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The effects of PRX-07034, a novel 5-HT6 antagonist, on cognitive flexibility and working memory in rats

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Abstract

Rationale

Accumulating evidence indicates that schizophrenia and autism spectrum disorder patients are marked by cognitive deficits in working memory and strategy switching. There is accumulating evidence that 5-hydroxytryptamine (5-HT)6 receptors may serve as a useful target to improve cognitive functioning.

Objectives

In the present experiments, the novel 5-HT6 antagonist, PRX-07034, was examined for its selectivity of the 5-HT6 receptor, as well as its effect on delayed spontaneous alternation and strategy switching.

Methods

The binding affinity of PRX-07034 to the 5-HT6 receptor, other 5-HT receptors, as well as other G-protein coupled receptors, ion channels, and transporters was evaluated. Cyclic AMP production was measured from transfected HEK-293 cells. In separate behavioral experiments, rats received different doses of PRX-07034 (0.1, 1, or 3 mg/kg, i.p.) 30 min prior to delayed spontaneous alternation testing or prior to the acquisition and switch phases in a place–response switch test.

Results

The results indicated that PRX-07034 is both a potent (Ki = 4–8 nM) and highly selective 5-HT6 receptor antagonist (≥100-fold selectivity for the 5-HT6 receptor compared to 68 other GPCRs, ion channels, and transporters, except D3 (Ki = 71 nM) and 5-HT1B (Ki = 260 nM) receptors. For cyclic AMP quantification, PRX-07034 demonstrated antagonist activity (IC50 = 19 nM) without an effect on basal levels and did not show any agonist activity up to 10 μM. PRX-07034 at 1 and 3 mg/kg (but not 0.1 mg/kg) significantly enhanced delayed spontaneous alternation. The drug at 1 and 3 mg/kg also enhanced switching between a place and response strategy, but did not affect initial learning of either a place or response discrimination.

Conclusions

These findings demonstrate that PRX-07034 is a selective 5-HT6 receptor antagonist that may represent a novel treatment for enhancing working memory and cognitive flexibility.

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Acknowledgements

The research was supported by Epix Pharmaceuticals Inc. and P50HD055751 from the Eunice Kennedy Shriver National Institute of Child Health and Human Development. The content is solely the responsibility of the authors and does not necessarily represent the official views of the Eunice Kennedy Shriver National Institute of Child Health and Human Development or the National Institutes of Health.

Author information

Author notes

  1. Eric G. Mohler

    Present address: Abbott Laboratories, Abbott Park, IL, 60064, USA

  2. Kimberly S. Gannon

    Present address: NeuroPhage Pharmaceuticals Inc., Cambridge, MA, 02142, USA

  3. Simon S. Jones

    Present address: Acetylon Pharmaceuticals Inc., Boston, MA, 02118, USA

  4. Sharon Shacham

    Present address: Karyopharm Therapeutics, Newton, MA, 02456, USA

Authors and Affiliations

  1. Department of Psychology, University of Illinois at Chicago, 1007 West Harrison Street, Chicago, IL, 60607, USA

    Eric G. Mohler, Phillip M. Baker & Michael E. Ragozzino

  2. Laboratory of Integrative Neuroscience, University of Illinois at Chicago, Chicago, IL, 60607, USA

    Phillip M. Baker & Michael E. Ragozzino

  3. Center for Cognitive Medicine, University of Illinois at Chicago, Chicago, IL, 60607, USA

    John A. Sweeney

  4. Epix Pharmaceuticals, Lexington, MA, USA

    Kimberly S. Gannon, Simon S. Jones & Sharon Shacham

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  1. Eric G. Mohler
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Corresponding author

Correspondence to Michael E. Ragozzino.

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Supplementary Table 1

Receptor binding profile for PRX-07034. (DOC 70 kb)

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Mohler, E.G., Baker, P.M., Gannon, K.S. et al. The effects of PRX-07034, a novel 5-HT6 antagonist, on cognitive flexibility and working memory in rats. Psychopharmacology 220, 687–696 (2012). https://doi.org/10.1007/s00213-011-2518-7

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  • DOI: https://doi.org/10.1007/s00213-011-2518-7

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