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An Unsuspected Role for Organic Cation Transporter 3 in the Actions of Amphetamine
Author(s) -
Mayer Felix Paul,
Owens Anthony W.,
Boehm Stefan,
Gether Ulrik,
Koek Wouter,
Daws Lynette C.,
Sitte Harald H.
Publication year - 2018
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2018.32.1_supplement.820.8
Subject(s) - amphetamine , dopamine transporter , dopamine , monoamine neurotransmitter , chemistry , pharmacology , neurotransmitter transporter , transporter , norepinephrine transporter , vesicular monoamine transporter 2 , serotonin , neuroscience , norepinephrine , biochemistry , biology , receptor , gene
OBJECTIVE Psychostimulants such as amphetamines exert their actions by targeting the “classical” transporters for monoamine neurotransmitters, the dopamine (DAT), norepinephrine (NET) and serotonin (SERT) transporter. However, whether organic cation transporter 3 (OCT3), a transporter recently found to play an important role in the homeostasis of monoamine signaling, contributes to the actions of amphetamine remains unknown. METHODS Bidirectional radiotracer flux studies and real‐time measurements of fluorescent substrate accumulation were applied to monitor the effects of drugs on transporter mediated uptake and release, respectively, in vitro . Furthermore, we performed high‐speed chronoamperometry experiments to determine amphetamine induced dopamine release in vivo . Locomotor activity was measured to determine the effects of amphetamine on behavior. RESULTS Here we show that a major component of amphetamine‐induced neurotransmitter efflux is mediated by OCT3 in primary neuronal cultures. High‐speed chronoamperometry revealed that the OCT3‐inhibitor decynium‐22 (D22) markedly attenuated amphetamine‐induced dopamine release in striatum. This effect was lost in mice deficient in OCT3. Finally, systemically administered D22 reduced amphetamine‐induced locomotion in wild‐type but not in OCT3‐knockout mice. CONCLUSION Our findings reveal that amphetamine induces release via OCT3. Hence, this study identified an additional transporter, aside from DAT, NET and SERT, that contributes to the actions of amphetamine, which might serve as a new target for the treatment of psychostimulant abuse. Support or Funding Information Austrian Science Fund/FWF (grants F3506 and W1232 to H.H.S.) NIH MH093320 (L.C.D. & W.K.), NIH MH106978 (L.C.D.), NIH P01 DA12408 (U.G.), Danish Council for Independent Research – Medical Sciences (U.G.), Lundbeck Foundation Center for Biomembranes in Nanomedicine (U.G.), F.P.M. is a recipient of a DOC‐fellowship of the Austrian Academy of Sciences. This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .