Molecular mechanisms underlying the rewarding effects of cocaine.
The initially surprising observation that cocaine retains its rewarding effects in dopamine transporter (DAT) knockout (KO) mice led our laboratory to examine the effects of deletion of other monoaminergic genes on cocaine reward. Our initial approach to this problem was to combine DAT KO mice with serotonin transporter (SERT) KO mice to make combined DAT/SERT KO mice. The combination of these knockouts eliminates cocaine reward as assessed in the conditioned place preference (CPP) paradigm. We have also identified evidence that, in the absence of DAT, there is greater participation in cocaine reward by serotonin (SERT) and norepinephrine (NET) transporters. Both NET and SERT blockers (nisoxetine and fluoxetine) produced significant CPPs in DAT KO mice, but not in wild-type (WT) mice. The striking elimination of cocaine CPP in combined DAT/SERT KO mice contrasts with effects that we have identified in combined NET/SERT knockout mice, which display increases in cocaine reward, and with recent reports that suggest that DAT/NET combined KOs retain substantial cocaine CPP. Overall, these studies indicate important requirements for several monoaminergic system genes to fully explain cocaine reward, in particular those expressed by dopamine and serotonin systems.
Hall
F Scott
FS
Molecular Neurobiology Branch, NIDA-IRP, NIH/DHHS, Baltimore, Maryland 21224, USA. shall@intra.nida.nih.gov
Sora
Ichiro
I
Drgonova
Jana
J
Li
Xiao-Fei
XF
Goeb
Michelle
M
Uhl
George R
GR
D000818:Animals; D016739:Behavior, Addictive / Q000235:genetics* / Q000378:metabolism; D003042:Cocaine / Q000008:administration & dosage*; D003213:Conditioning, Psychological / Q000187:drug effects / Q000502:physiology; D050483:Dopamine Plasma Membrane Transport Proteins; D008562:Membrane Glycoproteins / Q000172:deficiency / Q000235:genetics; D026901:Membrane Transport Proteins / Q000172:deficiency / Q000235:genetics; D051379:Mice; D018345:Mice, Knockout; D009419:Nerve Tissue Proteins / Q000172:deficiency / Q000235:genetics; D050484:Norepinephrine Plasma Membrane Transport Proteins; D012201:Reward; D050486:Serotonin Plasma Membrane Transport Proteins; D027981:Symporters / Q000172:deficiency / Q000235:genetics
D050483:Dopamine Plasma Membrane Transport Proteins; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D009419:Nerve Tissue Proteins; D050484:Norepinephrine Plasma Membrane Transport Proteins; D050486:Serotonin Plasma Membrane Transport Proteins; C493228:Slc6a2 protein, mouse; C493215:Slc6a3 protein, mouse; C493231:Slc6a4 protein, mouse; D027981:Symporters; D003042:Cocaine