Norepinephrine-mediated Regulation of 5HT1 Receptor Functioning in Human Platelets


Adaptive changes in serotonergic 5HT1 receptor signalling are believed to underlie the therapeutic effectiveness of antidepressant drugs. Since cells are continuously exposed to neurotransmitters/neuromodulators, spatially and temporally integrated, the responsiveness of a receptor system is dependent upon the physio-pathological state of the cell and the interaction between different neurotransmitters. In the present work, we investigated heterologous regulation of 5HT1 receptors induced by norepinephrine (NE) in human platelets. NE platelet treatment induced a time and concentration dependent 5HT1 receptor desensitisation mediated by both alpha and beta receptors through activation of intracellular protein kinases. In particular NE, through PKC activation, regulated 5HT1 receptor phosphorylation on threonine residues, causing in turn serotonin receptor-G protein uncoupling and functional responsiveness drop. These results suggest that high NE levels (released i.e. during stress disorders) may play an important role in regulating the 5HT1 responsiveness and in controlling effectiveness of drugs acting on these neurotransmitter systems.

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

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7


  1. 1.

    Blier P (2001) Crosstalk between the norepinephrine and serotonin systems and its role in the antidepressant response. J Psych Neurosci 26:3–10

    Google Scholar 

  2. 2.

    Mongeau R, de Montigny C, Blier P (1994) Electrophysiologic evidence for desensitization of alpha 2-adrenoceptors on serotonin terminals following long-term treatment with drugs increasing norepinephrine synaptic concentration. Neuropsychopharmacol 10:41–51

    CAS  Google Scholar 

  3. 3.

    Yoshioka M, Matsumoto M, Numazawa R et al (1995) Changes in the regulation of 5-hydroxytryptamine release by alpha2-adrenoceptors in the rat hippocampus after long-term desipramine treatment. Eur J Pharmacol 294:565–570

    PubMed  Article  CAS  Google Scholar 

  4. 4.

    Szabo ST, Blier P (2001) Effects of the selective norepinephrine reuptake inhibitor reboxetine on norepinephrine and serotonin transmission in the rat hippocampus. Neuropsychopharmacol 25:845–857

    Article  CAS  Google Scholar 

  5. 5.

    Bandoh T, Hayashi M, Ino K et al (2004) Acute effect of milnacipran on the relationship between the locus coeruleus noradrenergic and dorsal raphe serotonergic neuronal transmitters. Eur Neuropsychopharmacol 14:471–478

    PubMed  Article  CAS  Google Scholar 

  6. 6.

    Werry TD, Wilkinson GF, Willars GB (2003) Mechanisms of cross-talk between G-protein-coupled receptors resulting in enhanced release of intracellular Ca2+. Biochem J 374:281–296

    PubMed  Article  CAS  Google Scholar 

  7. 7.

    Freedman NJ, Lefkowitz RJ (1996) Desensitization of G protein-coupled receptors. Recent Progress Hormon Res 51:319–351

    CAS  Google Scholar 

  8. 8.

    Bohm SK, Grady EF, Bunnet NW (1997) Regulatory mechanisms that modulate signaling by G protein coupled receptors. Biochem J 322:1–18

    PubMed  CAS  Google Scholar 

  9. 9.

    Bunemann M, Hosey MM (1999) G-protein coupled receptor kinases as modulators of G protein signalling. J Physiol 517:5–23

    PubMed  Article  CAS  Google Scholar 

  10. 10.

    Luttrell LM, Lefkowitz RJ (2002) The role of beta-arrestins in the termination and transduction of G-protein-coupled receptor signals. J Cell Sci 115:455–465

    PubMed  CAS  Google Scholar 

  11. 11.

    Chuang TT, Iacovelli L, Sallese M et al (1996) G protein-coupled receptors: heterologous regulation of homologous desensitization and its implications. Trends Pharmacol Sci 17:416–421

    PubMed  Article  CAS  Google Scholar 

  12. 12.

    Popoli M, Mori S, Brunello N et al (2001) Serine/threonine kinases as molecular targets of antidepressants: implications for pharmacological treatment and pathophysiology of affective disorders. Pharmacol Ther 89:149–170

    PubMed  Article  CAS  Google Scholar 

  13. 13.

    Wieland S, Lucki I (1990) Antidepressant-like activity of 5-HT1A agonists measured with the forced swim test. Psychopharmacol 101:497–504

    Article  CAS  Google Scholar 

  14. 14.

    Lesch KP, Wiesmann M, Hoh A et al (1992) 5-HT1A receptor-effector system responsiveness in panic disorder. Psychopharmacol 106:111–117

    Article  CAS  Google Scholar 

  15. 15.

    Van den Hove DL, Lauder JM, Scheepens A et al (2006) Prenatal stress in the rat alters 5-HT1A receptor binding in the ventral hippocampus. Brain Res 1090:29–34

    PubMed  Article  CAS  Google Scholar 

  16. 16.

    Kalynchuk LE, Pinel JP, Meaney MJ (2006) Serotonin receptor binding and mRNA expression in the hippocampus of fearful amygdala-kindled rats. Neurosci Lett 396:38–43

    PubMed  Article  CAS  Google Scholar 

  17. 17.

    Broocks A, Bandelow B, George A et al (2000) Increased psychological responses and divergent neuroendocrine responses to m-CPP and ipsapirone in patients with panic disorder. Int Clin Psychopharmacol 15:153–161

    PubMed  CAS  Article  Google Scholar 

  18. 18.

    Dell’Osso L, Carmassi C, Palego L et al (2004) Serotonin-mediated cyclic AMP inhibitory pathway in platelets of patients affected by panic disorder. Neuropsychobiol 50:28–36

    Article  CAS  Google Scholar 

  19. 19.

    Martini C, Trincavelli ML, Tuscano D et al (2004) Serotonin-mediated phosphorylation of extracellular regulated kinases in platelets of patients with panic disorder versus controls. Neurochem Int 44:627–639

    PubMed  Article  CAS  Google Scholar 

  20. 20.

    Braune S, Albus M, Frohler M et al (1994) Psychophysiological and biochemical changes in patients with panic attacks in a defined situational arousal. Eur Arch Psych Clin Neurosci 244:86–92

    Article  CAS  Google Scholar 

  21. 21.

    Bremner JD, Krystal JH, Southwick SM et al (1996) Noradrenergic mechanisms in stress and anxiety: II, clinical studies. Synapse 23:39–51

    PubMed  Article  CAS  Google Scholar 

  22. 22.

    Sullivan GM, Oquendo MA, Huang YY et al (2006) Elevated cerebrospinal fluid 5-hydroxyindoleacetic acid levels in women with comorbid depression and panic disorder. Int J Neuropsychopharmacol 9:547–556

    PubMed  Article  CAS  Google Scholar 

  23. 23.

    Pejchal T, Foley MA, Kosofsky BE et al (2002) Chronic fluoxetine treatment selectively uncouples raphe 5-HT(1A) receptors as measured by [(35)S]-GTP gamma S autoradiography. Br J Pharmacol 135:1115–1122

    PubMed  Article  CAS  Google Scholar 

  24. 24.

    Bouali S, Evrard A, Chastanet M et al (2003) Sex hormone-dependent desensitization of 5-HT1A autoreceptors in knockout mice deficient in the 5-HT transporter. Eur J Neurosci 18:2203–2212

    PubMed  Article  Google Scholar 

  25. 25.

    Bradbury MJ, Giracello DR, Chapman DF et al (2003) Metabotropic glutamate receptor 5 antagonist-induced stimulation of hypothalamic-pituitary-adrenal axis activity: interaction with serotonergic systems. Neuropharmacol 44:562–572

    Article  CAS  Google Scholar 

  26. 26.

    Hensler JG (2003) Regulation of 5-HT1A receptor function in brain following agonist or antidepressant administration. Life Sci 72:1665–1682

    PubMed  Article  CAS  Google Scholar 

  27. 27.

    El Mansari M, Blier P (2005) Responsiveness of 5-HT(1A) and 5-HT2 receptors in the rat orbitofrontal cortex after long-term serotonin reuptake inhibition. J Psych Neurosci 30:268–274

    Google Scholar 

  28. 28.

    Werkman TR, Glennon JC, Wadman WJ et al (2006) Dopamine receptor pharmacology: interactions with serotonin receptors and significance for the aetiology and treatment of schizophrenia. CNS Neurol Disord Drug Targets 5:3–23

    PubMed  Article  CAS  Google Scholar 

  29. 29.

    Aharonovitz O, Granot Y (1996) Stimulation of mitogen-activated protein kinase and Na+/H+ exchanger in human platelets. J Biol Chem 271:16494–16499

    PubMed  Article  CAS  Google Scholar 

  30. 30.

    Stahl SM (1977) The human platelet. A diagnostic and research tool for the study of biogenic amines in psychiatric and neurologic disorders. Arch Gen Psych 34:509–516

    CAS  Google Scholar 

  31. 31.

    Owens MJ, Nemeroff CB (1994) Role of serotonin in the pathophysiology of depression: focus on the serotonin transporter. Clin Chem 40:288–295

    PubMed  CAS  Google Scholar 

  32. 32.

    Barkan T, Peled A, Modai I et al (2006) Serotonin transporter characteristics in lymphocytes and platelets of male aggressive schizophrenia patients compared to non-aggressive schizophrenia patients. Eur Neuropsychopharmacol 16:572–579

    PubMed  Article  CAS  Google Scholar 

  33. 33.

    Lauterbach E, Brunner J, Hawellek B et al (2006) Platelet 5-HT2A receptor binding and tryptophan availability in depression are not associated with recent history of suicide attempts but with personality traits characteristic for suicidal behavior. J Affect Disord 91:57–62

    PubMed  Article  CAS  Google Scholar 

  34. 34.

    Nakanishi S, Kakita S, Takahashi I et al (1992) Wortmannin, a microbial product inhibitor of myosin light chain kinase. J Biol Chem 267:2157–2163

    PubMed  CAS  Google Scholar 

  35. 35.

    Penn RB, Parent JL, Pronin AN et al (1999) Pharmacological inhibition of protein kinases in intact cells: antagonism of beta adrenergic receptor ligand binding by H-89 reveals limitations of usefulness. J Pharmacol Exp Ther 288:428–437

    PubMed  CAS  Google Scholar 

  36. 36.

    Davies SP, Reddy H, Caivano M et al (2000) Specificity and mechanism of action of some commonly used protein kinase inhibitors. Biochem J 351:95–105

    PubMed  Article  CAS  Google Scholar 

  37. 37.

    Brodde OE, Hardung A, Ebel H et al (1982) GTP regulates binding of agonists to alpha 2-adrenergic receptors in human platelets. Arch Int Pharm Ther 258:193–207

    CAS  Google Scholar 

  38. 38.

    Zawilska JB, Zalewska-Kaszubska J, Marczak G et al (2000) Characterization of beta-adrenergic receptors in duck cerebral cortex. Acta Neurobiol Exp 60:301–307

    CAS  Google Scholar 

  39. 39.

    Gessi S, Campi F, Varani K et al (1999) Alpha2-adrenergic agonist modulation of [35S]GTP gammaS binding to guanine-nucleotide-binding-proteins in human platelet membranes. Life Sci 64:1403–1413

    PubMed  Article  CAS  Google Scholar 

  40. 40.

    Freitag CM, Domschke K, Rothe C et al (2006) Interaction of serotonergic and noradrenergic gene variants in panic disorder. Psychiatr Genet 16:59–65

    PubMed  Article  Google Scholar 

  41. 41.

    Maron E, Shlik J (2006) Serotonin function in panic disorder: important, but why? Neuropsychopharmacol 31:1–11

    Article  CAS  Google Scholar 

  42. 42.

    Mongeau R, Weiss M, de Montigny C et al (1998) Effect of acute, short- and long-term milnacipran administration on rat locus coeruleus noradrenergic and dorsal raphe serotonergic neurons. Neuropharmacol 37:905–918

    Article  CAS  Google Scholar 

  43. 43.

    Butler J, O’Halloran A, Leonard BE (1992) The Galway Study of Panic Disorder II: changes in some peripheral markers of noradrenergic and serotonergic function in DSM III-R panic disorder. J Affect Disorders 26:89–99

    PubMed  Article  CAS  Google Scholar 

  44. 44.

    Varrault A, Bockaert J, Waeber C (1992) Activation of 5-HT1A receptors expressed in NIH-3T3 cells induces focus formation and potentiates EGF effect on DNA synthesis. Mol Biol Cell 3:961–969

    PubMed  CAS  Google Scholar 

  45. 45.

    Banerjee P, Berry-Kravis E, Bonafede-Chhabra D, et al (1993) Heterologous expression of the serotonin 5-HT1A receptor in neural and non-neural cell lines. Biochem Biophys Res Comm 192:104–110

    PubMed  Article  CAS  Google Scholar 

  46. 46.

    Liu YF, Albert PR (1991) Cell-specific signaling of the 5-HT1A receptor. Modulation by protein kinases C and A. J Biol Chem 266:23689–23697

    PubMed  CAS  Google Scholar 

  47. 47.

    Popoli M, Brunello N, Perez J et al (2000) Second messenger-regulated protein kinases in the brain: their functional role and the action of antidepressant drugs. J Neurochem 74:21–33

    PubMed  Article  CAS  Google Scholar 

  48. 48.

    Raymond JR (1991) Protein kinase C induces phosphorylation and desensitization of the human 5-HT1A receptor. J Biol Chem 266:14747–14753

    PubMed  CAS  Google Scholar 

  49. 49.

    Raymond JR, Olsen CL (1994) Protein kinase A induces phosphorylation of the human 5-HT1A receptor and augments its desensitization by protein kinase C in CHO-K1 cells. Biochem 33:11264–11269

    Article  CAS  Google Scholar 

  50. 50.

    Lembo PM, Albert PR (1995) Multiple phosphorylation sites are required for pathway-selective uncoupling of the 5-hydroxytryptamine1A receptor by protein kinase C. Mol Pharmacol 48:1024–1029

    PubMed  CAS  Google Scholar 

  51. 51.

    Lembo PM, Ghahremani MH, Morris SJ et al (1997) A conserved threonine residue in the second intracellular loop of the 5-hydroxytryptamine 1A receptor directs signaling specificity. Mol Pharmacol 52:164–171

    PubMed  CAS  Google Scholar 

  52. 52.

    Raymond JR, Mukhin YV, Gettys TW et al (1999) The recombinant 5-HT1A receptor: G protein coupling and signalling pathways. Br J Pharmacol 127:1751–1764

    PubMed  Article  CAS  Google Scholar 

Download references

Author information



Corresponding author

Correspondence to C. Martini.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Trincavelli, M.L., Cuboni, S., Montali, M. et al. Norepinephrine-mediated Regulation of 5HT1 Receptor Functioning in Human Platelets. Neurochem Res 33, 1292–1300 (2008).

Download citation


  • 5HT1 receptors
  • Human platelets
  • Receptor desensitisation
  • Norepinephrine
  • Adrenergic receptors