Cocaine-insensitive dopamine transporters with intact substrate transport produced by self-administration.
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)).
Ferris
Mark J
MJ
Department of Physiology and Pharmacology, Wake Forest University School of Medicine, Winston-Salem, North Carolina 27157, USA.
Mateo
Yolanda
Y
Roberts
David C S
DC
Jones
Sara R
SR
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*
D050483:Dopamine Plasma Membrane Transport Proteins; D018765:Dopamine Uptake Inhibitors; D000661:Amphetamine; D003042:Cocaine; D004298:Dopamine
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