Skip to main content
SpringerLink
Log in

A PET study on regional coexpression of 5-HT1A receptors and 5-HTT in the human brain

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

Abstract

Rationale

Several lines of evidence suggest inter-dependency between the serotonin transporter (5-HTT) and the 5HT1A receptor, two recognised targets for the treatment of anxiety and depression.

Objectives

to examine the correlation of regional expression levels for these two serotonergic markers in the human brain in vivo.

Methods

Twelve male control subjects were examined with PET twice on the same day, using the radioligands [11C]WAY 100635 and [11C]MADAM for quantification of the 5-HT1A receptor and the 5-HTT, respectively. The binding potential (BP) was calculated for raphe nuclei, hippocampus and frontal cortex.

Results

In all regions, the BP for both [11C]WAY 100635 (raphe nuclei 1.85–4.71, hippocampus 2.52–6.17, frontal cortex 2.03–3.79) and [11C]MADAM (2.70–7.65, 0.47–1.76, 0.18–0.51) varied several fold between subjects. In the raphe nuclei, where the two markers are situated on the same neurons, the ratio of [11C]WAY 100635 binding to [11C]MADAM BP binding varied considerably (0.43–1.05). There was a positive correlation between the two markers in the raphe nuclei (r xy = 0.68, p < 0.05) and in the hippocampus (r xy = 0.97, p < 0.001) but not in the frontal cortex (r xy = −0.25, p = 0.44).

Conclusions

The results support a correlation between density levels of the 5-HT1A-receptor and the 5-HTT in the raphe nuclei and hippocampus but not in the frontal cortex. A suggested clinical implication is that the inter-individual variability in 5-HT1A-receptor and 5-HTT densities, as well as the ratio of these, is of particular interest in relation to individual responses to selective serotonin reuptake inhibitor treatment.

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

Access this article

Log in via an institution

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

Similar content being viewed by others

References

  • Andree B, Halldin C, Pike VW, Gunn RN, Olsson H, Farde L (2002) The PET radioligand [carbonyl-(11)C]desmethyl-WAY-100635 binds to 5- HT(1A) receptors and provides a higher radioactive signal than [carbonyl-(11)C]WAY-100635 in the human brain. J Nucl Med 43:292–303

    PubMed  CAS  Google Scholar 

  • Arango V, Underwood MD, Gubbi AV, Mann JJ (1995) Localized alterations in pre- and postsynaptic serotonin binding sites in the ventrolateral prefrontal cortex of suicide victims. Brain Res 688:121–133

    Article  PubMed  CAS  Google Scholar 

  • 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 19:378–383

    Article  PubMed  CAS  Google Scholar 

  • Baker KG, Halliday GM, Tork I (1990) Cytoarchitecture of the human dorsal raphe nucleus. J Comp Neurol 301:147–161

    Article  PubMed  CAS  Google Scholar 

  • Ballesteros J, Callado LF (2004) Effectiveness of pindolol plus serotonin uptake inhibitors in depression: a meta-analysis of early and late outcomes from randomised controlled trials. J Affect Disord 79:137–147

    Article  PubMed  CAS  Google Scholar 

  • Barbui C, Hotopf M (2001) Amitriptyline v. the rest: still the leading antidepressant after 40 years of randomised controlled trials. Br J Psychiatry 178:129–144

    Article  PubMed  CAS  Google Scholar 

  • Barnes NM, Sharp T (1999) A review of central 5-HT receptors and their function. Neuropharmacology 38:1083–1152

    Article  PubMed  CAS  Google Scholar 

  • Bengel D, Johren O, Andrews AM, Heils A, Mossner R, Sanvitto GL, Saavedra JM, Lesch KP, Murphy DL (1997) Cellular localization and expression of the serotonin transporter in mouse brain. Brain Res 778:338–345

    Article  PubMed  CAS  Google Scholar 

  • Bergstrom M, Boethius J, Eriksson L, Greitz T, Ribbe T, Widen L (1981) Head fixation device for reproducible position alignment in transmission CT and positron emission tomography. J Comput Assist Tomogr 5:136–141

    Article  PubMed  CAS  Google Scholar 

  • Bhagwagar Z, Montgomery AJ, Grasby PM, Cowen PJ (2003) Lack of effect of a single dose of hydrocortisone on serotonin(1A) receptors in recovered depressed patients measured by positron emission tomography with [11C]WAY-100635. Biol Psychiatry 54:890–895

    Article  PubMed  CAS  Google Scholar 

  • Bhagwagar Z, Rabiner EA, Sargent PA, Grasby PM, Cowen PJ (2004) Persistent reduction in brain serotonin1A receptor binding in recovered depressed men measured by positron emission tomography with [11C]WAY-100635. Mol Psychiatry 9:386–392

    Article  PubMed  CAS  Google Scholar 

  • Borg J, Andree B, Soderstrom H, Farde L (2003) The serotonin system and spiritual experiences. Am J Psychiatry 160:1965–1969

    Article  PubMed  Google Scholar 

  • Borg J, Andrée B, Lundberg J, Halldin C, Farde L (2006) Search for correlations between serotonin 5-HT<sub>1A</sub> receptor expression and cognitive functionsâ”a strategy in translational psychopharmacology. Psychopharmacology 185:389–394

    Article  PubMed  CAS  Google Scholar 

  • Buhot MC (1997) Serotonin receptors in cognitive behaviors. Curr Opin Neurobiol 7:243–254

    Article  PubMed  CAS  Google Scholar 

  • Burnet PW, Eastwood SL, Lacey K, Harrison PJ (1995) The distribution of 5-HT1A and 5-HT2A receptor mRNA in human brain. Brain Res 676:157–168

    Article  PubMed  CAS  Google Scholar 

  • Caspi A, Sugden K, Moffitt TE, Taylor A, Craig IW, Harrington H, McClay J, Mill J, Martin J, Braithwaite A, Poulton R (2003) Influence of life stress on depression: moderation by a polymorphism in the 5-HTT gene. Science 301:386–389

    Article  PubMed  CAS  Google Scholar 

  • Collier DA, Stober G, Li T, Heils A, Catalano M, Di Bella D, Arranz MJ, Murray RM, Vallada HP, Bengel D, Muller CR, Roberts GW, Smeraldi E, Kirov G, Sham P, Lesch KP (1996) A novel functional polymorphism within the promoter of the serotonin transporter gene: possible role in susceptibility to affective disorders. Mol Psychiatry 1:453–460

    PubMed  CAS  Google Scholar 

  • Cortes R, Soriano E, Pazos A, Probst A, Palacios JM (1988) Autoradiography of antidepressant binding sites in the human brain: localization using [3H]imipramine and [3H]paroxetine. Neuroscience 27:473–496

    Article  PubMed  CAS  Google Scholar 

  • Cryan JF, Valentino RJ, Lucki I (2005) Assessing substrates underlying the behavioral effects of antidepressants using the modified rat forced swimming test. Neurosci Biobehav Rev 29:547–569

    Article  PubMed  CAS  Google Scholar 

  • David SP, Murthy NV, Rabiner EA, Munafo MR, Johnstone EC, Jacob R, Walton RT, Grasby PM (2005) A functional genetic variation of the serotonin (5-HT) transporter affects 5-HT1A receptor binding in humans. J Neurosci 25:2586–2590

    Article  PubMed  CAS  Google Scholar 

  • Drevets WC, Frank E, Price JC, Kupfer DJ, Holt D, Greer PJ, Huang Y, Gautier C, Mathis C (1999) Pet imaging of serotonin 1A receptor binding in depression. Biol Psychiatry 46:1375–1387

    Article  PubMed  CAS  Google Scholar 

  • 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 12:2299–2310

    Article  PubMed  CAS  Google Scholar 

  • Farde L, Hall H, Pauli S, Halldin C (1995) Variability in D2-dopamine receptor density and affinity: a PET study with [11C]raclopride in man. Synapse 20:200–208

    Article  PubMed  CAS  Google Scholar 

  • Farde L, Ito H, Swahn CG, Pike VW, Halldin C (1998) Quantitative analyses of carbonyl-carbon-11-WAY-100635 binding to central 5-hydroxytryptamine-1A receptors in man. J Nucl Med 39:1965–1971

    PubMed  CAS  Google Scholar 

  • Fujita M, Shimada S, Maeno H, Nishimura T, Tohyama M (1993) Cellular localization of serotonin transporter mRNA in the rat brain. Neurosci Lett 162:59–62

    Article  PubMed  CAS  Google Scholar 

  • Gunn RN, Sargent PA, Bench CJ, Rabiner EA, Osman S, Pike VW, Hume SP, Grasby PM, Lammertsma AA (1998) Tracer kinetic modeling of the 5-HT1A receptor ligand [carbonyl-11C]WAY-100635 for PET. Neuroimage 8:426–440

    Article  PubMed  CAS  Google Scholar 

  • Gunn RN, Lammertsma AA, Grasby PM (2000) Quantitative analysis of [carbonyl-11C]WAY-100635 PET studies. Nucl Med Biol 27:477–482

    Article  PubMed  CAS  Google Scholar 

  • Hales RE, Hilty DA, Wise MG (1997) A treatment algorithm for the management of anxiety in primary care practice. J Clin Psychiatry 58(Suppl 3):76–80

    PubMed  CAS  Google Scholar 

  • Hall H, Lundkvist C, Halldin C, Farde L, Pike VW, McCarron JA, Fletcher A, Cliffe IA, Barf T, Wikstrom H, Sedvall G (1997) Autoradiographic localization of 5-HT1A receptors in the post-mortem human brain using [3H]WAY-100635 and [11C]way-100635. Brain Res 745:96–108

    Article  PubMed  CAS  Google Scholar 

  • Heils A, Teufel A, Petri S, Seemann M, Bengel D, Balling U, Riederer P, Lesch KP (1995) Functional promoter and polyadenylation site mapping of the human serotonin (5-HT) transporter gene. J Neural Transm Gen Sect 102:247–254

    Article  PubMed  CAS  Google Scholar 

  • Hoffman BJ, Hansson SR, Mezey E, Palkovits M (1998) Localization and dynamic regulation of biogenic amine transporters in the mammalian central nervous system. Front Neuroendocrinol 19:187–231

    Article  PubMed  CAS  Google Scholar 

  • Hoyer D, Martin G (1997) 5-HT receptor classification and nomenclature: towards a harmonization with the human genome. Neuropharmacology 36:419–428

    Article  PubMed  CAS  Google Scholar 

  • Hoyer D, Pazos A, Probst A, Palacios JM (1986) Serotonin receptors in the human brain. I. Characterization and autoradiographic localization of 5-HT1A recognition sites. Apparent absence of 5-HT1B recognition sites. Brain Res 376:85–96

    Article  PubMed  CAS  Google Scholar 

  • Kampf-Sherf O, Zlotogorski Z, Gilboa A, Speedie L, Lereya J, Rosca P, Shavit Y (2004) Neuropsychological functioning in major depression and responsiveness to selective serotonin reuptake inhibitors antidepressants. J Affect Disord 82:453–459

    PubMed  CAS  Google Scholar 

  • Kugaya A, Sanacora G, Staley JK, Malison RT, Bozkurt A, Khan S, Anand A, van Dyck CH, Baldwin RM, Seibyl JP (2004) Brain serotonin transporter availability predicts treatment response to selective serotonin reuptake inhibitors. Biol Psychiatry 56:497–502

    Article  PubMed  CAS  Google Scholar 

  • Lammertsma AA, Hume SP (1996) Simplified reference tissue model for PET receptor studies. Neuroimage 4:153–158

    Article  PubMed  CAS  Google Scholar 

  • Lesch K-P, Bengel D, Heils A, Sabol SZ, Greenberg BD, Petri S, Benjamin J, Muller CR, Hamer DH, Murphy DL (1996) Association of anxiety-related traits with a polymorphism in the serotonin transporter gene regulatory region. Science 274:1527–1531

    Article  PubMed  CAS  Google Scholar 

  • Lundberg J, Odano I, Olsson H, Halldin C, Farde L (2005) Quantification of [11C]MADAM binding to the serotonin transporter in the human brain. J Nucl Med 46:1505–1515

    PubMed  CAS  Google Scholar 

  • Lundberg J, Halldin C, Farde L (2006) Measurement of serotonin transporter binding with PET and [11C]MADAM: a test–retest reproducibility study. Synapse 60:256–263

    Article  PubMed  CAS  Google Scholar 

  • Maes F, Collignon A, Vandermeulen D, Marchal G, Suetens P (1997) Multimodality image registration by maximization of mutual information. IEEE Trans Med Imaging 16:187–198

    Article  PubMed  CAS  Google Scholar 

  • Mannoury la Cour C, Boni C, Hanoun N, Lesch KP, Hamon M, Lanfumey L (2001) Functional consequences of 5-HT transporter gene disruption on 5-HT(1a) receptor-mediated regulation of dorsal raphe and hippocampal cell activity. J Neurosci 21:2178–2185

    PubMed  CAS  Google Scholar 

  • Melke J, Landen M, Baghei F, Rosmond R, Holm G, Bjorntorp P, Westberg L, Hellstrand M, Eriksson E (2001) Serotonin transporter gene polymorphisms are associated with anxiety-related personality traits in women. Am J Med Genet 105:458–463

    Article  PubMed  CAS  Google Scholar 

  • Meltzer CC, Price JC, Mathis CA, Butters MA, Ziolko SK, Moses-Kolko E, Mazumdar S, Mulsant BH, Houck PR, Lopresti BJ, Weissfeld LA, Reynolds CF (2004) Serotonin 1A receptor binding and treatment response in late-life depression. Neuropsychopharmacology 29:2258–2265

    Article  PubMed  CAS  Google Scholar 

  • Meyer JH, Houle S, Sagrati S, Carella A, Hussey DF, Ginovart N, Goulding V, Kennedy J, Wilson AA (2004) Brain serotonin transporter binding potential measured with carbon 11-labeled DASB positron emission tomography: effects of major depressive episodes and severity of dysfunctional attitudes. Arch Gen Psychiatry 61:1271–1279

    Article  PubMed  CAS  Google Scholar 

  • Mintun MA, Raichle ME, Kilbourn MR, Wooten GF, Welch MJ (1984) A quantitative model for the in vivo assessment of drug binding sites with positron emission tomography. Ann Neurol 15:217–227

    Article  PubMed  CAS  Google Scholar 

  • Miquel M-C, Doucet E, Boni C, El Mestikawy S, Matthiessen L, Daval G, Verge D, Hamon M (1991) Central serotonin 1A receptors: respective distributions of encoding mRNA, receptor protein and binding sites by in situ hybridization histochemistry, radioimmunohistochemistry and autoradiographic mapping in the rat brain. Neurochem Int 19:453–465

    Article  CAS  Google Scholar 

  • Moret C, Briley M (2000) The possible role of 5-HT1B/D receptors in psychiatric disorders and their potential as a target for therapy. Eur J Pharmacol 404:1–12

    Article  PubMed  CAS  Google Scholar 

  • Morley-Fletcher S, Darnaudery M, Mocaer E, Froger N, Lanfumey L, Laviola G, Casolini P, Zuena AR, Marzano L, Hamon M, Maccari S (2004) Chronic treatment with imipramine reverses immobility behaviour, hippocampal corticosteroid receptors and cortical 5-HT1A receptor mRNA in prenatally stressed rats. Neuropharmacology 47:841–847

    Article  PubMed  CAS  Google Scholar 

  • Parsey RV, Hastings RS, Oquendo MA, Hu X, Goldman D, Huang YY, Simpson N, Arcement J, Huang Y, Ogden RT, Van Heertum RL, Arango V, Mann JJ (2006a) Effect of a triallelic functional polymorphism of the serotonin-transporter-linked promoter region on expression of serotonin transporter in the human brain. Am J Psychiatry 163:48–51

    Article  PubMed  Google Scholar 

  • Parsey RV, Hastings RS, Oquendo MA, Huang Y-y, Simpson N, Arcement J, Huang Y, Ogden RT, Van Heertum RL, Arango V, Mann JJ (2006b) Lower serotonin transporter binding potential in the human brain during major depressive episodes. Am J Psychiatry 163:52–58

    Article  PubMed  Google Scholar 

  • Parsey RV, Olvet DM, Oquendo MA, Huang YY, Ogden RT, Mann JJ (2006c) Higher 5-HT(1A) receptor binding potential during a major depressive episode predicts poor treatment response: preliminary data from a naturalistic study. Neuropsychopharmacology 31:1745–1749

    Article  PubMed  CAS  Google Scholar 

  • Parsey RV, Oquendo MA, Ogden RT, Olvet DM, Simpson N, Huang YY, Van Heertum RL, Arango V, Mann JJ (2006d) Altered serotonin 1A binding in major depression: a [carbonyl-C-11]WAY100635 positron emission tomography study. Biol Psychiatry 59:106–113

    Article  PubMed  CAS  Google Scholar 

  • Plenge P, Mellerup ET, Laursen H (1990) Regional distribution of the serotonin transport complex in human brain, identified with 3H-paroxetine, 3H-citalopram and 3H-imipramine. Prog Neuropsychopharmacol Biol Psychiatry 14:61–72

    Article  PubMed  CAS  Google Scholar 

  • Pucadyil TJ, Kalipatnapu S, Chattopadhyay A (2005) The serotonin 1A receptor: a representative member of the serotonin receptor family. Cell Mol Neurobiol 25:553–580

    Article  PubMed  CAS  Google Scholar 

  • Qian Y, Melikian HE, Rye DB, Levey AI, Blakely RD (1995) Identification and characterization of antidepressant-sensitive serotonin transporter proteins using site-specific antibodies. J Neurosci 15:1261–1274

    PubMed  CAS  Google Scholar 

  • Sargent PA, Kjaer KH, Bench CJ, Rabiner EA, Messa C, Meyer J, Gunn RN, Grasby PM, Cowen PJ (2000) Brain serotonin1A receptor binding measured by positron emission tomography with [11C]WAY-100635: effects of depression and antidepressant treatment. Arch Gen Psychiatry 57:174–180

    Article  PubMed  CAS  Google Scholar 

  • Sotelo C, Cholley B, El Mestikawy S, Gozlan H, Hamon M (1990) Direct immunohistochemical evidence of the existence of 5-HT1A autoreceptors on serotoninergic neurons in the midbrain raphe nuclei. Eur J Neurosci 2:1144–1154

    Article  PubMed  Google Scholar 

  • Sur C, Betz H, Schloss P (1996) Immunocytochemical detection of the serotonin transporter in rat brain. Neuroscience 73:217–231

    Article  PubMed  CAS  Google Scholar 

  • Tarkiainen J, Vercouillie J, Emond P, Sandell J, Hiltunen J, Frangin Y, Guilloteau D, Halldin C (2001) Carbon-11 labelling of MADAM in two different positions: a highly selective PET radioligand for the serotonin transporter. J Labelled Compd Radiopharm 44:1013–1023

    Article  CAS  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  PubMed  CAS  Google Scholar 

  • Verge D, Daval G, Marcinkiewicz M, Patey A, el Mestikawy S, Gozlan H, Hamon M (1986) Quantitative autoradiography of multiple 5-HT1 receptor subtypes in the brain of control or 5,7-dihydroxytryptamine-treated rats. J Neurosci 6:3474–3482

    PubMed  CAS  Google Scholar 

  • Wienhard K, Dahlbom M, Eriksson L, Michel C, Bruckbauer T, Pietrzyk U, Heiss W (1994) The ECAT EXACT HR: performance of a new high resolution positron scanner. J Comput Assist Tomogr 18:110–118

    Article  PubMed  CAS  Google Scholar 

  • Zhou FC, Xu Y, Bledsoe S, Lin R, Kelley MR (1996) Serotonin transporter antibodies: production, characterization, and localization in the brain. Mol Brain Res 43:267–278

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgements

All members of the PET group at Karolinska Institutet are greatly acknowledged. This work was supported by the Swedish Research Council (grant 09114). The experiments comply with Swedish law.

Statement of interest

None.

Author information

Authors and Affiliations

  1. Department of Clinical Neuroscience, Section of Psychiatry, Karolinska Institutet, Stockholm, Sweden

    Johan Lundberg, Jacqueline Borg, Christer Halldin & Lars Farde

  2. Department of Clinical Neuroscience, Section of Psychiatry, Psykiatricentrum Karolinska, Karolinska University Hospital Solna, 171 76, Stockholm, Sweden

    Johan Lundberg

Authors
  1. Johan Lundberg
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jacqueline Borg
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Christer Halldin
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Lars Farde
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Johan Lundberg.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Lundberg, J., Borg, J., Halldin, C. et al. A PET study on regional coexpression of 5-HT1A receptors and 5-HTT in the human brain. Psychopharmacology 195, 425–433 (2007). https://doi.org/10.1007/s00213-007-0928-3

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00213-007-0928-3

Keywords

Search

Navigation