5-HT7 receptor modulation of sleep patterns

  • David R. Thomas


The 5-HT7 receptor class is one of seven major subtypes of 5-HT receptor (5-HT1–7) exhibiting a distinct profile in terms of structural properties, functional coupling and pharmacology. The receptor is widely localized in the brain and is expressed neuronally, in both terminal and cell body regions, in a number of brain areas relevant to sleep including, pyramidal neurons of the hippocampus, the suprachiasmatic nucleus (SCN) of the hypothalamus and the dorsal raphe nucleus (DRN). Brain functional studies utilizing 5-HT7 receptor-selective antagonists suggest the 5-HT7 receptor plays a role in modulating 5-HT neuronal activity in the DRN, a brain area implicated in the control of sleep. Thus, alteration in 5-HT7 receptor function might indirectly modulate sleep architecture. Consistent with this possibility, systemic administration to rats of selective 5-HT7 receptor antagonists such as SB-269970, increases the latency to onset of REM sleep and reduces the density of REM sleep, without significant effects on other sleep parameters. A qualitatively similar profile has been reported in 5-HT7-/- knockout mice, which spend less time in REM sleep without alteration in wakefulness or slow-wave sleep. Microinjection of SB-269970 into the DRN in rats produces effects on REM sleep consistent with those observed following systemic administration. These findings support a role for 5-HT7 receptors in the DRN in the mechanisms underlying REM sleep formation. To date, no clinical studies have been carried out that investigate the therapeutic potential of selective 5-HT7 receptor ligands. However, based on the pre-clinical findings, it is tempting to speculate that such ligands might exhibit utility in disorders where disrupted REM sleep is a feature.


Receptor Modulation Dorsal Raphe Dorsal Raphe Nucleus Suprachiasmatic Nucleus NREM Sleep 
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  1. 1.
    Erdmann J, Nothen MM, Shimron-Abarbanell D, Rietschel M, Albus M, Borrmann M, Maier W, Franzek E, Korner J, Weigelt B et al (1996) The human serotonin7 (5-HT7) receptor gene — genomic organization and systematic mutation screening in schizophrenia and bipolar affective disorder. Mol Psychiatry 1: 392–397PubMedGoogle Scholar
  2. 2.
    Kiel S, Bonisch H, Bruss M, Gothert M (2003) Impairment of signal transduction in response to stimulation of the naturally occurring Pro(279)Leu variant of the h5-HT7(a) receptor. Pharmacogenetics 13: 119–126PubMedCrossRefGoogle Scholar
  3. 3.
    Bruss M, Kiel S, Bonisch H, Kostanian A, Gothert M (2005) Decreased agonist, but not antagonist, binding to the naturally occurring Thr(92)Lys variant of the h5-HT7(a) receptor. Neurochem Int 47: 196–203PubMedCrossRefGoogle Scholar
  4. 4.
    Barnes NM, Sharp T (1999) A review of central 5-HT receptors and their function. Neuropharmacology 38: 1083–1152PubMedCrossRefGoogle Scholar
  5. 5.
    Heidmann DEA, Szot P, Kohen R, Hamblin MW (1998) Function and distribution of three rat 5-hydroxytryptamine7 (5-HT7) receptor isoforms produced by alternative splicing. Neuropharmacology 37: 1621–1632PubMedCrossRefGoogle Scholar
  6. 6.
    Hagan JJ, Price GW, Jeffrey P, Deeks NJ, Stean T, Piper D, Smith MI, Upton N, Medhurst AD, Middlemiss DN et al (2000) Characterization of SB-269970-A, a selective 5-HT7 receptor antagonist. Br J Pharmacol 130: 539–548PubMedCrossRefGoogle Scholar
  7. 7.
    Bard JA, Zgombick J, Adham N, Vaysse P, Branchek TA, Weinshank RL (1993) Cloning of a novel human serotonin receptor (5-HT7) positively linked to adenylate cyclase. J Biol Chem 268: 23422–23426PubMedGoogle Scholar
  8. 8.
    Norum JH, Hart K, Levy FO (2003) Ras-dependent ERK activation by the human Gs-coupled serotonin receptors 5-HT4(b) and 5-HT7(a). J Biol Chem 278: 3098–3104PubMedCrossRefGoogle Scholar
  9. 9.
    Forbes IT, Dabbs S, Duckworth DM, Jennings AJ, King FD, Lovell PJ, Brown AM, Collin L, Hagan JJ, Middlemiss DN et al (1998) (R)-3,N-dimethyl-n-[1-methyl-3-(4-methyl-piperidin-1-yl)propyl]benzenesulfonamide — The first selective 5-HT7 receptor antagonist. J Med Chem 41: 655–657PubMedCrossRefGoogle Scholar
  10. 10.
    Lovell PJ, Bromidge SM, Dabbs S, Duckworth DM, Forbes IT, Jennings AJ, King FD, Middlemiss DN, Rahman SK, Saunders DV et al (2000) A novel, potent, and selective 5-HT7 antagonist: (R)-3-(2-(2-(4-methylpiperidin-1-yl)-ethyl)pyrrolidine-1-sulfonyl)phenol (SB-269970). J Med Chem 43: 342–345PubMedCrossRefGoogle Scholar
  11. 11.
    Forbes IT, Douglas S, Gribble AD, Ife RJ, Lightfoot AP, Garner AE, Riley GJ, Jeffrey P, Stevens AJ, Stean TO, Thomas DR (2002) SB-656104-A: A novel 5-HT7 receptor antagonist with improved in vivo properties. Bioorg Med Chem Lett 12: 3341–3344PubMedCrossRefGoogle Scholar
  12. 12.
    Plassat JL, Amlaiky N, Hen R (1993) Molecular cloning of a mammalian serotonin receptor that activates adenylate cyclase. Mol Pharmacol 44: 229–236PubMedGoogle Scholar
  13. 13.
    Ruat M, Traiffort E, Leurs R, Tardivellacombe J, Diaz J, Arrang JM, Schwartz JC (1993) Molecular cloning, characterization, and localization of a high-affinity serotonin receptor (5-HT7) activating cAMP formation. Proc Natl Acad Sci USA 90: 8547–8551PubMedCrossRefGoogle Scholar
  14. 14.
    Schoeffter P, Ullmer C, Bobirnac I, Gabbiani G, Lubbert H (1996) Functional, endogenously expressed 5-hydroxytryptamine 5-ht7 receptors in human vascular smooth muscle cells. Br J Pharmacol 117: 993–994PubMedGoogle Scholar
  15. 15.
    Heidmann DEA, Metcalf MA, Kohen R, Hamblin MW (1997) Four 5-hydroxytryptamine7 (5-HT7) receptor isoforms in human and rat produced by alternative splicing — species differences due to altered intron-exon organization. J Neurochem 68: 1372–1381PubMedGoogle Scholar
  16. 16.
    Neumaier JF, Sexton TJ, Yracheta Y, Diaz AM, Brownfield M (2001) Localization of 5-HT7 receptors in rat brain by immunocytochemistry, in situ hybridization, and agonist stimulated cFos expression. J Chem Neuroanat 21: 63–73PubMedCrossRefGoogle Scholar
  17. 17.
    Gustafson EL, Durkin MM, Bard JA, Zgombick J, Branchek TA (1996) A receptor autoradiographic and in situ hybridization analysis of the distribution of the 5-HT7 receptor in rat brain. Br J Pharmacol 117: 657–666PubMedGoogle Scholar
  18. 18.
    To ZP, Bonhaus DW, Eglen RM, Jakeman LB (1995) Characterization and distribution of putative 5-HT7 Receptors in guinea-pig brain. Br J Pharmacol 115: 107–116PubMedGoogle Scholar
  19. 19.
    Thomas DR, Atkinson PJ, Ho M, Bromidge SM, Lovell PJ, Villani AJ, Hagan JJ, Middlemiss DN, Price GW (2000) [3H]-SB-269970 — A selective antagonist radioligand for 5-HT7 receptors. Br J Pharmacol 130: 409–417PubMedCrossRefGoogle Scholar
  20. 20.
    Thomas DR, Atkinson PJ, Hastie PG, Roberts JC, Middlemiss DN, Price GW (2002) [3H]-SB-269970 radiolabels 5-HT7 receptors in rodent, pig and primate brain tissues. Neuropharmacology 42: 74–81PubMedCrossRefGoogle Scholar
  21. 21.
    Varnas K, Thomas DR, Tupala E, Tiihonen J, Hall H (2004) Distribution of 5-HT7 receptors in the human brain: a preliminary autoradiographic study using [3H]SB-269970. Neurosci Lett 367: 313–316.PubMedCrossRefGoogle Scholar
  22. 22.
    Stowe RL, Barnes NM (1998) Co-localisation of 5-HT7 receptor mRNA with GAD67-like immunoreactivity in rat brain. Br J Pharmacol 125: 55PCrossRefGoogle Scholar
  23. 23.
    Belenky MA, Pickard GE (2001) Subcellular distribution of 5-HT1B and 5-HT7 receptors in the mouse suprachiasmatic nucleus. J Comp Neurol 432: 371–388PubMedCrossRefGoogle Scholar
  24. 24.
    Shimizu M, Nishida A, Zensho H, Miyata M, Yamawaki S (1998) Agonist-induced desensitisation of adenylyl cyclase activity mediated by 5-hydroxytryptamine7 receptors in rat frontocortical astrocytes. Brain Res 784: 57–62PubMedCrossRefGoogle Scholar
  25. 25.
    Hirst WD, Price GW, Rattray M, Wilkin GP (1997) Identification of 5-hydroxytryptamine receptors positively coupled to adenylyl cyclase in rat cultured astrocytes. Br J Pharmacol 120: 509–515PubMedCrossRefGoogle Scholar
  26. 26.
    Duncan MJ, Short J, Wheeler DL (1999) Comparison of the effects of aging on 5-HT7 and 5-HT1A receptors in discrete regions of the circadian timing system in hamsters. Brain Res 829: 39–45PubMedCrossRefGoogle Scholar
  27. 27.
    Duncan MJ, Temel S, Jennes L (2001) Localisation of serotonin 5-HT7 receptor immunoreactivity in the rat brain. Soc Neurosci Abstr 380.18Google Scholar
  28. 28.
    Tsou AP, Kosaka A, Bach C, Zuppan P, Yee C, Tom L, Alvarez R, Ramsey S, Bonhaus DW, Stefanich E et al (1994) Cloning and expression of a 5-hydroxytryptamine7 receptor positively coupled to adenylyl cyclase. J Neurochem 63: 456–464PubMedCrossRefGoogle Scholar
  29. 29.
    Thomas DR, Middlemiss DN, Taylor SG, Nelson P, Brown AM (1999) 5-CT stimulation of adenylyl cyclase activity in guinea-pig hippocampus: evidence for involvement of 5-HT7 and 5-HT1A receptors. Br J Pharmacol 128: 158–164PubMedCrossRefGoogle Scholar
  30. 30.
    Markstein R, Matsumoto M, Kohler C, Togashi H, Yoshioka M, Hoyer D (1999) Pharmacological characterisation of 5-HT receptors positively coupled to adenylyl cyclase in the rat hippocampus. Arch Pharmacol 359: 454–459CrossRefGoogle Scholar
  31. 31.
    Errico H, Crozier RA, Plummer MR, Cowen DS (2001) 5-HT7 receptors activate the mitogen activated protein kinase extracellular signal related kinase in cultured rat hippocampal neurons. Neuroscience 102: 361–367PubMedCrossRefGoogle Scholar
  32. 32.
    Kvachnina E, Liu GQ, Dityatev A, Renner U, Dumuis A, Richter DW, Dityateva G, Schachner M, Voyno-Yasenetskaya TA, Ponimaskin EG (2005) 5-HT7 receptor is coupled to G alpha subunits of heterotrimeric G12-protein to regulate gene transcription and neuronal morphology. J Neurosci 25: 7821–7830PubMedCrossRefGoogle Scholar
  33. 33.
    Bacon WL, Beck SG (2000) 5-Hydroxytryptamine7 receptor activation decreases slow after-hyperpolarization amplitude in CA3 hippocampal pyramidal cells. J Pharmacol Exp Ther 294: 672–679PubMedGoogle Scholar
  34. 34.
    Gill CH, Soffin EM, Hagan JJ, Davies CH (2002) 5-HT7 receptors modulate synchronized network activity in rat hippocampus. Neuropharmacology 42: 82–92PubMedCrossRefGoogle Scholar
  35. 35.
    Goaillard JM, Vincent P (2002) Serotonin suppresses the slow after-hyperpolarization in rat intralaminar and midline thalamic neurones by activating 5-HT7 receptors. J Physiol 541: 453–465PubMedCrossRefGoogle Scholar
  36. 36.
    Chapin EM, Andrade R (2001) A 5-HT7 receptor-mediated depolarization in the anterodorsal thalamus. I. Pharmacological characterization. J Pharmacol Exp Ther 297: 395–402PubMedGoogle Scholar
  37. 37.
    Chapin EM, Andrade R (2001) A 5-HT7 receptor-mediated depolarization in the anterodorsal thalamus. II. Involvement of the hyperpolarization-activated current I-h. J Pharmacol Exp Ther 297: 403–409PubMedGoogle Scholar
  38. 38.
    Beique JC, Campbell B, Perring P, Hamblin MW, Walker P, Mladenovic L, Andrade R (2004) Serotonergic regulation of membrane potential in developing rat prefrontal cortex: Coordinated expression of 5-hydroxytryptamine 5-HT1A, 5-HT2A, and 5-HT7 receptors. J Neurosci 24: 4807–4817PubMedCrossRefGoogle Scholar
  39. 39.
    Rusak B, Zucker I (1979) Neural regulation of circadian rhythms. Physiol Rev 59: 449–526PubMedGoogle Scholar
  40. 40.
    Rea MA, Pickard GE (2000) Serotonergic modulation of photic entrainment in the Syrian hamster. Biol Rhythm Res 31: 284–314CrossRefGoogle Scholar
  41. 41.
    Lovenberg TW, Baron BM, Delecea L, Miller JD, Prosser RA, Rea MA, Foye PE, Racke M, Slone AL, Siegel BW et al (1993) A novel adenylyl cyclase-activating serotonin receptor 5-HT7 implicated in the regulation of mammalian circadian rhythms. Neuron 11: 449–458PubMedCrossRefGoogle Scholar
  42. 42.
    Ying SW, Rusak B (1997) 5-HT7 receptors mediate serotonergic effects on light-sensitive suprachiasmatic nucleus neurons. Brain Res 755: 246–254PubMedCrossRefGoogle Scholar
  43. 43.
    Ehlen JC, Grossman GH, Glass JD (2001) In vivo resetting of the hamster circadian clock by 5-HT7 receptors in the suprachiasmatic nucleus. J Neurosci 21: 5351–5357PubMedGoogle Scholar
  44. 44.
    Duncan MJ, Grear KE, Hoskins MA (2004) Aging and SB-269970-A, a selective 5-HT7 receptor antagonist, attenuate circadian phase advances induced by microinjections of serotonergic drugs in the hamster dorsal raphe nucleus. Brain Res 1008: 40–48PubMedCrossRefGoogle Scholar
  45. 45.
    Duncan MJ, Davis VA (2005) Cyclic AMP mediates circadian phase shifts induced by microinjection of serotonergic drugs in the hamster dorsal raphe nucleus. Brain Res 1058: 10–16PubMedCrossRefGoogle Scholar
  46. 46.
    Glass JD, Grossman GH, Farnbauch L, DiNardo L (2003) Midbrain raphe modulation of nonphotic circadian clock resetting and 5-HT release in the mammalian suprachiasmatic nucleus. J Neurosci 23: 7451–7460PubMedGoogle Scholar
  47. 47.
    Kawahara F, Saito H, Katsuki H (1994) Inhibition by 5-HT7 receptor stimulation of GABAA receptor-activated current in cultured rat suprachiasmatic neurones. J Physiol 478: 67–73PubMedGoogle Scholar
  48. 48.
    Prosser RA (2000) Serotonergic actions and interactions on the SCN circadian pacemaker: in vitro investigations. Biol Rhythm Res 31: 315–339CrossRefGoogle Scholar
  49. 49.
    Thomas DR, Larminie CG, Lyons HR, Fosberry A, Hill MJ, Hayes PD (2004) Cloning and pharmacological characterisation of the guinea pig 5-ht5A receptor. Eur J Pharmacol 494: 91–99.PubMedCrossRefGoogle Scholar
  50. 50.
    Sprouse J, Li XF, Stock J, McNeish J, Reynolds L (2005) Circadian rhythm phenotype of 5-HT7 receptor knockout mice: 5-HT and 8-OH-DPAT-induced phase advances of SCN neuronal firing. J Biol Rhythms 20: 122–131PubMedCrossRefGoogle Scholar
  51. 51.
    Guscott M, Bristow LJ, Hadingham K, Rosahl TW, Beer MS, Stanton JA, Bromidge F, Owens AP, Huscroft I, Myers J et al (2005) Genetic knockout and pharmacological blockade studies of the 5-HT7 receptor suggest therapeutic potential in depression. Neuropharmacology 48: 492–502PubMedCrossRefGoogle Scholar
  52. 52.
    Ursin R (2002) Serotonin and sleep. Sleep Med Rev 6: 55–67PubMedCrossRefGoogle Scholar
  53. 53.
    Trulson ME, Jacobs BL (1979) Raphe unit activity in freely moving cats: correlation with level of behavioral arousal. Brain Res 163: 135–150PubMedCrossRefGoogle Scholar
  54. 54.
    Starkey SJ, Skingle M (1994) 5-HT1D as well as 5-HT1A autoreceptors modulate 5-HT release in the guinea-pig dorsal raphe nucleus. Neuropharmacology 33: 393–402PubMedCrossRefGoogle Scholar
  55. 55.
    Gallager DW, Aghajanian GK (1976) Effect of antipsychotic drugs on the firing of dorsal raphe cells. II. Reversal by picrotoxin. Eur J Pharmacol 39: 357–364PubMedCrossRefGoogle Scholar
  56. 56.
    Levine ES, Jacobs BL (1992) Neurochemical afferents controlling the activity of serotonergic neurons in the dorsal raphe nucleus: microiontophoretic studies in the awake cat. J Neurosci 12: 4037–4044PubMedGoogle Scholar
  57. 57.
    Gervasoni D, Peyron C, Rampon C, Barbagli B, Chouvet G, Urbain N, Fort P, Luppi PH (2000) Role and origin of the GABAergic innervation of dorsal raphe serotonergic neurons. J Neurosci 20: 4217–4225PubMedGoogle Scholar
  58. 58.
    Pace-Schott EF, Hobson JA (2002) The neurobiology of sleep: Genetics, cellular physiology and subcortical networks. Nat Rev Neurosci 3: 591–605PubMedGoogle Scholar
  59. 59.
    Duncan MJ, Franklin KM, Davis VA, Grossman GH, Knoch ME, Glass JD (2005) Short-term constant light potentiation of large-magnitude circadian phase shifts induced by 8-OH-DPAT: Effects on serotonin receptors and gene expression in the hamster suprachiasmatic nucleus. Eur J Neurosci 22: 2306–2314PubMedCrossRefGoogle Scholar
  60. 60.
    Kikuchi C, Nagaso H, Hiranuma T, Koyama M (1999) Tetrahydrobenzindoles: Selective antagonists of the 5-HT7 receptor. J Med Chem 42: 533–535PubMedCrossRefGoogle Scholar
  61. 61.
    Roberts C, Thomas DR, Bate ST, Kew JNC (2004) GABAergic modulation of 5-HT7 receptor-mediated effects on 5-HT efflux in the guinea-pig dorsal raphe nucleus. Neuropharmacology 46: 935–941PubMedCrossRefGoogle Scholar
  62. 62.
    Harsing L, Prauda I, Barkoczy J, Matyus P, Juranyi Z (2007) A 5-HT7 heteroreceptormediated inhibition of [3H]serotonin release in raphe nuclei slices of the rat: evidence for a serotonergic-glutamatergic interaction. Neurochem Res 29: 1487–1497CrossRefGoogle Scholar
  63. 63.
    Thomas DR, Melotto S, Massagrande M, Stean TO, Gribble AD, Forbes IT (2003) SB-656104-A, a novel 5-HT7 receptor antagonist, inhibits REM sleep in rats. Br J Pharmacol 139: 705–714PubMedCrossRefGoogle Scholar
  64. 64.
    Hedlund PB, Huitron-Resendiz S, Henriksen SJ, Sutcliffe JG (2005) 5-HT7 Receptor inhibition and inactivation induce antidepressant-like behavior and sleep pattern. Biol Psychiatry 58: 831–837PubMedCrossRefGoogle Scholar
  65. 65.
    Monti J, Jantos H (2006) Effects of the 5-HT7 receptor antagonist SB-269970 microinjected into the dorsal raphe nucleus on REM sleep in the rat. Behav Brain Res 167: 245–250PubMedCrossRefGoogle Scholar
  66. 66.
    Dijk DJ, Czeisler CA (1995) Contribution of the circadian pacemaker and the sleep homeostat to sleep propensity, sleep structure, electroencephalographic slow waves, and sleep spindle activity in humans. J Neurosci 15: 3526–3538.PubMedGoogle Scholar
  67. 67.
    Dagan Y (2002) Circadian rhythm sleep disorders (CRSD). Sleep Med Rev 6: 45–54PubMedCrossRefGoogle Scholar
  68. 68.
    Brunello N, Armitage R, Feinberg I, Holsboer-Trachsler E, Leger D, Linkowski P, Mendelson WB, Racagni G, Saletu B, Sharpley AL et al (2000) Depression and sleep disorders: Clinical relevance, economic burden and pharmacological treatment. Neuropsychobiology 42: 107–119PubMedCrossRefGoogle Scholar
  69. 69.
    Bonaventure P, Kelly L, Aluisio L, Shelton J, Lord B, Galici R, Miller K, Lovenberg TW, Atack J, Dugovic C (2007) Selective blockade of 5-HT7 receptors enhances 5-HT transmission, antidepressant-like behavior and REM sleep suppression induced by citalopram in rodents. J Pharmacol Exp Ther 321: 690–698PubMedCrossRefGoogle Scholar
  70. 70.
    Sleight AJ, Carolo C, Petit N, Zwingelstein C, Bourson A (1995) Identification of 5-hydroxytryptamine7 receptor binding sites in rat hypothalamus — Sensitivity to chronic antidepressant treatment. Mol Pharmacol 47: 99–103PubMedGoogle Scholar
  71. 71.
    Mullins UL, Gianutsos G, Eison AS (1999) Effects of antidepressants on 5-HT7 receptor regulation in the rat hypothalamus. Neuropsychopharmacology 21: 352–367PubMedCrossRefGoogle Scholar
  72. 72.
    Atkinson P, Duxon MS, Price GW, Hastie PG, and Thomas DR (2001) Paroxetine down-regulates 5-HT7 receptors in rat hypothalamus but not in hippocampus following chronic administration. Br J Pharmacol 134: P40Google Scholar
  73. 73.
    Wesolowska A, Nikiforuk A, Stachowicz K (2006) Potential anxiolytic and antidepressant effects of the selective 5-HT7 receptor antagonist SB 269970 after intrahippocampal administration to rats. Eur J Pharmacol 553: 185–190PubMedCrossRefGoogle Scholar
  74. 74.
    Wesolowska A, Tatarczynska E, Nikiforuk A, Chojnacka-Wojcik E (2007) Enhancement of the anti-immobility action of antidepressants by a selective 5-HT7 receptor antagonist in the forced swimming test in mice. Eur J Pharmacol 555: 43–47PubMedCrossRefGoogle Scholar
  75. 75.
    Thomas DR, Gittins SA, Collin LL, Middlemiss DN, Riley G, Hagan J, Gloger I, Ellis CE, Forbes IT, Brown AM (1998) Functional characterisation of the human cloned 5-HT7 receptor (long form) — Antagonist profile of SB-258719. Br J Pharmacol 124: 1300–1306PubMedCrossRefGoogle Scholar

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© Birkhäuser Verlag/Switzerland 2008

Authors and Affiliations

  • David R. Thomas
    • 1
  1. 1.Psychiatry Centre of Excellence for Drug Discovery, GlaxoSmithKlineNew Frontiers Science Park (North)Harlow, EssexUK

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