Skip to main content
SpringerLink
Log in

Activation of 5-HT6 receptors facilitates attentional set shifting

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

Abstract

Rationale

Prefrontal cortex (PFC)-dependent executive function is disrupted in a range of psychiatric disorders and can be modelled in non-human primates and rodents using attentional set-shifting paradigms. There are few current pharmacological strategies for enhancing attentional set shifting, although the PFC is rich in relevant neurotransmitter targets, including 5-hydroxytryptamine (5-HT). Although 5-HT depletion studies do not support a role for 5-HT in attentional set shifting, the effect of 5-HT activation using specific receptor agonists has not been tested.

Objectives and methods

This study investigated the effect of a novel, selective 5-HT6 receptor agonist, WAY181187, in a rat model of PFC-dependent extra-dimensional (ED) attentional set shifting. The effect of this agent on immediate early gene expression in the medial PFC and other regions was also examined.

Results

Compared to vehicle-injected controls, WAY181187 facilitated ED set shifting but did not change other non-ED phases of the task (including intra-dimensional set shifting and reversal). This effect was blocked by the selective 5-HT6 antagonist SB399885, which alone had no effect. WAY181187 enhanced ED set shifting even when administered after the attentional set had been acquired, thereby ruling out impairments in attentional set formation. In separate experiments, at a dose that increased ED set shifting, WAY181187 increased Fos-like immunoreactivity in the medial PFC in a SB399885-sensitive manner, suggesting a 5-HT6 receptor-mediated activation of this region.

Conclusions

Through use of a novel 5-HT agonist, these experiments reveal a previously unrecognised role for 5-HT activation in PFC-dependent executive function, mediated by 5-HT6 receptor activation.

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
Fig. 4
Fig. 5

Similar content being viewed by others

References

  • Arnsten AF, Goldman-Rakic PS (1984) Selective prefrontal cortical projections to the region of the locus coeruleus and raphe nuclei in the rhesus monkey. Brain Res 306:9–18

    Article  CAS  PubMed  Google Scholar 

  • Austin MP, Mitchell P, Goodwin GM (2001) Cognitive deficits in depression: possible implications for functional neuropathology. Br J Psychiatry 178:200–206

    Article  CAS  PubMed  Google Scholar 

  • Birrell JM, Brown VJ (2000) Medial frontal cortex mediates perceptual attentional set shifting in the rat. J Neurosci 20:4320–4324

    CAS  PubMed  Google Scholar 

  • Bissonette GB, Martins GJ, Franz TM, Harper ES, Schoenbaum G, Powell EM (2008) Double dissociation of the effects of medial and orbital prefrontal cortical lesions on attentional and affective shifts in mice. J Neurosci 28:11124–11130

    Article  CAS  PubMed  Google Scholar 

  • Boothman LJ, Sharp T (2005) A role for midbrain raphe gamma aminobutyric acid neurons in 5-hydroxytryptamine feedback control. NeuroReport 16:891–896

    Article  CAS  PubMed  Google Scholar 

  • Boothman L, Raley J, Denk F, Hirani E, Sharp T (2006) In vivo evidence that 5-HT(2C) receptors inhibit 5-HT neuronal activity via a GABAergic mechanism. Br J Pharmacol 149:861–869

    Article  CAS  PubMed  Google Scholar 

  • Clarke HF, Walker SC, Crofts HS, Dalley JW, Robbins TW, Roberts AC (2005) Prefrontal serotonin depletion affects reversal learning but not attentional set shifting. J Neurosci 25:532–538

    Article  CAS  PubMed  Google Scholar 

  • de Foubert G, O'Neill MJ, Zetterstrom TS (2007) Acute onset by 5-HT(6)-receptor activation on rat brain brain-derived neurotrophic factor and activity-regulated cytoskeletal-associated protein mRNA expression. Neuroscience 147:778–785

    Article  PubMed  CAS  Google Scholar 

  • Dias R, Robbins TW, Roberts AC (1996) Dissociation in prefrontal cortex of affective and attentional shifts. Nature 380:69–72

    Article  CAS  PubMed  Google Scholar 

  • Floresco SB, Ghods-Sharifi S, Vexelman C, Magyar O (2006) Dissociable roles for the nucleus accumbens core and shell in regulating set shifting. J Neurosci 26:2449–2457

    Article  CAS  PubMed  Google Scholar 

  • Fone KC (2008) An update on the role of the 5-hydroxytryptamine6 receptor in cognitive function. Neuropharmacology 55:1015–1022

    Article  CAS  PubMed  Google Scholar 

  • Fox MT, Barense MD, Baxter MG (2003) Perceptual attentional set-shifting is impaired in rats with neurotoxic lesions of posterior parietal cortex. J Neurosci 23:676–681

    CAS  PubMed  Google Scholar 

  • 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 746:207–219

    Article  CAS  PubMed  Google Scholar 

  • Hajós M, Richards CD, Szekely AD, Sharp T (1998) An electrophysiological and neuroanatomical study of the medial prefrontal cortical projection to the midbrain raphe nuclei in the rat. Neuroscience 87:95–108

    Article  PubMed  Google Scholar 

  • Hajós M, Gartside SE, Varga V, Sharp T (2003) In vivo inhibition of neuronal activity in the rat ventromedial prefrontal cortex by midbrain-raphe nuclei: role of 5-HT1A receptors. Neuropharmacology 45:72–81

    Article  PubMed  CAS  Google Scholar 

  • Hatcher PD, Brown VJ, Tait DS, Bate S, Overend P, Hagan JJ, Jones DN (2005) 5-HT6 receptor antagonists improve performance in an attentional set shifting task in rats. Psychopharmacology (Berl) 181:253–259

    Article  CAS  Google Scholar 

  • Heal DJ, Smith SL, Fisas A, Codony X, Buschmann H (2008) Selective 5-HT6 receptor ligands: progress in the development of a novel pharmacological approach to the treatment of obesity and related metabolic disorders. Pharmacol Ther 117:207–231

    Article  CAS  PubMed  Google Scholar 

  • Hirst WD, Stean TO, Rogers DC, Sunter D, Pugh P, Moss SF, Bromidge SM, Riley G, Smith DR, Bartlett S, Heidbreder CA, Atkins AR, Lacroix LP, Dawson LA, Foley AG, Regan CM, Upton N (2006) SB-399885 is a potent, selective 5-HT6 receptor antagonist with cognitive enhancing properties in aged rat water maze and novel object recognition models. Eur J Pharmacol 553:109–119

    Article  CAS  PubMed  Google Scholar 

  • King MV, Sleight AJ, Woolley ML, Topham IA, Marsden CA, Fone KC (2004) 5-HT6 receptor antagonists reverse delay-dependent deficits in novel object discrimination by enhancing consolidation—an effect sensitive to NMDA receptor antagonism. Neuropharmacology 47:195–204

    Article  CAS  PubMed  Google Scholar 

  • Konishi S, Kawazu M, Uchida I, Kikyo H, Asakura I, Miyashita Y (1999) Contribution of working memory to transient activation in human inferior prefrontal cortex during performance of the Wisconsin card sorting test. Cereb Cortex 9:745–753

    Article  CAS  PubMed  Google Scholar 

  • Lewis SJ, Slabosz A, Robbins TW, Barker RA, Owen AM (2005) Dopaminergic basis for deficits in working memory but not attentional set-shifting in Parkinson's disease. Neuropsychologia 43:823–832

    Article  PubMed  Google Scholar 

  • Lynch G (2004) AMPA receptor modulators as cognitive enhancers. Current Opinion in Pharmacology 4:4–11

    Article  CAS  PubMed  Google Scholar 

  • Marder SR, Fenton W (2004) Measurement and treatment research to improve cognition in schizophrenia: NIMH MATRICS initiative to support the development of agents for improving cognition in schizophrenia. Schizophr Res 72:5–9

    Article  PubMed  Google Scholar 

  • Nakahara K, Hayashi T, Konishi S, Miyashita Y (2002) Functional MRI of macaque monkeys performing a cognitive set-shifting task. Science 295:1532–1536

    Article  CAS  PubMed  Google Scholar 

  • Oh MC, Derkach VA, Guire ES, Soderling TR (2006) Extrasynaptic membrane trafficking regulated by GluR1 serine 845 phosphorylation primes AMPA receptors for long-term potentiation. J Biol Chem 281:752–758

    Article  CAS  PubMed  Google Scholar 

  • O'Hearn E, Molliver ME (1984) Organization of raphe-cortical projections in rat: a quantitative retrograde study. Brain Res Bull 13:709–726

    Article  PubMed  Google Scholar 

  • Oswald CJ, Yee BK, Rawlins JN, Bannerman DB, Good M, Honey RC (2001) Involvement of the entorhinal cortex in a process of attentional modulation: evidence from a novel variant of an IDS/EDS procedure. Behav Neurosci 115:841–849

    Article  CAS  PubMed  Google Scholar 

  • Paxinos G, Watson C (1997) The rat brain in stereotaxic coordinates, compact 3rd edn. Academic, New York

    Google Scholar 

  • Porrino LJ, Goldman-Rakic PS (1982) Brainstem innervation of prefrontal and anterior cingulate cortex in the rhesus monkey revealed by retrograde transport of HRP. J Comp Neurol 205:63–76

    Article  CAS  PubMed  Google Scholar 

  • Robbins TW, Roberts AC (2007) Differential regulation of fronto-executive function by the monoamines and acetylcholine. Cereb Cortex 17(Suppl 1):i151–i160

    Article  PubMed  Google Scholar 

  • Schechter LE, Lin Q, Smith DL, Zhang G, Shan Q, Platt B, Brandt MR, Dawson LA, Cole D, Bernotas R, Robichaud A, Rosenzweig-Lipson S, Beyer CE (2008) Neuropharmacological profile of novel and selective 5-HT6 receptor agonists: WAY-181187 and WAY-208466. Neuropsychopharmacology 33:1323–1335

    Article  CAS  PubMed  Google Scholar 

  • Stefani MR, Groth K, Moghaddam B (2003) Glutamate receptors in the rat medial prefrontal cortex regulate set-shifting ability. Behav Neurosci 117:728–737

    Article  CAS  PubMed  Google Scholar 

  • Svenningsson P, Bateup H, Qi H, Takamiya K, Huganir RL, Spedding M, Roth BL, McEwen BS, Greengard P (2007a) Involvement of AMPA receptor phosphorylation in antidepressant actions with special reference to tianeptine. Eur J NeuroSci 26:3509–3517

    Article  PubMed  Google Scholar 

  • Svenningsson P, Tzavara ET, Qi H, Carruthers R, Witkin JM, Nomikos GG, Greengard P (2007b) Biochemical and behavioral evidence for antidepressant-like effects of 5-HT6 receptor stimulation. J Neurosci 27:4201–4209

    Article  CAS  PubMed  Google Scholar 

  • Talbot PS, Watson DR, Barrett SL, Cooper SJ (2006) Rapid tryptophan depletion improves decision-making cognition in healthy humans without affecting reversal learning or set shifting. Neuropsychopharmacology 31:1519–1525

    Article  CAS  PubMed  Google Scholar 

  • Upton N, Chuang TT, Hunter AJ, Virley DJ (2008) 5-HT6 receptor antagonists as novel cognitive enhancing agents for Alzheimer's disease. Neurotherapeutics 5:458–469

    Article  CAS  PubMed  Google Scholar 

  • Wesolowska A, Nikiforuk A (2007) Effects of the brain-penetrant and selective 5-HT6 receptor antagonist SB-399885 in animal models of anxiety and depression. Neuropharmacology 52:1274–1283

    Article  CAS  PubMed  Google Scholar 

  • Woolley ML, Marsden CA, Fone KC (2004) 5-HT6 receptors. Curr Drug Targets CNS Neurol Disord 3:59–79

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We acknowledge the support of a Medical Research Council Industrial Collaborative Studentship with GlaxoSmithKline (KB), a European Community Integrated Network (TS; NEWMOOD; LSHM-CT-2004-503474) and The Wellcome Trust (DMB; 074385).

Author information

Authors and Affiliations

  1. Department of Pharmacology, University of Oxford, Mansfield Road, Oxford, OX1 3QT, UK

    Katherine E. Burnham, John R. Bainton & Trevor Sharp

  2. Department of Experimental Psychology, University of Oxford, Oxford, OX1 3UD, UK

    Katherine E. Burnham, Mark G. Baxter & David M. Bannerman

  3. Psychiatry CEDD, GlaxoSmithKline, New Frontiers Science Park, Harlow, Essex, UK

    Eric Southam & Lee A. Dawson

Authors
  1. Katherine E. Burnham
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Mark G. Baxter
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. John R. Bainton
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Eric Southam
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Lee A. Dawson
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. David M. Bannerman
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Trevor Sharp
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Trevor Sharp.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Burnham, K.E., Baxter, M.G., Bainton, J.R. et al. Activation of 5-HT6 receptors facilitates attentional set shifting. Psychopharmacology 208, 13–21 (2010). https://doi.org/10.1007/s00213-009-1701-6

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00213-009-1701-6

Keywords

Search

Navigation