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Article

A Novel and Selective Dopamine Transporter Inhibitor, (S)-MK-26, Promotes Hippocampal Synaptic Plasticity and Restores Effort-Related Motivational Dysfunctions

by
Shima Kouhnavardi
1,2,3,†,
Alev Ecevitoglu
4,†,
Vladimir Dragačević
2,†,
Fabrizio Sanna
5,
Edgar Arias-Sandoval
6,
Predrag Kalaba
1,2,
Michael Kirchhofer
2,
Jana Lubec
1,
Marco Niello
7,
Marion Holy
7,
Martin Zehl
8,
Matthias Pillwein
1,2,3,
Judith Wackerlig
2,
Rita Murau
9,
Andrea Mohrmann
9,
Kathryn R. Beard
4,
Harald H. Sitte
7,
Ernst Urban
2,
Claudia Sagheddu
5,
Marco Pistis
5,
Roberto Plasenzotti
10,
John D. Salamone
4,
Thierry Langer
2,
Gert Lubec
1,* and
Francisco J. Monje
3,*add Show full author list remove Hide full author list
1
Programme for Proteomics, Paracelsus Medical University, 5020 Salzburg, Austria
2
Department of Pharmaceutical Chemistry, Faculty of Life Sciences, University of Vienna, 1090 Vienna, Austria
3
Center for Physiology and Pharmacology, Department of Neurophysiology and Neuropharmacology, Medical University of Vienna, 1090 Vienna, Austria
4
Department of Psychological Sciences, University of Connecticut, Storrs, CT 06269-1020, USA
5
Department of Biomedical Sciences, Division of Neuroscience and Clinical Pharmacology, University of Cagliari, 09100 Cagliari, Italy
6
Department of Psychobiology, Universitat Jaume I, 12071 Castellón de la Plana, Spain
7
Institute of Pharmacology, Center for Physiology and Pharmacology, Medical University of Vienna, 1090 Vienna, Austria
8
Department of Analytical Chemistry, Faculty of Chemistry, University of Vienna, 1090 Vienna, Austria
9
Center for Behavioral Brain Sciences, Institut für Biochemie und Zellbiologie, Otto-von-Guericke-Universität Magdeburg, 39120 Magdeburg, Germany
10
Division of Biomedical Research, Medical University of Vienna, 1090 Vienna, Austria
*
Authors to whom correspondence should be addressed.
†
These authors contributed equally to this work.
Biomolecules 2022, 12(7), 881; https://doi.org/10.3390/biom12070881
Submission received: 11 May 2022 / Revised: 9 June 2022 / Accepted: 21 June 2022 / Published: 24 June 2022
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Abstract

Dopamine (DA), the most abundant human brain catecholaminergic neurotransmitter, modulates key behavioral and neurological processes in young and senescent brains, including motricity, sleep, attention, emotion, learning and memory, and social and reward-seeking behaviors. The DA transporter (DAT) regulates transsynaptic DA levels, influencing all these processes. Compounds targeting DAT (e.g., cocaine and amphetamines) were historically used to shape mood and cognition, but these substances typically lead to severe negative side effects (tolerance, abuse, addiction, and dependence). DA/DAT signaling dysfunctions are associated with neuropsychiatric and progressive brain disorders, including Parkinson’s and Alzheimer diseases, drug addiction and dementia, resulting in devastating personal and familial concerns and high socioeconomic costs worldwide. The development of low-side-effect, new/selective medicaments with reduced abuse-liability and which ameliorate DA/DAT-related dysfunctions is therefore crucial in the fields of medicine and healthcare. Using the rat as experimental animal model, the present work describes the synthesis and pharmacological profile of (S)-MK-26, a new modafinil analogue with markedly improved potency and selectivity for DAT over parent drug. Ex vivo electrophysiology revealed significantly augmented hippocampal long-term synaptic potentiation upon acute, intraperitoneally delivered (S)-MK-26 treatment, whereas in vivo experiments in the hole-board test showed only lesser effects on reference memory performance in aged rats. However, in effort-related FR5/chow and PROG/chow feeding choice experiments, (S)-MK-26 treatment reversed the depression-like behavior induced by the dopamine-depleting drug tetrabenazine (TBZ) and increased the selection of high-effort alternatives. Moreover, in in vivo microdialysis experiments, (S)-MK-26 significantly increased extracellular DA levels in the prefrontal cortex and in nucleus accumbens core and shell. These studies highlight (S)-MK-26 as a potent enhancer of transsynaptic DA and promoter of synaptic plasticity, with predominant beneficial effects on effort-related behaviors, thus proposing therapeutic potentials for (S)-MK-26 in the treatment of low-effort exertion and motivational dysfunctions characteristic of depression and aging-related disorders.
Keywords: dopamine; dopamine transporter; synaptic plasticity; learning and memory; hippocampus; emotional behavior; effort-related behavior; modafinil dopamine; dopamine transporter; synaptic plasticity; learning and memory; hippocampus; emotional behavior; effort-related behavior; modafinil
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MDPI and ACS Style

Kouhnavardi, S.; Ecevitoglu, A.; Dragačević, V.; Sanna, F.; Arias-Sandoval, E.; Kalaba, P.; Kirchhofer, M.; Lubec, J.; Niello, M.; Holy, M.; et al. A Novel and Selective Dopamine Transporter Inhibitor, (S)-MK-26, Promotes Hippocampal Synaptic Plasticity and Restores Effort-Related Motivational Dysfunctions. Biomolecules 2022, 12, 881. https://doi.org/10.3390/biom12070881

AMA Style

Kouhnavardi S, Ecevitoglu A, Dragačević V, Sanna F, Arias-Sandoval E, Kalaba P, Kirchhofer M, Lubec J, Niello M, Holy M, et al. A Novel and Selective Dopamine Transporter Inhibitor, (S)-MK-26, Promotes Hippocampal Synaptic Plasticity and Restores Effort-Related Motivational Dysfunctions. Biomolecules. 2022; 12(7):881. https://doi.org/10.3390/biom12070881

Chicago/Turabian Style

Kouhnavardi, Shima, Alev Ecevitoglu, Vladimir Dragačević, Fabrizio Sanna, Edgar Arias-Sandoval, Predrag Kalaba, Michael Kirchhofer, Jana Lubec, Marco Niello, Marion Holy, and et al. 2022. "A Novel and Selective Dopamine Transporter Inhibitor, (S)-MK-26, Promotes Hippocampal Synaptic Plasticity and Restores Effort-Related Motivational Dysfunctions" Biomolecules 12, no. 7: 881. https://doi.org/10.3390/biom12070881

APA Style

Kouhnavardi, S., Ecevitoglu, A., Dragačević, V., Sanna, F., Arias-Sandoval, E., Kalaba, P., Kirchhofer, M., Lubec, J., Niello, M., Holy, M., Zehl, M., Pillwein, M., Wackerlig, J., Murau, R., Mohrmann, A., Beard, K. R., Sitte, H. H., Urban, E., Sagheddu, C., ... Monje, F. J. (2022). A Novel and Selective Dopamine Transporter Inhibitor, (S)-MK-26, Promotes Hippocampal Synaptic Plasticity and Restores Effort-Related Motivational Dysfunctions. Biomolecules, 12(7), 881. https://doi.org/10.3390/biom12070881

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