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A quantitative model of amphetamine action on the 5‐ HT transporter
Author(s) -
Sandtner Walter,
Schmid Diethart,
Schicker Klaus,
Gerstbrein Klaus,
Koenig Xaver,
Mayer Felix P,
Boehm Stefan,
Freissmuth Michael,
Sitte Harald H
Publication year - 2014
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/bph.12520
Subject(s) - xenopus , amphetamine , biophysics , dopamine transporter , dopamine , electrophysiology , agonist , monoamine neurotransmitter , chemistry , serotonin transporter , transporter , biology , serotonin , microbiology and biotechnology , neuroscience , biochemistry , receptor , gene , dopaminergic
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. Experimental Approach Xenopus laevis oocytes and HEK 293 cells expressing human (h) SERT were voltage‐clamped and exposed to 5‐ HT , p‐chloroamphetamine ( p CA ) or methylenedioxyamphetamine (MDMA). Key Results In contrast to the currents induced by 5‐ HT , p CA ‐triggered currents through SERT decayed slowly in X enopus laevis oocytes once the agonist was removed (consistent with the molecular stent hypothesis). However, when SERT was expressed in HEK 293 cells, currents induced by 3 or 100 μM p CA decayed 10 or 100 times faster, respectively, after p CA 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.