Cocaine increases dopamine uptake and cell surface expression of dopamine transporters.
In HEK 293 cells expressing the human dopamine transporter (DAT), a 10-min incubation with 10 microM cocaine followed by extensive washing resulted in a 30% increase in [3H]dopamine (DA) uptake as well as an increase in cell surface DAT in biotinylation experiments. Consistent with this novel regulation, [3H]DA uptake into synaptosomes prepared from the nucleus accumbens of rats sacrificed 30 min after a single cocaine injection (30 mg/kg) was significantly increased compared to controls (56% increase in V(max), no change in K(m)). In addition, DA clearance in the striatum of anesthetized rats was increased after local application of a low (3 pmol) but not high (65 pmol) dose of cocaine, presumably as a result of mobilization of DAT to the cell surface. Cocaine-induced increases in cell surface expression of DAT and associated changes in DA clearance represent a novel mechanism that may play a role in its addictive properties.
Daws
Lynette C
LC
Department of Pharmacology, University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Drive, MC 7764, San Antonio, Texas 78229-3900, USA.
Callaghan
Paul D
PD
Morón
José A
JA
Kahlig
Kris M
KM
Shippenberg
Toni S
TS
Javitch
Jonathan A
JA
Galli
Aurelio
A
D018686:Anesthetics, Intravenous / Q000008:administration & dosage; D000818:Animals; D001426:Bacterial Proteins / Q000096:biosynthesis / Q000235:genetics; D002460:Cell Line; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D003042:Cocaine / Q000494:pharmacology*; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism; D004298:Dopamine / Q000235:genetics / Q000493:pharmacokinetics*; D050483:Dopamine Plasma Membrane Transport Proteins; D004305:Dose-Response Relationship, Drug; D004563:Electrochemistry; D006801:Humans; D008164:Luminescent Proteins / Q000096:biosynthesis / Q000235:genetics; D008297:Male; D008562:Membrane Glycoproteins / Q000096:biosynthesis* / Q000493:pharmacokinetics; D026901:Membrane Transport Proteins / Q000096:biosynthesis* / Q000493:pharmacokinetics; D009419:Nerve Tissue Proteins; D051381:Rats; D017207:Rats, Sprague-Dawley; D013574:Synaptosomes / Q000378:metabolism; D014162:Transfection; D014316:Tritium / Q000493:pharmacokinetics; D015854:Up-Regulation / Q000187:drug effects / Q000235:genetics
D018686:Anesthetics, Intravenous; D001426:Bacterial Proteins; D050483:Dopamine Plasma Membrane Transport Proteins; D008164:Luminescent Proteins; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D009419:Nerve Tissue Proteins; C493214:SLC6A3 protein, human; C493216:Slc6a3 protein, rat; C054562:yellow fluorescent protein, Bacteria; D014316:Tritium; D003042:Cocaine; D004298:Dopamine