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Impact of regional 5-HT depletion on the cognitive enhancing effects of a typical 5-ht6 receptor antagonist, Ro 04-6790, in the Novel Object Discrimination task

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Abstract

Rationale

Selective 5-ht6 receptor antagonists like Ro 04-6790 prolong memory in many rodent preclinical paradigms, possibly by blocking tonic 5-HT-evoked GABA release and allowing disinhibition of cortico-limbic glutamatergic and cholinergic neurones. If this is the case, behavioural responses to Ro 04-6790 should be abolished by depletion of endogenous 5-HT, and selective lesions of dorsal raphé (DR) or median raphé (MR) 5-HT pathways would allow the neuroanatomical substrates underlying the cognitive effects of 5-ht6 receptor antagonists to be elucidated.

Objectives

This study compared the effect of Ro 04-6790 on novel object discrimination (NOD) before and after sham or 5,7-dihydroxytryptamine (5,7-DHT)-induced lesions produced by injection into the lateral ventricles (LV), DR or MR.

Materials and methods

NOD tests used a 4 h inter-trial interval (ITI) and Ro 04-6790 (10 mg kg−1 i.p.) was administered 20 min before the familiarisation trial. Brain region-specific 5-HT depletion was assessed by high performance liquid chromatography with electrochemical detection (HPLC-ED).

Results

Widespread LV or selective MR, but not DR lesions, abolished the ability of Ro 04-6790 to delay natural forgetting. Successful performance of all lesioned rats in subsequent ‘drug-free’ NOD tests using a 1 h ITI excluded the possibility of any confounding effects on visual acuity or motivation.

Conclusions

The ability of Ro 04-6790 to prolong object recognition memory requires blockade of MR 5-HT function. Because DR lesions did not produce the expected depletion of striatal 5-HT an additional contribution of DR inputs to this region cannot be completely excluded.

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Acknowledgements

This research was funded by F. Hoffmann La-Roche and the University of Nottingham. The authors would like to thank Mr I.A. Topham for technical assistance with HPLC.

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Authors and Affiliations

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

    M. V. King, C. H. Spicer, C. A. Marsden & K. C. F. Fone

  2. PRBD-N, F. Hoffmann-La Roche, CH-4070, Basel, Switzerland

    A. J. Sleight

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  1. M. V. King
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  2. C. H. Spicer
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Correspondence to M. V. King.

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King, M.V., Spicer, C.H., Sleight, A.J. et al. Impact of regional 5-HT depletion on the cognitive enhancing effects of a typical 5-ht6 receptor antagonist, Ro 04-6790, in the Novel Object Discrimination task. Psychopharmacology 202, 111–123 (2009). https://doi.org/10.1007/s00213-008-1334-1

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  • DOI: https://doi.org/10.1007/s00213-008-1334-1

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