Optimizing cognitive enhancement through dopamine transporter modulation
) would enhance cognitive function more effectively. To test this, we evaluated a series of R-modafinil analogs using in vitro equilibrium and non-equilibrium measurements, in vivo fast-scan cyclic voltammetry, and highly translational cognitive assays in both healthy and scopolamine-treated rats modelling cognitive impairment. Our findings show that prolonging DAT occupancy improves dopamine signalling and leads to more robust enhancements in cognitive flexibility. Compounds with longer DAT resident time-such as S-MK-26 and (S,S)-CE-158-produced the strongest cognitive effects. These results highlight the importance of DAT binding kinetics in shaping the behavioural actions of psychostimulants and support the development of safer and more effective dopamine-based cognitive enhancers.
Authors
- Michael Kirchhofer
- Michele Santoni (ORCID: https://orcid.org/0000-0003-4603-2369)
- Simone B. Sartori (ORCID: https://orcid.org/0000-0002-2396-1838)
- Nicolas Singewald (ORCID: https://orcid.org/0000-0002-0166-3370)
- Karl Ebner (ORCID: https://orcid.org/0000-0002-8662-2817)
- Claudia Sagheddu (ORCID: https://orcid.org/0000-0002-5315-2898)
- Jana Lubec (ORCID: https://orcid.org/0000-0003-0657-7647)
- Tamara Stojanovic (ORCID: https://orcid.org/0000-0002-0199-0291)
- Iva Spreitzer (ORCID: https://orcid.org/0000-0002-7327-6388)
- Harald H. Sitte (ORCID: https://orcid.org/0000-0002-1339-7444)
- Gert Lübec (ORCID: https://orcid.org/0000-0002-6333-9461)
- Predrag Kalaba (ORCID: https://orcid.org/0000-0003-0480-2337)
- Marco Niello (ORCID: https://orcid.org/0000-0002-0518-5791)
- Judith Wackerlig-Damle
- Marco Pistis
- Markus Spreitzer (ORCID: https://orcid.org/0009-0001-7796-1147)
- Ahmed M. Hussein (ORCID: https://orcid.org/0000-0002-7315-9886)
- Anita Cybulska-Klosowicz
Institutions
- University of Vienna (AT)
- University of Cagliari (IT)
- Universität Innsbruck (AT)
- Paracelsus Medical University (AT)
- Italian Institute of Technology (IT)
- Medical University of Vienna (AT)
- BOKU University (AT)
- Polish Academy of Sciences (PL)
Publication Details
- Journal
- Neuropharmacology
- Published
- 2026-04-12
- DOI
- https://doi.org/10.1016/j.neuropharm.2026.110969
- Primary Topic
- Neurotransmitter Receptor Influence on Behavior
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- Austrian Science Fund
- Ministero della Salute
- Regione Autonoma della Sardegna
- Ministero dell'Università e della Ricerca
- Ministero dell'Istruzione e del Merito