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Cutamesine Overcomes REM Sleep Deprivation-Induced Memory Loss: Relationship to Sigma-1 Receptor Occupancy

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Abstract

Purpose

Rapid eye movement (REM) sleep deprivation (SD) decreases cerebral sigma-1 receptor expression and causes cognitive deficits. Sigma-1 agonists are cognitive enhancers. Here, we investigate the effect of cutamesine treatment in the REM SD model.

Procedures

Sigma-1 receptor occupancy (RO) in the rat brain by cutamesine was determined using 1-[2-(3,4-dimethoxyphenethyl)]-4-(3-phenylpropyl)piperazine ([11C]SA4503) and positron emission tomography (PET), and tissue cutamesine levels were measured by ultra performance liquid chromatography (UPLC)-MS. RO was calculated from a Cunningham-Lassen plot, based on the total distribution volume of [11C]SA4503 determined by Logan graphical analysis. Cognitive performance was assessed using the passive avoidance (PA) test.

Results

Cutamesine at a dose of 1.0 mg/kg reversed REM SD-induced cognitive deficit and occupied 92 % of the sigma-1 receptor population. A lower dose (0.3 mg/kg) occupied 88 % of the receptors but did not significantly improve cognition.

Conclusion

The anti-amnesic effect of cutamesine in this animal model may be related to longer exposure at a higher dose and/or drug binding to secondary targets.

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Acknowledgments

During the period of this research, NKR was supported by university funding (Ubbo Emmius Bursary Position).

Conflict of Interest

No conflict of interest concerning this paper can be reported.

Author information

Authors and Affiliations

  1. Department of Nuclear Medicine and Molecular Imaging, University Medical Center Groningen, University of Groningen, Hanzeplein 1, 9713 GZ, Groningen, Netherlands

    Nisha K. Ramakrishnan, Marianne Schepers, Gert Luurtsema, Philip H. Elsinga, Rudi A. J. O. Dierckx & Aren van Waarde

  2. Brain Physiology Research Unit, Semmelweis University, Budapest, Hungary

    Csaba J. Nyakas

  3. Tokyo Metropolitan Institute of Gerontology, Tokyo, Japan

    Kiichi Ishiwata

Authors
  1. Nisha K. Ramakrishnan
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  2. Marianne Schepers
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  3. Gert Luurtsema
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  4. Csaba J. Nyakas
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  5. Philip H. Elsinga
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  6. Kiichi Ishiwata
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  8. Aren van Waarde
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Correspondence to Aren van Waarde.

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Ramakrishnan, N.K., Schepers, M., Luurtsema, G. et al. Cutamesine Overcomes REM Sleep Deprivation-Induced Memory Loss: Relationship to Sigma-1 Receptor Occupancy. Mol Imaging Biol 17, 364–372 (2015). https://doi.org/10.1007/s11307-014-0808-2

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  • DOI: https://doi.org/10.1007/s11307-014-0808-2

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