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Selective serotonin 5-HT2A receptor antagonist EMD 281014 improves delayed matching performance in young and aged rhesus monkeys

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Abstract

Rationale

The superior cognitive effects of atypical neuroleptics over typical agents reported in the schizophrenia literature are often attributed to the more prominent antagonist activity of the atypical drugs at serotonin 5HT2A receptors. However, atypical neuroleptics also have activity at many additional neurotransmitter receptors and few studies have specifically (and prospectively) tested the hypothesis that 5HT2A antagonism alone results in enhanced cognitive function.

Objectives

The purpose of this study was to evaluate the selective 5-HT2A antagonist, 7-{4-[2-(4-fluoro-phenyl)-ethyl]-piperazine-1-carbonyl}-1H-indole-3-carbonitrile HCl (EMD 281014) in young and aged monkeys in a test designed to assess working memory function.

Methods

Four oral doses (0.1, 1.0, 3.0, and 10.0 mg/kg) of EMD 281014 were evaluated in six young adult (mean age=9.2 years) and eight aged rhesus macaques (mean age=24.9 years) trained to perform a computer-assisted delayed matching-to-sample (DMTS) task.

Results

Depending on dose, EMD 281014 improved DMTS accuracy in young and aged monkeys primarily at either the medium or long retention intervals. While the latencies associated with incorrect color selections (choices latencies) tended to be longer than those associated with correct selections (particularly in the aged subjects) under baseline conditions, there were no significant effects of EMD 281014 on either sample or choice latencies in either age group. In addition, no adverse effects were observed across the range of doses evaluated in either cohort of animals.

Conclusion

These experiments, conducted in a non-human primate model, suggest that selective 5HT2A antagonists such as EMD 281014 could offer therapeutic benefit to younger and older psychiatric patients by improving working memory function.

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Acknowledgements

This work was supported in part by Merck KGaA (Darmstadt, Germany), the Alzheimer’s Association, and the Office of Research and Development, Medical Research Service, Department of Veterans Affairs. The authors also wish to acknowledge the technical support of primate technicians Ms. Nancy Kille and Ms. Ritu Duhan.

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Authors and Affiliations

  1. Program in Clinical and Experimental Therapeutics, CJ-1020 The Medical College of Georgia, University of Georgia College of Pharmacy (Augusta Campus), Augusta, GA, 30912, USA

    Alvin V. Terry Jr

  2. Alzheimer’s Research Center, and Department of Pharmacology and Toxicology, Medical College of Georgia, Augusta, GA, 30912, USA

    Alvin V. Terry Jr & Jerry J. Buccafusco

  3. Department of Veterans Affairs Medical Center, Augusta, GA, 30910, USA

    Jerry J. Buccafusco

  4. Preclinical Research Merck KGaA, 64271, Darmstadt, Germany

    Gerd D. Bartoszyk

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  1. Alvin V. Terry Jr
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  2. Jerry J. Buccafusco
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  3. Gerd D. Bartoszyk
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Correspondence to Alvin V. Terry Jr.

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Terry, A.V., Buccafusco, J.J. & Bartoszyk, G.D. Selective serotonin 5-HT2A receptor antagonist EMD 281014 improves delayed matching performance in young and aged rhesus monkeys. Psychopharmacology 179, 725–732 (2005). https://doi.org/10.1007/s00213-004-2114-1

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  • DOI: https://doi.org/10.1007/s00213-004-2114-1

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