, Volume 126, Issue 3, pp 234–240 | Cite as

Interactions of selective serotonin reuptake inhibitors with the serotonin 5-HT2C receptor

  • E. -P. Pälvimäki
  • H. Majasuo
  • A. Laakso
  • M. Kuoppamäki
  • E. Syvälahti
  • B. L. Roth
  • J. Hietala
Original Investigation


Interactions of the selective serotonin reuptake inhibitors (SSRIs) citalopram, fluoxetine and its main metabolite norfluoxetine, and the tricyclic anti-depressant (TCA) imipramine with the rat serotonin 5-HT2C receptor in a clonal cell line and in the rat choroid plexus were investigated by radioligand binding and phosphoinositide (PI) hydrolysis assays. For comparison, the affinities of a variety of other antidepressants of different chemical classes for the cloned rat 5-HT2C and 5-HT2A receptors were also determined by radioligand binding assays. Fluoxetine displayed relatively high affinity for the 5-HT2C receptor in the choroid plexus, with a Ki value for inhibition of [3H]mesulergine binding of 55.4 nM. The Ki values for imipramine, norfluoxetine and citalopram were 136 nM, 203 nM, and 298 nM, respectively. Similar rank order of potency was detected in PI hydrolysis assays, which showed that these drugs are antagonists at the 5-HT2C receptor without exhibiting inverse agonist activity. [3H]Ketanserin (5-HT2A) binding assays revealed that the SSRIs fluoxetine, norfluoxetine and citalopram show 10- to 23-fold selectivity for the 5-HT2C receptor in vitro, whereas the TCA imipramine does not. Many other TCAs also had high to intermediate affinity for both 5-HT2A and 5-HT2C receptors. The present data provide evidence that fluoxetine, norfluoxetine and citalopram, along with many other antidepressant compounds, interact directly with the 5-HT2C receptor.

Key words

Citalopram Fluoxetine Imipramine Antidepressants Serotonin 5-HT2C receptor Serotonin 5-HT2A receptor 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. Abramowski D, Staufenbiel M (1995) Identification of the 5-hydroxytryptamine2C receptor as a 60-kDaN-glycosylated protein in choroid plexus and hippocampus. J Neurochem 65:782–790Google Scholar
  2. Appel NM, Mitchell WM, Garlick RK, Glennon RA, Teitler M, De Souza EB (1990) Autoradiographic characterization of (±)-1-(2,5-dimethoxy-4-[125I]iodophenyl)-2-aminopropane ([125I]DOI) binding to 5-HT2 and 5-HT1C receptors in the rat brain. J Pharmacol Exp Ther 255:843–857Google Scholar
  3. Beasley CM, Masica DN, Potvin JH (1992) Fluoxetine: a review of receptor and functional effects and their clinical implications. Psychopharmacology 107:1–10Google Scholar
  4. Benfield P, Heel RC, Lewis SP (1986) Fluoxetine — a review of its pharmacodynamic and pharmacokinetic properties, and therapeutic efficacy in depressive illness. Drugs 32:481–508Google Scholar
  5. Caccia S, Fracasso C, Garattini S, Guiso G, Darati S (1992) Effects of short- and long-term administration of fluoxetine on the monoamine content in rat brain. Neuropharmacology 31:343–347Google Scholar
  6. Canton H, Verrièle L, Colpaert FC (1990) Binding of typical and atypical antipsychotics to 5-HT1C and 5-HT2C sites: clozapine potently interacts with 5-HT1C sites. Eur J Pharmacol 191:93–96Google Scholar
  7. Cheetham SC, Viggers JA, Slater NA, Heal DJ, Buckett WR (1993) [3H]Paroxetine binding in rat frontal cortex strongly correlates with [3H]5-HT uptake: effect of administration of various antidepressant treatments. Neuropharmacology 32[8]:737–743Google Scholar
  8. Conn PJ, Sanders-Bush E (1986) Agonist-induced phosphoinositide hydrolysis in choroid plexus. J Neurochem 47:1754–1760Google Scholar
  9. Fabre LF, Crismon ML (1985) Efficacy of fluoxetine in outpatients with major depression. Curr Ther Res 37[1]:115–123Google Scholar
  10. Fuller RW, Snoddy HD, Perry KW, Bymaster FP, Wong DT (1978) Importance of duration of drug action in the antagonism ofp-chloroamphetamine depletion of brain serotonin — comparison of fluoxetine and chlorimipramine. Biochem Pharmacol 27:193–198Google Scholar
  11. Gerione RA, Codina J, Benovic JL, Lefkowitz RJ, Birnbaumer L, Caron MG (1984) The mammalian beta 2-adrenergic receptor: reconstitution of functional interactions between pure receptor and pure stimulatory nucleotide binding protein of the adenylate cyclase system. Biochemistry 23:4519–4525Google Scholar
  12. Han C, Minneman KP (1991) Interaction of subtype-selective antagonists with α1-adrenergic receptor binding sites in rat tissues. Mol Pharmacol 40:531–538Google Scholar
  13. Harker EL, Westphal RS, Schmidt D, Sanders-Bush E (1994) Constitutively active 5-hydroxytryptamine 2C (5-HT2C) receptors reveal novel inverse agonist activity of receptor ligands. J Biol Chem 269:11687–11690Google Scholar
  14. Havlik S, Peroutka SJ (1992) Differential radioligand binding properties of [3H]5-hydroxytryptamine and [3H]mesulergine in a clonal 5-hydroxytryptamine2C cell line. Brain Res 584:191–196Google Scholar
  15. Hietala J, Salonen I, Lappalainen J, Syvälahti E (1990) Ethanol administration does not alter dopamine D1 and D2 receptor characteristics in rat brain. Neurosci Lett 108:289Google Scholar
  16. Hietala J, Koulu M, Kuoppamäki M, Lappalainen J, Syvälahti E (1992) Chronic clozapine treatment down-regulates serotonin 5-HT-1c receptors in rat brain. Prog Neuropsychopharmacol Biol Psychiatry 16:727–732Google Scholar
  17. Hoffman BJ, Mezey E (1989) Distribution of serotonin 5-HT1C receptor mRNA in adult rat brain. FEBS Lett 247[2]:453–462Google Scholar
  18. Jenck F, Moreau J-L, Mutel V, Martin JR, Haefely WE (1993) Evidence for a role of 5-HT1C receptors in the antiserotonergic properties of some antidepressant drugs. Eur J Pharmacol 231:223–229Google Scholar
  19. Karson CN, Newton JEO, Livingston R, Jolly JB, Cooper TB, Sprigg J, Komoroski RA (1993) Human brain fluoxetine concentrations. J Neuropsychiatr Clin Neurosci 5:322–329Google Scholar
  20. Kuoppamäki M, Syvälahti E, Hietala J (1993) Clozapine andN-desmethylclozapine are potent 5-HT1C receptor antagonists. Eur J Pharmacol [Mol Pharmacol Sect] 245:179–182Google Scholar
  21. Kuoppamäki M, Pälvimäki E-P, Syvälahti E, Hietala J (1994) 5-HT1C receptor-mediated phosphoinositide hydrolysis in the rat choroid plexus after chronic treatment with clozapine. Eur J Pharmacol 255:91–97Google Scholar
  22. Kuoppamäki M, Pälvimäki E-P, Hietala J, Syvälahti E (1995) Differential regulation of rat 5-HT2A and 5-HT2C receptors after chronic treatment with clozapine, chlorpromazine and three putative atypical antipsychotic drugs. Neuropsychopharmacology 13:139–151Google Scholar
  23. Laakso A, Pälvimäki E-P, Kuoppamäki M, Suvälahti E, Hietala J (1996) Chronic citalopram and fluoxetine treatments up-regulate 5-HT2C receptors in the rat choroid plexus. Neuropsychopharmacology (in press)Google Scholar
  24. Leonhardt S, Gorospe E, Hoffman BJ, Teitler M (1992) Molecular pharmacological differences in the interaction of serotonin with 5-hydroxytryptamine1C and 5-hydroxytryptamine2 receptors. Mol Pharmacol 42:328–335Google Scholar
  25. Leysen JE, Niemegeers CJE, Van Nueten JM, Laduron PM (1982) [3H]Ketanserin (R 41 468), a selective3H-ligand for serotonin2 receptor binding sites; binding properties, brain distribution and functional role. Mol Pharmacol 21:301Google Scholar
  26. Mann CD, Bich Vu T, Hrdina PD (1995) Protein kinase C in rat brain cortex and hippocampus: effect of repeated administration of fluoxetine and desipramine. Brit J Pharmacol 115:595–600Google Scholar
  27. Milligan G, Bond RA, Lee M (1995) Inverse agonism: pharmacological curiosity or potential therapeutic strategy? Trneds Pharmacol Sci 16:10–13Google Scholar
  28. Molineaux SM, Jessell TM, Axel R, Julius D (1989) 5-HT1C receptor is a prominent serotonin receptor subtype in the central nervous system. Proc Natl Acad Sci USA 86[17]:6793–6797Google Scholar
  29. Morin D, Zini R, Urien S, Tillement JP (1989) Pharmacological profile of binedaline, a new antidepressant drug. J Pharmacol Exp Ther 249[1]:288–296Google Scholar
  30. Pazos A, Palacios JM (1985) Quantitative autoradiographic mapping of serotonin receptors in the rat brain. I. Serotonin-1 receptors. Brain Res 346:205–230Google Scholar
  31. Pompeiano M, Palacios JM, Mengod G (1994) Distribution of the serotonin 5-HT2 receptor family mRNAs: comparison between 5-HT2A and 5-HT2C receptors. Brain Res Mol Brain Res 23[1–2]:163–178Google Scholar
  32. Richelson E, Pfenning M (1984) Blockade by antidepressants and related compounds of biogenic amine uptake into rat brain synaptosomes: most antidepressants selectively block norepinephrine uptake. Eur J Pharmacol 104:277–286Google Scholar
  33. Rickels K, Amsterdam JD, Avallone MF (1986) Fluoxetine in major depression: a controlled study. Curr Ther Res 39[4]:559–563Google Scholar
  34. Roth BL, Hamblin MW, Ciaranello RD (1991) Mianserin decreases 5-HT2 radioligand binding without altering 5-HT2 receptor mRNA levels. Eur J Pharmacol 207:169–172Google Scholar
  35. Roth BL, Ciaranello RD, Meltzer HY (1992) Binding of typical and atypical antipsychotic agents to transiently expressed 5-HT1C receptors. J Pharmacol Exp Ther 260:1361–1366Google Scholar
  36. Sanders-Bush E, Breeding M (1988) Putative selective 5-HT-2 antagonists block 5-HT-1c receptors in the choroid plexus. J Pharmacol Exp Ther 247:169–173Google Scholar
  37. Sanders-Bush E, Breeding M (1990) Serotonin1c receptor reserve in choroid plexus masks receptor subsensitivity. J Pharmacol Exp Ther 252[3]:984–988Google Scholar
  38. Sommi RW, Crismon ML, Bowden CL (1987) Fluoxetine: a serotonin-specific, second-generation antidepressant. Pharmacotherapy 7[1]:001–015Google Scholar
  39. Torok-Both GA, Baker GB, Coutts RT, McKenna KF, Aspeslet LJ (1992) Simultaneous determination of fluoxetine and norfluoxetine enantiomers in biological samples by gas chromatography with electron-capture detection. J Chromatogr 579:99–106Google Scholar
  40. Westphal RS, Sanders-Bush E (1994) Reciprocal binding properties of 5-hydroxytryptamine type 2C receptor agonists and inverse agonists. Mol Pharmacol 46:937–942Google Scholar
  41. Wong DT, Threlkeld PG, Robertson DW (1991) Affinities of fluoxetine, its enantiomers, and other inhibitors of serotonin uptake for subtypes of serotonin receptors. Neuropsychopharmacology 5[1]:43–47Google Scholar
  42. Wood MD, Glen A, Blackburn TP, Lee JA, Sutiphong JA, Kumar C, Carey J, Robinson J (1993) (-)-Fluoxetine has high affinity for the cloned rat and human 5-HT1C receptor and the human 5-HT2 receptor. Br J Pharmacol 110 [Proceedings Supplement]: 102PGoogle Scholar

Copyright information

© Springer-Verlag 1996

Authors and Affiliations

  • E. -P. Pälvimäki
    • 1
  • H. Majasuo
    • 1
  • A. Laakso
    • 1
  • M. Kuoppamäki
    • 1
  • E. Syvälahti
    • 1
  • B. L. Roth
    • 2
  • J. Hietala
    • 3
  1. 1.Department of Pharmacology and Clinical Pharmacology, Institute of BiomedicineUniversity of TurkuTurkuFinland
  2. 2.Departments of Psychiatry and Biochemistry, School of MedicineCase Western Reserve UniversityClevelandUSA
  3. 3.Department of PsychiatryTurku University Central HospitalTurkuFinland

Personalised recommendations