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Sertindole improves sub-chronic PCP-induced reversal learning and episodic memory deficits in rodents: involvement of 5-HT6 and 5-HT2A receptor mechanisms

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Abstract

Aim

This study examined the efficacy of sertindole in comparison with a selective 5-HT6 and a 5-HT2A receptor antagonist to reverse sub-chronic phencyclidine (PCP)-induced cognitive deficits in female rats.

Methods

In the first test, adult female hooded Lister rats were trained to perform an operant reversal learning task to 90% criterion. After training, rats were treated with PCP at 2 mg/kg (i.p.) or vehicle twice daily for 7 days, followed by 7 days washout. For the second test, novel object recognition (NOR), a separate batch of rats, had the same sub-chronic PCP dosing regime and washout period. In reversal learning, rats were treated acutely with sertindole, the selective 5-HT2A receptor antagonist M100.907 or the selective 5-HT6 receptor antagonist SB-742457.

Results

The PCP-induced selective reversal learning deficit was significantly improved by sertindole, M100.907 and SB-742457. Sertindole also significantly improved the sub-chronic PCP-induced deficit in NOR, a test of episodic memory following a 1 min and 1 h inter-trial interval. In vivo binding studies showed that the dose–response relationship for sertindole in this study most closely correlates with affinity for 5-HT6 receptor in vivo binding in striatum, although contribution from binding to 5-HT2A receptors in vivo in cortex may also provide an important mechanism.

Conclusion

The efficacies of selective 5-HT2A and 5-HT6 receptor antagonists suggest potential mechanisms mediating the effects of sertindole, which has high affinity for these 5-HT receptor subtypes. The sertindole-induced improvement in cognitive function in this animal model suggests relevance for the management of cognitive deficit symptoms in schizophrenia.

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Authors and Affiliations

  1. Bradford School of Pharmacy, The University of Bradford, Bradford, West Yorkshire, BD7 1DP, UK

    Nagi Idris, Jo Neill & Ben Grayson

  2. Research Laboratories, H. Lundbeck A/S, Ottiliavej 9, 2500, Valby, Denmark

    Benny Bang-Andersen, Louise M. Witten, Lise Tøttrup Brennum & Jørn Arnt

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  1. Nagi Idris
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  2. Jo Neill
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  3. Ben Grayson
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  4. Benny Bang-Andersen
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Correspondence to Jo Neill.

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Idris, N., Neill, J., Grayson, B. et al. Sertindole improves sub-chronic PCP-induced reversal learning and episodic memory deficits in rodents: involvement of 5-HT6 and 5-HT2A receptor mechanisms. Psychopharmacology 208, 23–36 (2010). https://doi.org/10.1007/s00213-009-1702-5

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