Persistent binding at dopamine transporters determines sustained psychostimulant effects

Research output: Contribution to journal › Journal article › Research › peer-review

Standard

Persistent binding at dopamine transporters determines sustained psychostimulant effects. / Niello, Marco; Sideromenos, Spyridon; Gradisch, Ralph; O'Shea, Ronan; Schwazer, Jakob; Maier, Julian; Kastner, Nina; Sandtner, Walter; Jäntsch, Kathrin; Lupica, Carl R.; Hoffman, Alexander F.; Lubec, Gert; Loland, Claus J.; Stockner, Thomas; Pollak, Daniela D.; Baumann, Michael H.; Sitte, Harald H.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 120, No. 6, e2114204120, 2023.

Research output: Contribution to journal › Journal article › Research › peer-review

Harvard

Niello, M, Sideromenos, S, Gradisch, R, O'Shea, R, Schwazer, J, Maier, J, Kastner, N, Sandtner, W, Jäntsch, K, Lupica, CR, Hoffman, AF, Lubec, G, Loland, CJ, Stockner, T, Pollak, DD, Baumann, MH & Sitte, HH 2023, 'Persistent binding at dopamine transporters determines sustained psychostimulant effects', Proceedings of the National Academy of Sciences of the United States of America, vol. 120, no. 6, e2114204120. https://doi.org/10.1073/pnas.2114204120

APA

Niello, M., Sideromenos, S., Gradisch, R., O'Shea, R., Schwazer, J., Maier, J., Kastner, N., Sandtner, W., Jäntsch, K., Lupica, C. R., Hoffman, A. F., Lubec, G., Loland, C. J., Stockner, T., Pollak, D. D., Baumann, M. H., & Sitte, H. H. (2023). Persistent binding at dopamine transporters determines sustained psychostimulant effects. Proceedings of the National Academy of Sciences of the United States of America, 120(6), [e2114204120]. https://doi.org/10.1073/pnas.2114204120

Vancouver

Niello M, Sideromenos S, Gradisch R, O'Shea R, Schwazer J, Maier J et al. Persistent binding at dopamine transporters determines sustained psychostimulant effects. Proceedings of the National Academy of Sciences of the United States of America. 2023;120(6). e2114204120. https://doi.org/10.1073/pnas.2114204120

Author

Niello, Marco ; Sideromenos, Spyridon ; Gradisch, Ralph ; O'Shea, Ronan ; Schwazer, Jakob ; Maier, Julian ; Kastner, Nina ; Sandtner, Walter ; Jäntsch, Kathrin ; Lupica, Carl R. ; Hoffman, Alexander F. ; Lubec, Gert ; Loland, Claus J. ; Stockner, Thomas ; Pollak, Daniela D. ; Baumann, Michael H. ; Sitte, Harald H. / Persistent binding at dopamine transporters determines sustained psychostimulant effects. In: Proceedings of the National Academy of Sciences of the United States of America. 2023 ; Vol. 120, No. 6.

Bibtex

@article{1be19fb2465a42209ada0586f21fc04c,

title = "Persistent binding at dopamine transporters determines sustained psychostimulant effects",

abstract = "Psychostimulants interacting with the dopamine transporter (DAT) can be used illicitly or for the treatment of specific neuropsychiatric disorders. However, they can also produce severe and persistent adverse events. Often, their pharmacological properties in vitro do not fully correlate to their pharmacological profile in vivo. Here, we investigated the pharmacological effects of enantiomers of pyrovalerone, α-pyrrolidinovalerophenone, and 3,4-methylenedioxypyrovalerone as compared to the traditional psychostimulants cocaine and methylphenidate, using a variety of in vitro, computational, and in vivo approaches. We found that in vitro drug-binding kinetics at DAT correlate with the time-course of in vivo psychostimulant action in mice. In particular, a slow dissociation (i.e., slow koff) of S-enantiomers of pyrovalerone analogs from DAT predicts their more persistent in vivo effects when compared to cocaine and methylphenidate. Overall, our findings highlight the critical importance of drug-binding kinetics at DAT for determining the in vivo profile of effects produced by psychostimulant drugs. ",

keywords = "cathinones, dopamine transporter, drug-binding kinetics, new psychoactive substances, psychostimulants",

author = "Marco Niello and Spyridon Sideromenos and Ralph Gradisch and Ronan O'Shea and Jakob Schwazer and Julian Maier and Nina Kastner and Walter Sandtner and Kathrin J{\"a}ntsch and Lupica, {Carl R.} and Hoffman, {Alexander F.} and Gert Lubec and Loland, {Claus J.} and Thomas Stockner and Pollak, {Daniela D.} and Baumann, {Michael H.} and Sitte, {Harald H.}",

note = "Publisher Copyright: {\textcopyright} 2023 the Author(s).",

year = "2023",

doi = "10.1073/pnas.2114204120",

language = "English",

volume = "120",

journal = "Proceedings of the National Academy of Sciences of the United States of America",

issn = "0027-8424",

publisher = "The National Academy of Sciences of the United States of America",

number = "6",

}

RIS

TY - JOUR

T1 - Persistent binding at dopamine transporters determines sustained psychostimulant effects

AU - Niello, Marco

AU - Sideromenos, Spyridon

AU - Gradisch, Ralph

AU - O'Shea, Ronan

AU - Schwazer, Jakob

AU - Maier, Julian

AU - Kastner, Nina

AU - Sandtner, Walter

AU - Jäntsch, Kathrin

AU - Lupica, Carl R.

AU - Hoffman, Alexander F.

AU - Lubec, Gert

AU - Loland, Claus J.

AU - Stockner, Thomas

AU - Pollak, Daniela D.

AU - Baumann, Michael H.

AU - Sitte, Harald H.

PY - 2023

Y1 - 2023

N2 - Psychostimulants interacting with the dopamine transporter (DAT) can be used illicitly or for the treatment of specific neuropsychiatric disorders. However, they can also produce severe and persistent adverse events. Often, their pharmacological properties in vitro do not fully correlate to their pharmacological profile in vivo. Here, we investigated the pharmacological effects of enantiomers of pyrovalerone, α-pyrrolidinovalerophenone, and 3,4-methylenedioxypyrovalerone as compared to the traditional psychostimulants cocaine and methylphenidate, using a variety of in vitro, computational, and in vivo approaches. We found that in vitro drug-binding kinetics at DAT correlate with the time-course of in vivo psychostimulant action in mice. In particular, a slow dissociation (i.e., slow koff) of S-enantiomers of pyrovalerone analogs from DAT predicts their more persistent in vivo effects when compared to cocaine and methylphenidate. Overall, our findings highlight the critical importance of drug-binding kinetics at DAT for determining the in vivo profile of effects produced by psychostimulant drugs.

AB - Psychostimulants interacting with the dopamine transporter (DAT) can be used illicitly or for the treatment of specific neuropsychiatric disorders. However, they can also produce severe and persistent adverse events. Often, their pharmacological properties in vitro do not fully correlate to their pharmacological profile in vivo. Here, we investigated the pharmacological effects of enantiomers of pyrovalerone, α-pyrrolidinovalerophenone, and 3,4-methylenedioxypyrovalerone as compared to the traditional psychostimulants cocaine and methylphenidate, using a variety of in vitro, computational, and in vivo approaches. We found that in vitro drug-binding kinetics at DAT correlate with the time-course of in vivo psychostimulant action in mice. In particular, a slow dissociation (i.e., slow koff) of S-enantiomers of pyrovalerone analogs from DAT predicts their more persistent in vivo effects when compared to cocaine and methylphenidate. Overall, our findings highlight the critical importance of drug-binding kinetics at DAT for determining the in vivo profile of effects produced by psychostimulant drugs.

KW - cathinones

KW - dopamine transporter

KW - drug-binding kinetics

KW - new psychoactive substances

KW - psychostimulants

U2 - 10.1073/pnas.2114204120

DO - 10.1073/pnas.2114204120

M3 - Journal article

C2 - 36730201

AN - SCOPUS:85147318750

VL - 120

JO - Proceedings of the National Academy of Sciences of the United States of America

JF - Proceedings of the National Academy of Sciences of the United States of America

SN - 0027-8424

IS - 6

M1 - e2114204120

ER -

ID: 335665939

Department of Neuroscience