Click here to close
Hello! We notice that you are using Internet Explorer, which is not supported by Xenbase and may cause the site to display incorrectly.
We suggest using a current version of Chrome,
FireFox, or Safari.
S(+)amphetamine induces a persistent leak in the human dopamine transporter: molecular stent hypothesis.
Rodriguez-Menchaca AA, Solis E, Cameron K, De Felice LJ.
???displayArticle.abstract???
Wherever they are located, dopamine transporters (DATs) clear dopamine (DA) from the extracellular milieu to help regulate dopaminergic signalling. Exposure to amphetamine (AMPH) increases extracellular DA in the synaptic cleft, which has been ascribed to DAT reverse transport. Increased extracellular DA prolongs postsynaptic activity and reinforces abuse and hedonic behaviour. Xenopus laevis oocytes expressing human (h) DAT were voltage-clamped and exposed to DA, R(-)AMPH, or S(+)AMPH. At -60mV, near neuronal resting potentials, S(+)AMPH induced a depolarizing current through hDAT, which after removing the drug, persisted for more than 30 min. This persistent leak in the absence of S(+)AMPH was in contrast to the currents induced by R(-)AMPH and DA, which returned to baseline immediately after their removal. Our data suggest that S(+)AMPH and Na(+) carry the initial S(+)AMPH-induced current, whereas Na+ and Cl(-) carry the persistent leak current. We propose that the persistent current results from the internal action of S(+)AMPH on hDAT because the temporal effect was consistent with S(+)AMPH influx, and intracellular S(+)AMPH activated the effect. The persistent current was dependent on Na(+) and was blocked by cocaine. Intracellular injection of S(+)AMPH also activated a DA-induced persistent leak current. We report a hitherto unknown action of S(+)AMPH on hDAT that potentially affects AMPH-induced DA release. We propose that internal S(+)AMPH acts as a molecular stent that holds the transporter open even after external S(+)AMPH is removed. Amphetamine-induced persistent leak currents are likely to influence dopaminergic signalling, DA release mechanisms, and amphetamine abuse.
Amara,
Neurotransmitter transporters as molecular targets for addictive drugs.
1998, Pubmed
Amara,
Neurotransmitter transporters as molecular targets for addictive drugs.
1998,
Pubmed Burnette,
Human norepinephrine transporter kinetics using rotating disk electrode voltammetry.
1996,
Pubmed Carvelli,
Dopamine transporters depolarize neurons by a channel mechanism.
2004,
Pubmed Carvelli,
Dopamine transporter/syntaxin 1A interactions regulate transporter channel activity and dopaminergic synaptic transmission.
2008,
Pubmed DeFelice,
Transporters as channels.
2007,
Pubmed Erreger,
Currents in response to rapid concentration jumps of amphetamine uncover novel aspects of human dopamine transporter function.
2008,
Pubmed Falkenburger,
Dendrodendritic inhibition through reversal of dopamine transport.
2001,
Pubmed Fischer,
Chemical release of dopamine from striatal homogenates: evidence for an exchange diffusion model.
1979,
Pubmed Fleckenstein,
New insights into the mechanism of action of amphetamines.
2007,
Pubmed Furman,
Dopamine and amphetamine rapidly increase dopamine transporter trafficking to the surface: live-cell imaging using total internal reflection fluorescence microscopy.
2009,
Pubmed Galici,
Selective decreases in amphetamine self-administration and regulation of dopamine transporter function in diabetic rats.
2003,
Pubmed Galli,
Drosophila serotonin transporters have voltage-dependent uptake coupled to a serotonin-gated ion channel.
1997,
Pubmed
,
Xenbase Galli,
Patch-clamp and amperometric recordings from norepinephrine transporters: channel activity and voltage-dependent uptake.
1998,
Pubmed Giros,
Hyperlocomotion and indifference to cocaine and amphetamine in mice lacking the dopamine transporter.
1996,
Pubmed Gu,
Cloned catecholamine transporters expressed in polarized epithelial cells: sorting, drug sensitivity, and ion-coupling stoichiometry.
1998,
Pubmed Ingram,
Dopamine transporter-mediated conductances increase excitability of midbrain dopamine neurons.
2002,
Pubmed Ingram,
Arachidonic acid stimulates a novel cocaine-sensitive cation conductance associated with the human dopamine transporter.
2000,
Pubmed
,
Xenbase Iversen,
Neurotransmitter transporters and their impact on the development of psychopharmacology.
2006,
Pubmed Iwamoto,
Na+, Cl-, and pH dependence of the human choline transporter (hCHT) in Xenopus oocytes: the proton inactivation hypothesis of hCHT in synaptic vesicles.
2006,
Pubmed
,
Xenbase Jones,
Mechanisms of amphetamine action revealed in mice lacking the dopamine transporter.
1998,
Pubmed Kahlig,
Amphetamine induces dopamine efflux through a dopamine transporter channel.
2005,
Pubmed Khoshbouei,
Amphetamine-induced dopamine efflux. A voltage-sensitive and intracellular Na+-dependent mechanism.
2003,
Pubmed Machaca,
Asymmetrical distribution of Ca-activated Cl channels in Xenopus oocytes.
1998,
Pubmed
,
Xenbase Mofenson,
Letter: Physostigmine as an antidote: use with caution.
1975,
Pubmed Nelson,
The family of Na+/Cl- neurotransmitter transporters.
1998,
Pubmed Nelson,
The significance of molecular slips in transport systems.
2002,
Pubmed Petersen,
Ionic interactions in the Drosophila serotonin transporter identify it as a serotonin channel.
1999,
Pubmed
,
Xenbase Piscitelli,
Neurotransmitter/sodium symporter orthologue LeuT has a single high-affinity substrate site.
2010,
Pubmed Potkin,
Phenylethylamine in paranoid chronic schizophrenia.
1979,
Pubmed Romanelli,
Clinical effects and management of methamphetamine abuse.
2006,
Pubmed Rudnick,
Bioenergetics of neurotransmitter transport.
1998,
Pubmed Rudnick,
Ion-coupled neurotransmitter transport: thermodynamic vs. kinetic determinations of stoichiometry.
1998,
Pubmed Samuvel,
Dysregulation of dopamine transporter trafficking and function after abstinence from cocaine self-administration in rats: evidence for differential regulation in caudate putamen and nucleus accumbens.
2008,
Pubmed Saunders,
Amphetamine-induced loss of human dopamine transporter activity: an internalization-dependent and cocaine-sensitive mechanism.
2000,
Pubmed Schmitz,
Amphetamine distorts stimulation-dependent dopamine overflow: effects on D2 autoreceptors, transporters, and synaptic vesicle stores.
2001,
Pubmed Seidel,
Amphetamines take two to tango: an oligomer-based counter-transport model of neurotransmitter transport explores the amphetamine action.
2005,
Pubmed Seiden,
Amphetamine: effects on catecholamine systems and behavior.
1993,
Pubmed Shan,
The substrate-driven transition to an inward-facing conformation in the functional mechanism of the dopamine transporter.
2011,
Pubmed Shi,
The mechanism of a neurotransmitter:sodium symporter--inward release of Na+ and substrate is triggered by substrate in a second binding site.
2008,
Pubmed Sonders,
Channels in transporters.
1996,
Pubmed Sonders,
Multiple ionic conductances of the human dopamine transporter: the actions of dopamine and psychostimulants.
1997,
Pubmed
,
Xenbase Sulzer,
Dopamine transport currents are promoted from curiosity to physiology.
2003,
Pubmed Sulzer,
Amphetamine redistributes dopamine from synaptic vesicles to the cytosol and promotes reverse transport.
1995,
Pubmed Sulzer,
Amphetamine and other weak bases act to promote reverse transport of dopamine in ventral midbrain neurons.
1993,
Pubmed Verstraete,
Oral fluid testing for driving under the influence of drugs: history, recent progress and remaining challenges.
2005,
Pubmed Verstraete,
Comparison of the sensitivity and specificity of six immunoassays for the detection of amphetamines in urine.
2005,
Pubmed Volz,
The role of the plasmalemmal dopamine and vesicular monoamine transporters in methamphetamine-induced dopaminergic deficits.
2007,
Pubmed Winslow,
Methamphetamine abuse.
2007,
Pubmed Yamashita,
Crystal structure of a bacterial homologue of Na+/Cl--dependent neurotransmitter transporters.
2005,
Pubmed Zhao,
Substrate-modulated gating dynamics in a Na+-coupled neurotransmitter transporter homologue.
2011,
Pubmed
