These authors contributed equally.
A quantitative model of amphetamine action on the 5-HT transporter
Version of Record online: 24 JAN 2014
© 2013 The Authors. British Journal of Pharmacology published by John Wiley &. Sons Ltd on behalf of The British Pharmacological Society.
This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
British Journal of Pharmacology
Special Issue: Themed Section: Midkine. Guest Editors: Takashi Muramatsu and Kenji Kadomatsu
Volume 171, Issue 4, pages 1007–1018, February 2014
How to Cite
Sandtner, W., Schmid, D., Schicker, K., Gerstbrein, K., Koenig, X., Mayer, F. P., Boehm, S., Freissmuth, M. and Sitte, H. H. (2014), A quantitative model of amphetamine action on the 5-HT transporter. British Journal of Pharmacology, 171: 1007–1018. doi: 10.1111/bph.12520
- Issue online: 24 JAN 2014
- Version of Record online: 24 JAN 2014
- Accepted manuscript online: 20 NOV 2013 03:30AM EST
- Manuscript Accepted: 5 NOV 2013
- Manuscript Revised: 30 OCT 2013
- Manuscript Received: 4 JUL 2013
- Austrian Science Fund/FWF. Grant Numbers: F3506, F3510, P22893-B1
Background and Purpose
Amphetamines bind to the plasmalemmal transporters for the monoamines dopamine (DAT), noradrenaline (NET) and 5-HT (SERT); influx of amphetamine leads to efflux of substrates. Various models have been proposed to account for this amphetamine-induced reverse transport in mechanistic terms. A most notable example is the molecular stent hypothesis, which posits a special amphetamine-induced conformation that is not likely in alternative access models of transport. The current study was designed to evaluate the explanatory power of these models and the molecular stent hypothesis.
Xenopus laevis oocytes and HEK293 cells expressing human (h) SERT were voltage-clamped and exposed to 5-HT, p-chloroamphetamine (pCA) or methylenedioxyamphetamine (MDMA).
In contrast to the currents induced by 5-HT, pCA-triggered currents through SERT decayed slowly in Xenopus laevis oocytes once the agonist was removed (consistent with the molecular stent hypothesis). However, when SERT was expressed in HEK293 cells, currents induced by 3 or 100 μM pCA decayed 10 or 100 times faster, respectively, after pCA removal.
Conclusions and Implications
This discrepancy in decay rates is inconsistent with the molecular stent hypothesis. In contrast, a multistate version of the alternative access model accounts for all the observations and reproduces the kinetic parameters extracted from the electrophysiological recordings. A crucial feature that explains the action of amphetamines is their lipophilic nature, which allows for rapid diffusion through the membrane.