Amphetamine induces dopamine efflux through a dopamine transporter channel.
Drugs of abuse, including cocaine, amphetamine (AMPH), and heroin, elevate extracellular dopamine (DA) levels in the brain, thereby altering the activity/plasticity of reward circuits and precipitating addiction. The physiological release of DA occurs through the calcium-dependent fusion of a synaptic vesicle with the plasma membrane. Extracellular DA is cleared by uptake through the Na+/Cl- -dependent DA transporter (DAT). In contrast, the substrate AMPH induces nonvesicular release of DA mediated by DAT. Extracellular AMPH is generally believed to trigger DA efflux through DAT by facilitating exchange for cytosolic DA. Here, in outside-out patches from heterologous cells stably expressing DAT or from dopaminergic neurons, by using ionic conditions in the patch pipette that mimic those produced by AMPH stimulation, we report that AMPH causes DAT-mediated DA efflux by two independent mechanisms: (i) a slow process consistent with an exchange mechanism and (ii) a process that results in rapid (millisecond) bursts of DA efflux through a channel-like mode of DAT. Because channel-like release of DA induced by AMPH is rapid and contains a large number of DA molecules, with a single burst of DA on par with a quantum of DA from exocytotic release of a vesicle, this burst mode of release may play a role in the synaptic actions and psychostimulant properties of AMPH and related compounds. Unlike AMPH, the endogenous substrate DA, when present on both sides of the plasma membrane, inhibits this channel-like activity, thereby suggesting that the DAT channel-like mode cannot accumulate DA against a concentration gradient.
Kahlig
Kristopher M
KM
Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, 465 21st Avenue South, Nashville, TN 37232-8548, USA.
Binda
Francesca
F
Khoshbouei
Habibeh
H
Blakely
Randy D
RD
McMahon
Douglas G
DG
Javitch
Jonathan A
JA
Galli
Aurelio
A
D000661:Amphetamine / Q000494:pharmacology*; D001692:Biological Transport; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D002460:Cell Line; D004298:Dopamine / Q000378:metabolism*; D006801:Humans; D018613:Microscopy, Confocal; D018408:Patch-Clamp Techniques
D000661:Amphetamine; D004298:Dopamine
Biotechniques. 1998 Aug;25(2):240-4
9714883
Proc Natl Acad Sci U S A. 1998 Aug 4;95(16):9238-43
9689064
Proc Natl Acad Sci U S A. 1998 Oct 27;95(22):13260-5
9789076
Proc Natl Acad Sci U S A. 2004 Nov 9;101(45):16046-51
15520385
Rev Neurosci. 2000;11(2-3):159-212
10718152
Science. 2001 Sep 28;293(5539):2465-70
11577238
Nat Neurosci. 2002 Oct;5(10):971-8
12352983
Nat Rev Neurosci. 2003 Jan;4(1):13-25
12511858
Proc Natl Acad Sci U S A. 2003 Jan 21;100(2):386-8
12525688
J Neurosci. 2003 Mar 1;23(5):1697-709
12629174
J Biol Chem. 2003 Apr 4;278(14):12070-7
12556446
Ann N Y Acad Sci. 2003 Apr;986:116-26
12763784
J Neurosci. 2003 Jul 2;23(13):5835-45
12843288
Science. 2003 Aug 1;301(5633):610-5
12893935
Eur J Pharmacol. 2003 Oct 31;479(1-3):153-8
14612146
J Biol Chem. 2004 Mar 5;279(10):8966-75
14699142
PLoS Biol. 2004 Mar;2(3):E78
15024426
Trends Neurosci. 2004 May;27(5):270-7
15111009
Mol Pharmacol. 2004 Jul;66(1):137-43
15213305
Neuroreport. 2004 Aug 6;15(11):1761-5
15257143
Nature. 1966 Aug 27;211(5052):969-70
5968307
Nat New Biol. 1972 Feb 16;235(59):217-8
4334931
Proc Natl Acad Sci U S A. 1991 Dec 1;88(23):10754-8
1961743
Trends Pharmacol Sci. 1993 Feb;14(2):43-9
8480373
J Neurosci. 1994 Oct;14(10):6084-93
7931564
J Exp Biol. 1994 Nov;196:263-81
7823027
J Physiol. 1982 Feb;323:211-27
6808119
J Neurosci. 1995 May;15(5 Pt 2):4102-8
7751968
Proc Natl Acad Sci U S A. 1996 Jan 23;93(2):723-7
8570623
Nature. 1996 Feb 15;379(6566):606-12
8628395
Proc Natl Acad Sci U S A. 1996 Aug 6;93(16):8671-6
8710929
Curr Opin Neurobiol. 1996 Jun;6(3):294-302
8794089
Biophys J. 1996 Dec;71(6):3126-35
8968583
J Neurosci. 1997 Feb 1;17(3):960-74
8994051
J Neurosci. 1997 May 15;17(10):3401-11
9133366
J Pharmacol Exp Ther. 1998 Feb;284(2):592-8
9454802
J Neurochem. 1998 Sep;71(3):1289-97
9721755