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E-6801, a 5-HT6 receptor agonist, improves recognition memory by combined modulation of cholinergic and glutamatergic neurotransmission in the rat

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Abstract

Rationale and objectives

In rats, 5-hydroxytryptamine6 (5-HT6) receptor antagonists improve learning and memory, but the effects of agonists are poorly defined. This study investigated the effects of 5-HT6 receptor agonists and antagonists on a rodent model of recognition memory.

Methods

Selective 5-HT6 receptor agonists and antagonists were administered either alone, after a scopolamine-induced impairment, or combined with sub-effective doses of the acetylcholinesterase inhibitor, donepezil, or the glutamate NMDA receptor antagonist, memantine, in a novel object discrimination paradigm in adult rats.

Results

After a 4-h inter-trial delay to induce natural forgetting, vehicle-treated rats spent an equivalent time exploring novel and familiar objects during the choice trial. The 5-HT6 receptor agonists, E-6801 (1.25–10 mg/kg i.p.) and EMD-386088 (5–10 mg/kg i.p.), and antagonists, SB-271046 and Ro 04–6790 (5 and 10 mg/kg), along with donepezil (0.1–3 mg/kg) and memantine (5–20 mg/kg) all produced significant and mostly dose-dependent increases in novel object exploration, indicative of memory enhancement. Furthermore, sub-effective doses of E-6801 (1 mg/kg) when co-administered with either SB-271046 (3 mg/kg), donepezil (0.1 mg/kg) or memantine (5 mg/kg), and EMD-386088 (2 mg/kg) co-administered with SB-271046 (3 mg/kg) also significantly enhanced object-recognition memory. Additionally, using a 1-min inter-trial delay, E-6801 (2.5 and 5 mg/kg) was as effective as donepezil (0.3 and 1 mg/kg) in reversing a scopolamine-induced (0.5 mg/kg) impairment in object recognition.

Conclusions

This is the first study to demonstrate that E-6801, a potent 5-HT6 receptor agonist, improves recognition memory by combined modulation of cholinergic and glutamatergic neurotransmission.

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Acknowledgments

The authors would like to thank Ramon Mercè for synthesising E-6801. The behavioural studies reported in this manuscript were performed at The University of Nottingham by HAS and IK who were funded by a grant awarded by ESTEVE. The commercial radioligand binding and functional assays were performed by CEREP and MDS Pharma. The animal experiments performed comply with the current UK laws.

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Authors and Affiliations

  1. Institute of Neuroscience, School of Biomedical Sciences, Queen’s Medical Centre, University of Nottingham Medical School, NG7 2UH, Nottingham, UK

    Ian Kendall, Helge A. Slotten & Kevin C. F. Fone

  2. ESTEVE, Av. Mare de Déu de Montserrat 221, 08041, Barcelona, Spain

    Xavier Codony, Javier Burgueño, Peter J. Pauwels & Jose M. Vela

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  1. Ian Kendall
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  2. Helge A. Slotten
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  3. Xavier Codony
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  4. Javier Burgueño
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  7. Kevin C. F. Fone
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Correspondence to Kevin C. F. Fone.

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Kendall and Slotten, Joint Co-authors.

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Kendall, I., Slotten, H.A., Codony, X. et al. E-6801, a 5-HT6 receptor agonist, improves recognition memory by combined modulation of cholinergic and glutamatergic neurotransmission in the rat. Psychopharmacology 213, 413–430 (2011). https://doi.org/10.1007/s00213-010-1854-3

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