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Reinstatement of synaptic plasticity in the aging brain through specific dopamine transporter inhibition

Molecular Psychiatry volume 26, pages 7076–7090 (2021)Cite this article

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Abstract

Aging-related neurological deficits negatively impact mental health, productivity, and social interactions leading to a pronounced socioeconomic burden. Since declining brain dopamine signaling during aging is associated with the onset of neurological impairments, we produced a selective dopamine transporter (DAT) inhibitor to restore endogenous dopamine levels and improve cognitive function. We describe the synthesis and pharmacological profile of (S,S)-CE-158, a highly specific DAT inhibitor, which increases dopamine levels in brain regions associated with cognition. We find both a potentiation of neurotransmission and coincident restoration of dendritic spines in the dorsal hippocampus, indicative of reinstatement of dopamine-induced synaptic plasticity in aging rodents. Treatment with (S,S)-CE-158 significantly improved behavioral flexibility in scopolamine-compromised animals and increased the number of spontaneously active prefrontal cortical neurons, both in young and aging rodents. In addition, (S,S)-CE-158 restored learning and memory recall in aging rats comparable to their young performance in a hippocampus-dependent hole board test. In sum, we present a well-tolerated, highly selective DAT inhibitor that normalizes the age-related decline in cognitive function at a synaptic level through increased dopamine signaling.

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Fig. 1: In silico and in vitro profiling of a novel atypical dopamine reuptake inhibitor.
Fig. 2: In vitro and in vivo pharmacology of (S,S)-CE-158.
Fig. 3: Brain dopamine levels after (S,S)-CE-158 treatment.
Fig. 4: Neuronal activity after (S,S)-CE-158 pretreatment.
Fig. 5: Effect of (S,S)-CE-158 on spine density and morphology in aged rats.
Fig. 6: Enhancing effect of (S,S)-CE-158 on cognitive flexibility.
Fig. 7: Effects of (S,S)-CE-158 on spatial learning and memory in aged rats.
Fig. 8: Effects of (S,S)-CE-158 on spatial reference memory in poorly and intermediately performing aged rats.

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Acknowledgements

This project was sponsored by Personengesellschaft Barbara Lubec with partial funding by the Austrian Science Fund (FWF: 12433-B26, NS).

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Author notes

  1. These authors contributed equally: Jana Lubec, Predrag Kalaba.

Authors and Affiliations

  1. Programme for Proteomics, Paracelsus Medical University, Salzburg, Austria

    Jana Lubec, Marija Ilic, Johann Jakob Leban, Volker Korz, Jovana Malikovic & Gert Lubec

  2. Department of Pharmaceutical Chemistry, Faculty of Life Sciences, University of Vienna, Vienna, Austria

    Predrag Kalaba, Ahmed M. Hussein, Daniel Daba Feyissa, Mohamed H. Kotob, Rasha R. Mahmmoud, Oliver Wieder, Arthur Garon, Marija Ilic, Vladimir Dragačević, Judith Wackerlig, Shima Kouhnavardi, Thierry Langer & Ernst Urban

  3. Department of Zoology, Al-Azhar University, Assiut, Egypt

    Ahmed M. Hussein

  4. Department of Pathology, Faculty of Veterinary Medicine, Assiut University, Assiut, Egypt

    Mohamed H. Kotob

  5. Department of Pediatrics, Faculty of Medicine, Assuit University, Assuit, Egypt

    Rasha R. Mahmmoud

  6. Department of Biomedical Sciences, Division of Neuroscience and Clinical Pharmacology, University of Cagliari, Monserrato, Italy

    Claudia Sagheddu & Marco Pistis

  7. Institute of Pharmacology, Centre of Physiology and Pharmacology, Medical University of Vienna, Vienna, Austria

    Marija Ilic & Harald H. Sitte

  8. Laboratory of Neuroplasticity, Nencki Institute of Experimental Biology, Polish Academy of Sciences, Warsaw, Poland

    Anita Cybulska-Klosowicz

  9. Department of Analytical Chemistry, Faculty of Chemistry, University of Vienna, Vienna, Austria

    Martin Zehl

  10. Department of Pharmacology and Toxicology, Institute of Pharmacy and Center for Molecular Biosciences Innsbruck (CMBI), Leopold Franzens University Innsbruck, Innsbruck, Austria

    Simone B. Sartori, Karl Ebner & Nicolas Singewald

  11. X-ray Structure Analysis Centre, Faculty of Chemistry, University of Vienna, Vienna, Austria

    Alexander Roller & Natalie Gajic

  12. Neuroscience Institute, National Research Council of Italy (CNR), Section of Cagliari, Cagliari, Italy

    Marco Pistis

  13. Division of Biomedical Research, Medical University of Vienna, Vienna, Austria

    Roberto Plasenzotti

  14. Center for Physiology and Pharmacology, Department of Neurophysiology and Neuropharmacology, Medical University of Vienna, Vienna, Austria

    Francisco J. Monje

  15. Center for Brain Research, Medical University of Vienna, Vienna, Austria

    Christian Pifl

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  1. Jana Lubec
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Contributions

JL, PK, AMH, DDF, MHK, RRM, OW, AG, CS, MI, VD, ACK, MZ, JW, SBS, KE, SK, AR, NG, MP, NS, JJL, RP, HHS, FJM, TL, EU, VK, JM, and CP performed experiments and analyzed data. GL, JL, and PK designed and supervised the study and wrote the manuscript with input from all co-authors.

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Correspondence to Gert Lubec.

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Lubec, J., Kalaba, P., Hussein, A.M. et al. Reinstatement of synaptic plasticity in the aging brain through specific dopamine transporter inhibition. Mol Psychiatry 26, 7076–7090 (2021). https://doi.org/10.1038/s41380-021-01214-x

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