title: Cocaine-insensitive dopamine transporters with intact substrate transport produced by self-administration.
abstract: BACKGROUND
  Psychomotor stimulant drugs such as cocaine and amphetamine activate brain dopamine (DA) neurotransmission and support self-administration in humans and laboratory animals. Cocaine amplifies DA signaling by blocking the DA transporter (DAT), and this has been described as the most important mechanism underlying cocaine's reinforcing effects. Amphetamine has the added mechanism of reverse transport of intracellular DA through the DAT.
  
  
  METHODS
  We used cocaine and amphetamine self-administration under a fixed-ratio 1 schedule followed by microdialysis in freely moving rats to measure extracellular DA levels and fast scan cyclic voltammetry in brain slices to measure subsecond DA release and uptake parameters.
  
  
  RESULTS
  Following a high dose (1.5 mg/kg intravenous) cocaine self-administration paradigm (40 injections/day × 5 days), the DAT was markedly less sensitive to cocaine, as measured by microdialysis and voltammetry in the nucleus accumbens core. In contrast, the DAT substrate amphetamine retained the same efficacy at the DAT in cocaine self-administering animals, and amphetamine did not mimic cocaine's effect on the DAT when self-administered. A single session of cocaine self-administration caused a significant decrease in the ability of cocaine to inhibit the DAT, a finding that may provide a neurochemical basis for rapid tolerance. The effects of cocaine returned to normal within a few weeks following cessation of self-administration.
  
  
  CONCLUSIONS
  Here, we, for the first time, demonstrate an in vivo, pharmacologically induced alteration in the sensitivity of the DAT to cocaine that is specific to cocaine, spares DAT and substrate/releaser interactions, and is independent of maximal rate of DA uptake (V(max)).
authors.affiliation: Department of Physiology and Pharmacology, Wake Forest University School of Medicine, Winston-Salem, North Carolina 27157, USA.
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Ferris
authors.forename: Yolanda
authors.initials: Y
authors.lastname: Mateo
authors.forename: David C S
authors.initials: DC
authors.lastname: Roberts
authors.forename: Sara R
authors.initials: SR
authors.lastname: Jones
mesh_terms: D000661:Amphetamine / Q000008:administration & dosage / Q000494:pharmacology; D000818:Animals; D003042:Cocaine / Q000008:administration & dosage / Q000494:pharmacology*; D004298:Dopamine / Q000378:metabolism; D050483:Dopamine Plasma Membrane Transport Proteins / Q000187:drug effects*; D018765:Dopamine Uptake Inhibitors / Q000008:administration & dosage / Q000494:pharmacology; D004361:Drug Tolerance; D055664:Electrochemical Techniques / Q000379:methods; D008297:Male; D017551:Microdialysis / Q000379:methods; D009714:Nucleus Accumbens / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D012646:Self Administration / Q000379:methods*
chemical_list: D050483:Dopamine Plasma Membrane Transport Proteins; D018765:Dopamine Uptake Inhibitors; D000661:Amphetamine; D003042:Cocaine; D004298:Dopamine
references.citation: Mol Pharmacol. 2003 Mar;63(3):653-8
references.pmid: 12606774
references.citation: J Neurosci. 2009 May 27;29(21):6794-808
references.pmid: 19474307
references.citation: J Neurochem. 2006 Jan;96(1):267-82
references.pmid: 16300629
references.citation: Synapse. 2005 Nov;58(2):72-94
references.pmid: 16088952
references.citation: Eur J Pharmacol. 2003 Oct 31;479(1-3):71-82
references.pmid: 14612139
references.citation: Semin Cell Dev Biol. 2009 Jun;20(4):411-7
references.pmid: 19560046
references.citation: J Biol Chem. 1994 Jun 10;269(23):15985-8
references.pmid: 8206893
references.citation: Science. 1975 Feb 14;187(4176):547-9
references.pmid: 1114313
references.citation: J Pharmacol Exp Ther. 2009 Oct;331(1):204-11
references.pmid: 19602552
references.citation: J Neurochem. 2005 Jul;94(2):352-9
references.pmid: 15998286
references.citation: Neuropharmacology. 2005 Nov;49(6):750-8
references.pmid: 16212991
references.citation: Mol Pharmacol. 2002 Feb;61(2):436-45
references.pmid: 11809869
references.citation: Brain Res. 2006 Jun 20;1095(1):148-53
references.pmid: 16712814
references.citation: Neuropsychopharmacology. 2005 Aug;30(8):1455-63
references.pmid: 15702135
references.citation: Curr Drug Abuse Rev. 2009 May;2(2):195-213
references.pmid: 19630749
references.citation: Trends Neurosci. 2007 May;30(5):203-10
references.pmid: 17400301
references.citation: Neuropharmacology. 2008 Mar;54(3):605-12
references.pmid: 18164041
references.citation: J Neurosci. 2009 Mar 11;29(10):3328-36
references.pmid: 19279270
references.citation: J Neurochem. 2008 Jun;105(5):1683-99
references.pmid: 18248623
references.citation: J Biol Chem. 2004 May 14;279(20):21012-20
references.pmid: 15024013
references.citation: Eur J Pharmacol. 2003 Oct 31;479(1-3):139-52
references.pmid: 14612145
references.citation: Science. 1998 Oct 9;282(5387):298-300
references.pmid: 9765157
references.citation: Eur J Pharmacol. 2006 May 24;538(1-3):43-7
references.pmid: 16674939
references.citation: Brain Res. 1989 Sep 25;498(1):199-203
references.pmid: 2790475
references.citation: J Neurosci. 2001 Apr 15;21(8):2799-807
references.pmid: 11306632
references.citation: Nat Neurosci. 2008 Jul;11(7):780-9
references.pmid: 18568020
references.citation: Biochem Biophys Res Commun. 2002 Feb 8;290(5):1545-50
references.pmid: 11820798
references.citation: Psychopharmacology (Berl). 1976 Aug 17;48(3):311-8
references.pmid: 823588
references.citation: J Nucl Med. 1999 Aug;40(8):1285-91
references.pmid: 10450679
references.citation: J Neurochem. 2009 May;109(4):981-94
references.pmid: 19519772
references.citation: J Neurosci Methods. 1996 May;66(1):1-11
references.pmid: 8794935
references.citation: Neuropsychopharmacology. 2001 Feb;24(2):97-129
references.pmid: 11120394
references.citation: J Neurosci. 1999 Sep 15;19(18):7699-710
references.pmid: 10479674
references.citation: J Psychopharmacol. 1999 Dec;13(4):337-45
references.pmid: 10667609
references.citation: Pharmacol Biochem Behav. 1997 Jul;57(3):441-7
references.pmid: 9218268
references.citation: J Subst Abuse Treat. 2001 Oct;21(3):111-7
references.pmid: 11728784
references.citation: J Pharmacol Exp Ther. 2009 Mar;328(3):912-20
references.pmid: 19098163
references.citation: J Neurochem. 1992 Aug;59(2):449-55
references.pmid: 1352798
references.citation: Proc Natl Acad Sci U S A. 2006 Jun 13;103(24):9333-8
references.pmid: 16754872
references.citation: Proc Natl Acad Sci U S A. 1996 Sep 17;93(19):10388-92
references.pmid: 8816810
references.citation: J Neurochem. 2007 Apr;101(2):377-88
references.pmid: 17250655
references.citation: Neuroscience. 1988 May;25(2):513-23
references.pmid: 3399057