain microdialysis. Life Sci 55:163–167

    Article  CAS  PubMed  Google Scholar 

  • Gelenberg AJ, Lydiard RB, Rudolph RL, Aguiar L, Haskins JT, Salinas E (2000) Efficacy of venlafaxine extended-release capsules in nondepressed outpatient with generalized anxiety disorder: a 6-month randomized controlled trial. JAMA 283:3082–3088

    Article  CAS  PubMed  Google Scholar 

  • Hascoët M, Bourin M, Colombel MC, Fiocco AJ, Baker GB (2000a) Anxiolytic-like effects of antidepressants after acute administration in a four-plate test in mice. Pharmacol Biochem Behav 65:339–344

    Article  PubMed  Google Scholar 

  • Hascoët M, Bourin M, Nic Dhonnchadha BÁ (2000b) The influence of buspirone, and its metabolite 1-PP, on the activity of paroxetine in the mouse light/dark paradigm and four plates test. Pharmacol Biochem Behav 67:45–53

    Article  PubMed  Google Scholar 

  • Hashimoto S, Inoue T, Koyama T (1996) Serotonin reuptake inhibitors reduce conditioned fear stress-induced freezing behaviour in rats. Psychopharmacology 123:182–186

    CAS  PubMed  Google Scholar 

  • Hyttel J (1994) Pharmacological characterisation of selective serotonin reuptake inhibitors (SSRIs). Int Clin Psychopharmacol 9:19–26

    PubMed  Google Scholar 

  • Kent JM (2000) SNaRIs, NaSSAs and NaRIs: new agents for the treatment of depression. Lancet 355:911–918

    Article  CAS  PubMed  Google Scholar 

  • Kõks S, Beljajev S, Koovit I, Abramov U, Bourin M, Vasar E (2001) 8-OH-DPAT, but not deramciclane, antagonizes the anxiogenic-like action of paroxetine in an elevated plus-maze. Psychopharmacology 153:365–372

    Article  PubMed  Google Scholar 

  • Kreiss DS, Lucki I (1995) Effects of acute and repeated administration of antidepressant drugs on extracellular levels of 5-hydroxytryptamine measured in vivo. J Pharmacol Exp Ther 274:866–876

    CAS  PubMed  Google Scholar 

  • Lambert O, Bourin M (2002) SNRIs: mechanism of action and clinical features. Expert Rev Neurother 2:849–858

    CAS  Google Scholar 

  • Lightowler S, Kennett GA, Williamson IJ, Blackburn TP, Tulloch IF (1994) Anxiolytic-like effect of paroxetine in a rat social interaction test. Pharmacol Biochem Behav 49:281–285

    Article  CAS  PubMed  Google Scholar 

  • McDougle CJ, Epperson CN, Pelton GH, Wasylink S, Price LH (2000) A double-blind, placebo-controlled study of risperidone addition in serotonin reuptake inhibitor-refractory obsessive-compulsive disorder. Arch Gen Psychiatry 57:794–801

    Article  CAS  PubMed  Google Scholar 

  • Millan MJ, Gobert A, Lejeune F, Newman-Tancredi A, Rivet JM, Auclair A, Peglion JL (2001a) S33005, a novel ligand at both serotonin and norepinephrine transporters: I. Receptor binding, electrophysiological, and neurochemical profile in comparison with venlafaxine, reboxetine, citalopram, and clomipramine. J Pharmacol Exp Ther 298:565–580

    CAS  PubMed  Google Scholar 

  • Millan MJ, Dekeyne A, Papp M, La Rochelle CD, MacSweeney C, Peglion JL, Brocco M (2001b) S33005, a novel ligand at both serotonin and norepinephrine transporters. II. Behavioral profile in comparison with venlafaxine, reboxetine, citalopram, and clomipramine. J Pharmacol Exp Ther 298:581–591

    CAS  PubMed  Google Scholar 

  • Mork A, Hogg S (2002) The 5-HT2C antagonist, irindalone has the potential as add-on therapy in combination with SSRIs: Microdialysis and light dark box studies. Int J Neuropsychopharmacol 5(Suppl 1):S69

    Google Scholar 

  • Muth EA, Haskins JT, Moyer JA, Husbands GE, Nielsen ST, Sigg EB (1986) Antidepressant biochemical profile of the novel bicyclic compound Wy-45,030, an ethyl cyclohexanol derivative. Biochem Pharmacol 35:4493–4497

    Article  CAS  PubMed  Google Scholar 

  • Nemeroff CB (2003) Anxiolytics: past, present, and future agents. J Clin Psychiatry 64:3–6

    CAS  Google Scholar 

  • Nic Dhonnchadha BÁ, Hascoët M, Bourin M (2003) Anxiolytic-like effects of 5-HT2 ligands on three mouse models of anxiety. Behav Brain Res 140:203–214

    Article  CAS  PubMed  Google Scholar 

  • Nierenberg AA (2001)Do some antidepressants work faster than others? J Clin Psychiatry 62:22–25

    CAS  Google Scholar 

  • Ninan PT (2000) Use of venlafaxine in other psychiatric disorders. Depress Anxiety 12:90–94

    Article  PubMed  Google Scholar 

  • Njung’e K, Handley SL (1991) Effects of 5-HT uptake inhibitors, agonists and antagonists on the burying of harmless objects by mice; a putative test for anxiolytic agents. Br J Pharmacol 104:105–112

    CAS  PubMed  Google Scholar 

  • Owens MJ, Morgan WN, Plott SJ, Nemeroff CB (1997) Neurotransmitter receptor and transporter binding profile of antidepressants and their metabolites. J Pharmacol Exp Ther 283:1305–1322

    CAS  PubMed  Google Scholar 

  • Petersen EN, Lassen JB (1981) A water lick conflict paradigm using drug experienced rats. Psychopharmacology 75:236–239

    CAS  PubMed  Google Scholar 

  • Pollack MH, Zaninelli R, Goddard A (2001) Paroxetine in the treatment of generalised anxiety disorders: results of a placebo controlled, flexible-dosage trial. J Clin Psychiatry 62:350–357

    CAS  PubMed  Google Scholar 

  • Prut L, Belzung C (2003) The open field as a paradigm to measure the effects of drugs on anxiety-like behaviours: a review. Eur J Pharmacol 463:3–33

    Article  CAS  PubMed  Google Scholar 

  • Rasmussen BB, Brosen K (2000) Is therapeutic drug monitoring a case for optimizing clinical outcome and avoiding interactions of the selective serotonin reuptake inhibitors? Ther Drug Monit 22:143–154

    Article  CAS  PubMed  Google Scholar 

  • Rickels K, Pollack MH, Sheehan DV, Haskins JT (2000) Efficacy of extended-release venlafaxine in nondepressed outpatients with generalized anxiety disorder. Am J Psychiatry 157:968–974

    Article  CAS  PubMed  Google Scholar 

  • Rosen RC, Lane RM, Menza M (1999) Effects of SSRIs on sexual function: a critical review. J Clin Psychopharmacol 19:67–85

    Article  CAS  PubMed  Google Scholar 

  • Rupniak NM, Carlson EC, Harrison T, Oates B, Seward E, Owen S, De Felipe C, Hunt S, Wheeldon A (2000) Pharmacological blockade or genetic deletion of substance P (NK(1)) receptors attenuates neonatal vocalisation in guinea-pigs and mice. Neuropharmacology 39:1413–1421

    Google Scholar 

  • Sanchez C (2003) Stress-induced vocalisation in adult animals. A valid model of anxiety? Eur J Pharmacol 463:133–143

    Article  PubMed  Google Scholar 

  • Sanchez C, Meier E (1997) Behavioural profiles of SSRIs in animal models of depression, anxiety and aggression. Are they all alike? Psychopharmacology 129:197–205

    Article  CAS  PubMed  Google Scholar 

  • Schreiber R, Melon C, De Vry J (1998) The role of 5-HT receptor subtypes in the anxiolytic effects of selective serotonin reuptake inhibitors in the rat ultrasonic vocalization test. Psychopharmacology 135:383–391

    Article  CAS  PubMed  Google Scholar 

  • Stahl SM (1998) Mechanism of action of serotonin selective reuptake inhibitors. Serotonin receptors and pathways mediate therapeutic effects and side effects. J Affect Disord 51:215–235

    Article  CAS  PubMed  Google Scholar 

  • Stahl SM, Entsuah R, Rudolph RL (2002) Comparative efficacy between venlafaxine and SSRIs: a pooled analysis of patients with depression. Biol Psychiatry 52:1166–1174

    Article  CAS  PubMed  Google Scholar 

  • Szabo ST, Blier P (2002) Effects of serotonin (5-hydroxytryptamine, 5-HT) reuptake inhibition plus 5-HT2A receptor antagonism on the firing activity of norepinephrine neurons. J Pharmacol Exp Ther 302:983–991

    Article  CAS  PubMed  Google Scholar 

  • Vaswani M, Linda FK, Ramesh S (2003) Role of selective serotonin reuptake inhibitors in psychiatric disorders: a comprehensive review. Prog Neuropsychopharmacol Biol Psychiatry 27:85–102

    Article  CAS  PubMed  Google Scholar 

  • Winslow JT, Insel TR (1991) The infant rat separation paradigm: a novel test for novel anxiolytics. Trends Pharmacol Sci 12:402–404

    Article  CAS  PubMed  Google Scholar 

  • Woods A, Smith C, Szewczak M, Dunn RW, Cornfeldt M, Corbett R (1993) Selective serotonin re-uptake inhibitors decrease schedule-induced polydipsia in rats: a potential model for obsessive compulsive disorder. Psychopharmacology 112:195–198

    CAS  PubMed  Google Scholar 

  • Zohar J, Westenberg HG (2000) Anxiety disorders: a review of tricyclic antidepressants and selective serotonin reuptake inhibitors. Acta Psychiatr Scand Suppl 403:39–49

    CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. EA 3256, Neurobiologie de l’anxiété et de la dépression, Faculté de Médecine, BP 53508, 1 rue Gaston Veil, 44035, Nantes Cedex 01, France

    Bríd Áine Nic Dhonnchadha, Nadège Ripoll, Florence Clénet, Martine Hascoët & Michel Bourin

Authors
  1. Bríd Áine Nic Dhonnchadha
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Nadège Ripoll
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Florence Clénet
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Martine Hascoët
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Michel Bourin
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Michel Bourin.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Nic Dhonnchadha, B.Á., Ripoll, N., Clénet, F. et al. Implication of 5-HT2 receptor subtypes in the mechanism of action of antidepressants in the four plates test. Psychopharmacology 179, 418–429 (2005). https://doi.org/10.1007/s00213-004-2044-y

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00213-004-2044-y

Keywords

Search

Navigation