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Persistent binding at dopamine transporters determines sustained psychostimulant effects.

Marco NielloSpyridon SideromenosRalph GradischRonan O SheaJakob SchwazerJulian MaierNina KastnerWalter SandtnerKathrin JäntschCarl R LupicaAlexander F HoffmanGert LubecClaus J LølandThomas StocknerDaniela D PollakMichael H BaumannHarald H Sitte
Published in: Proceedings of the National Academy of Sciences of the United States of America (2023)
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 k off ) 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.
Keyphrases
  • attention deficit hyperactivity disorder
  • emergency department
  • type diabetes
  • binding protein
  • early onset
  • dna binding
  • prefrontal cortex
  • mass spectrometry
  • high fat diet induced
  • working memory
  • high speed