, Volume 181, Issue 2, pp 253–259

5-HT6 receptor antagonists improve performance in an attentional set shifting task in rats

  • Paula D. Hatcher
  • Verity J. Brown
  • David S. Tait
  • Simon Bate
  • Philip Overend
  • Jim J. Hagan
  • Declan N. C. Jones
Original Investigation


Rationale and objective

Performance on the Wisconsin Card Sorting Test (WCST), which requires patients to ‘shift attention’ between stimulus dimensions (sorting categories), is impaired in diseases such as schizophrenia. The rat attentional set shifting task is an analogue of the WCST. Given that 5-HT6 receptor antagonists improve cognitive performance and influence cortical neurochemistry in rats, the present study investigated the effects of 5-HT6 receptor antagonists upon attentional set shifting in rats.


Rats were tested in this paradigm following sub-chronic SB-399885-T or SB-271046-A (both 10 mg kg−1 bid, p.o. for 8 days prior to testing and either 4 or 2 h prior to testing on day 9, respectively). Rats were trained to dig in baited bowls for a food reward and to discriminate based on odour or digging media (Habituation, day 8). In a single session (day 9), rats performed a series of discriminations, including reversals (REV), intra-dimensional (ID) and extra-dimensional (ED) shifts.


Neither compound altered performance during Habituation. On the test day, both SB-399885-T and SB-271046-A reduced the total trials to reach criterion and the total errors made when data were collapsed across all discriminations (P<0.05–0.01). Further, both compounds significantly reduced the trials to criterion for REV-1 (P<0.05–0.01) and abolished the ID/ED shift. SB-399885-T, but not SB-271046-A, reduced trials required to complete the ED shift (P<0.05) and the number of errors made during completion of the ID (P<0.05) and ED shifts (P<0.01).


5-HT6 receptor antagonists improved performance in the attentional set shifting task and may have therapeutic potential in the treatment of disorders where cognitive deficits are a feature, including schizophrenia.


SB-271046-A SB-399885-T Intra-dimensional shift (ID) Extra-dimensional shift (ED) Wisconsin Card Sorting Task (WCST) Cognition 


  1. Barense MD, Fox MT, Baxter MG (2002) Aged rats are impaired on an attentional set-shifting task sensitive to medial frontal cortex damage in young rats. Learn Mem 9:191–201CrossRefPubMedGoogle Scholar
  2. Barnes NM, Sharp T (1999) A review of central 5-HT receptors and their function. Neuropharmacology 38:1083–1152CrossRefPubMedGoogle Scholar
  3. Bentley JC, Sleight AJ, Marsden CA, Fone KCF (1997) 5-HT6 antisense oligonucleotide i.c.v. affects rat performance in the water maze and feeding. J Psychopharmacol 11:A64Google Scholar
  4. Bentley JC, Bourson A, Boess FG, Fone KCF, Marsden CA, Petit N, Sleight AJ (1999) Investigation of stretching behaviour induced by the selective 5-HT6 receptor antagonist RE 04-6790 in rats. Br J Pharmacol 126:1537–1542CrossRefPubMedGoogle Scholar
  5. Berg EA (1948) A simple objective treatment for measuring flexibility in thinking. J Gen Psychol 39:15–22PubMedCrossRefGoogle Scholar
  6. Birrell JM, Brown VJ (2000) Medial frontal cortex mediates perceptual attentional set shifting in the rat. J Neurosci 20(11):4320–4324PubMedGoogle Scholar
  7. Bourson A, Borroni E, Austin RH, Monsma F Jr, Sleight AJ (1995) Determination of the role of the 5-HT6 receptor in the rat brain: a study using antisense oligonucleotides. J Pharmacol Exp Ther 274:173–180PubMedGoogle Scholar
  8. Bourson A, Boess FG, Bos M, Sleight AJ (1998) Involvement of 5-HT6 receptors in nigro-striatal function in rodents. Br J Pharmacol 125:1562–1566CrossRefPubMedGoogle Scholar
  9. Bromidge SM, Brown AM, Clarke SE, Dodgson K, Gager T, Grassam HL, Jeffrey PM, Joiner GF, King FD, Middlemiss DN, Moss SF, Newman H, Riley G, Routledge C, Wyman P (1999) 5-Chloro-N-(4-methoxy-3-piperazin-1-yl-phenyl)-3-methyl-2-benzothiophenesulfonamide (SB-271046): a potent, selective, and orally bioavailable 5-HT6 receptor antagonist. J Med Chem 42(2):202–205CrossRefPubMedGoogle Scholar
  10. Foley AG, Murphey KJ, Hirst WD, Gallagher HC, Hagan JJ, Upton N, Walsh FS, Regan CM (2004) The 5-HT6 receptor antagonist SB-271046 reverses scopolamine-disrupted consolidation of a passive avoidance task and ameliorates spatial task deficits in aged rats. Neuropsychopharmacology 29(1):93–100CrossRefPubMedGoogle Scholar
  11. Fox MT, Barense MD, Baxter MG (2003) Perceptual attentional set-shifting is impaired in rats with neurotoxic lesions of the posterior parietal cortex. J Neurosci 23(2):676–681PubMedGoogle Scholar
  12. Frederick JA, Meador-Woodruff JH (1999) Effects of clozapine and haloperidol on 5-HT6 receptor mRNA levels in the rat brain. Schizophr Res 38:7–12CrossRefPubMedGoogle Scholar
  13. Gerard C, El Mestikawy S, Lebrand C, Adrien J, Ruat M, Traiffort B, Hamon M, Martres MP (1996) Quantitative RT-PCR distribution of serotonin 5-HT6 receptor mRNA in the central nervous system of control or 5,7-dihydroxytruptamine-treated rats. Synapse 23(3):164–173CrossRefPubMedGoogle Scholar
  14. Gerard C, Martres MP, Lefevre K, Miquel MC, Verge D, Lanfumey L, Doucet E, Hamon M, El Mestikawy S (1997) Immuno-localization of serotonin 5-HT6 receptor-like material in the rat central nervous system. Brain Res 746:207–219CrossRefPubMedGoogle Scholar
  15. Hamon M, Doucet E, Lefevre K, Miquel MC, Lanfumey L, Insausti R, Frechilla D, Del Rio J, Verge D (1999) Antibodies and antisense oligonucleotide for probing the distribution and putative functions of central 5-HT6 receptor. Neuropsychopharmacology 21:68–76Google Scholar
  16. Hatcher PD, Brown VJ, Tait DS, Jones DNC (2002) 5-HT6 receptor antagonists improve performance in an attentional set shifting task. J Psychopharmacol 16(3):A16Google Scholar
  17. Hirst WD, Stean TO, Rogers DC, Sunters D, Pugh P, Moss SF, Bromidge SM, Riley G, Smith DR, Barlett S, Heidbreder CA, Atkins AR, Lacroix LP, Dawson LA, Foley AG, Regan CM, Upton N. SB-399885 is a potent, selective 5-HT6 receptor antagonist active in rat water maze and novel object recognition models, Br J Pharmacol (personal communication)Google Scholar
  18. Jay TM (2003) Dopamine: a potential substrate for synaptic plasticity and memory mechanisms. Prog Neurobiol 69(6):375–390CrossRefPubMedGoogle Scholar
  19. Kolb B, Wilshaw IQ (1983) Performance of schizophrenic patients on tests sensitive to left or right frontal temporal, or parietal function in neurological patients. J Nerv Ment Dis 171:435–443PubMedCrossRefGoogle Scholar
  20. Lacroix LP, Dawson LA, Hagan JJ, Heidbreder CA (2004) 5-HT6 receptor antagonist SB-271046 enhances extracellular levels of monoamines in the rat medial prefrontal cortex. Synapse 51(2):158–164PubMedCrossRefGoogle Scholar
  21. Lindner MD, Hodges DB, Hogan JB, Orie AF, Corsa JA, Barten DM, Polson C, Robertson BJ, Guss VL, Gillman KW, Starrett JE, Gribkoff VK (2003) An assessment of the effects of serotonin 6 (5-HT6) receptor antagonists in rodent models of learning. J Pharmacol Exp Ther 307(2):682–691CrossRefPubMedGoogle Scholar
  22. McAlonan K, Brown VJ (2003) Orbital prefrontal cortex mediates reversal learning and not attentional set shifting in the rat. Behav Brain Res 146(1–2):97–103CrossRefPubMedGoogle Scholar
  23. Meltzer HY, McGurk SR (1999) The effects of clozapine, risperidone, and olanzapine on cognitive function in schizophrenia. Schizophr Bull 25(2):233–255PubMedGoogle Scholar
  24. Meneses A (2001) Effects of the 5-HT6 receptor antagonist RO 04-6790 on learning consolidation. Behav Brain Res 118:107–110CrossRefPubMedGoogle Scholar
  25. Pantelis C, Barber FZ, Barnes TRE, Nelson HE, Owen AM, Robbins TW (1999) Comparison of set shifting ability in patients with chronic schizophrenia and frontal lobe damage. Schizophr Res 37:251–270CrossRefPubMedGoogle Scholar
  26. Pare D (2003) Role of the basolateral amygdala in memory consolidation. Prog Neurobiol 70(5):409–420CrossRefPubMedGoogle Scholar
  27. Ragozzino ME, Wilcox C, Raso M, Kesner RP (1999) Involvement of rodent prefrontal cortex subregions in strategy switching. Behav Neurosci 113:32–41CrossRefPubMedGoogle Scholar
  28. Regan CM, Foley AG, Murphy KJ, Hirst WD, Gallagher HC, Hagan JJ, Upton N, Walsh FS (2003) The 5-HT6 receptor antagonists SB-271046 and SB-399885 increase basal and learning induced NCAM-polysialylation in the rat dentate gyrus. Society for Neuroscience No. 835.21Google Scholar
  29. Riemer C, Borroni E, Levet-Treafit B, Martin JR, Poli S, Porter RHP, Bos M (2003) Influence of the 5-HT6 receptor on acetylcholine release in the cortex: pharmacological characterisation 4-(2-Bromo-6-pyrrolidin-1-ylpyridine-4-sulfonyl)phenylamine, a potent and selective 5-HT6 receptor antagonist. J Med Chem 46:1273–1276CrossRefPubMedGoogle Scholar
  30. Roberts AC, Robbins TW, Everitt BJ (1988) The effects of intradimensional and extra-dimensional shifts on visual discrimination learning in humans and non-human primates. Q J Exp Psychol 40B:321–341Google Scholar
  31. Rogers DC, Hagan JJ (2001) 5-HT6 receptor antagonists enhance retention of a water maze task in the rat. Psychopharmacology 158(2):114–119CrossRefPubMedGoogle Scholar
  32. Roth BL, Criago SC, Choudhary MS, Uluer A, Monsma FJ, Shen Y, Meltzer HY, Sibley DR (1994) Binding of typical and atypical antipsychotic agents to 5-HT6 and 5-HT7 receptors. J Pharmacol Exp Ther 268:1403–1410PubMedGoogle Scholar
  33. Roth BL, Sheffler DJ, Kroeze WK (2004) Magic shotgun versus magic bullets: selectively non-selective drugs for mood disorders and schizophrenia. Nat Rev 3:353–359Google Scholar
  34. Routledge C, Bromidge SM, Moss SF, Price GW, Hirst WD, Newman H, Riley G, Gager T, Stean TO, Upton N, Clarke SE, Brown AM, Middlemiss DN (2000) Characterisation of SB-271046-A: a potent, selective and orally active 5-HT6 receptor antagonist. Br J Pharmacol 130:1606–1612CrossRefPubMedGoogle Scholar
  35. Ruat M, Traiffort E, Arrang JM, Tardivel-Lacombe J, Diaz J, Leurs Schwartz JC (1993) A novel rat serotonin (5-HT6) receptor: molecular cloning, localization and stimulation of cAMP accumulation. Biochem Biophys Res Commun 193(1):268–276CrossRefPubMedGoogle Scholar
  36. Ward RP, Hamblin MW, Lachowicz JE, Hoffman BJ, Sibleys DR, Dorsa DM (1995) Localization of serotonin subtype 6 receptor messenger RNA in the rat brain by in situ hybridization histochemistry. Neuroscience 64(4):1105–1111CrossRefPubMedGoogle Scholar
  37. Woolley ML, Marsden CA, Sleight AJ, Fone KCF (2000) Reversal of a scopolamine-induced deficit in object discrimination by a selective 5-HT6 receptor antagonist, RO-06790, in rats. Br J Pharmacol 129:64PGoogle Scholar
  38. Woolley ML, Bentley JC, Sleight AJ, Marsden CA, Fone KCF (2001) A role for 5-HT6 receptors in retention of spatial learning in the Morris water maze. Neuropharmacology 41:210–219CrossRefPubMedGoogle Scholar
  39. Woolley ML, Marsden CA, Sleight AJ, Fone KCF (2003) Reversal of a cholinergic-induced deficit in a rodent model of recognition memory by the selective 5-HT6 receptor antagonist, Ro 04-6790. Psychopharmacology 170(4):358–367CrossRefPubMedGoogle Scholar
  40. Woolley ML, Marsden CA, Fone KCF (2004) 5HT6 receptors. Curr Drug Targets CNS Neurol Disord 3:59–79CrossRefPubMedGoogle Scholar
  41. Zhukovshaya NL, Neumaier JF (2000) Clozapine downregulates 5-HT6 and upregulates 5-HT7 receptors in HeLa cells. Neurosci Lett 288:236–240CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag 2005

Authors and Affiliations

  • Paula D. Hatcher
    • 1
  • Verity J. Brown
    • 2
  • David S. Tait
    • 2
  • Simon Bate
    • 3
  • Philip Overend
    • 3
  • Jim J. Hagan
    • 1
  • Declan N. C. Jones
    • 1
  1. 1.Schizophrenia and Bipolar Disorders Research, Psychiatry CEDDEssexUK
  2. 2.School of PsychologyUniversity of St AndrewsSt AndrewsUK
  3. 3.Statistical Sciences, Europe, GlaxoSmithKlineEssexUK

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