Psychostimulants that interact with the dopamine transporter can be found in the therapy of neuropsychiatric disorders such as ADHD or depression as well as on the illegal drug market. In order to better understand their exact mode of action and undesirable effects, a research team led by Harald Sitte from MedUni Vienna’s Center for Physiology and Pharmacology has long been investigating the question of why different substances in this group of substances have different effects: The answer, according to the results of current studies, lies in the respective binding time of the substances to the dopamine transporter. The study has just been published in the journal Proceedings of the National Academy of Sciences (PNAS).
Using a series of in vitro and in vivo studies, as well as computer simulations, the team investigated the pharmacological effects of various psychostimulants, both medicinal and abused, that interact with the dopamine transporter. These include substances such as α-pyrrolidinovalerophenone (also known as α-PVP or “Flakka”) and 3,4-methylenedioxypyrovalerone (also known as MDPV or “Cloud9”) on the one hand, and cocaine and methylphenidate, a common drug, on the other to treat ADHD (Attention Deficit Hyperactivity Disorder).
“Some of these substances showed a pronounced lasting effect in our cell culture models, which we were then also able to find in vivo in mouse models,” reports study leader Harald Sitte from the Institute of Pharmacology at MedUni Vienna’s Center for Physiology and Pharmacology from the analysis of the exact pharmacological relationships: “According to our research, it is the duration of binding to the dopamine transporter that makes the difference here.”
Central role of the dopamine transporter
Dopamine transporters are proteins responsible for the reuptake of the neurotransmitter dopamine. As a messenger substance that transmits signals between nerve cells, dopamine controls emotional, mental and motor reactions in the brain. It is also known as a “messenger of happiness” that makes us feel happy. If too much or too little dopamine is involved, neuropsychiatric problems are the result. The dopamine-related conditions can be both drug-induced and abusive through the action of psychostimulants. Dopamine transporters and dopamine levels play a central role in the development of substance use disorders.
“Our results allow us to conclude that the active substances we examined interact with the dopamine transporter to varying degrees and for different lengths of time,” explains lead author Marco Niello from MedUni Vienna’s Center for Physiology and Pharmacology. “This in turn is the molecular background for the differences in the duration and intensity of the effects of different psychostimulants,” adds Sitte and explains the medical and social relevance of the study, which was carried out in cooperation with the National Institute of Drug Abuse in Baltimore, the Paracelsus Medical University in Salzburg and the University of Copenhagen: “The findings from our research work will enable us to make better predictions regarding the mode of action and undesirable effects of e.g. B. new and unexplored street drugs and thus contribute to a more sustainable protection of the population. In addition, our study results may provide the basis for further research to improve the therapeutic use of psychostimulants.”
Publikation: Proceedings of the National Academy of Sciences (PNAS)
Persistent binding at dopamine transporters determines sustained psychostimulant effects;
Marco Niello, Spyridon Sideromenos, Ralph Gradisch, Ronan O’Shea, Jakob Schwazer, Julian Maier, Nina Kastner, Walter Sandtner, Kathrin Jäntsch, Carl R. Lupica, Alexander F. Hoffman, Gert Lubec, Claus J. Loland, Thomas Stockner, Daniela D Pollak, Michael H Baumann, Harald H Sitte;
DOI: 10.1073/pnas.2114204120
