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Molecular Mechanisms Underlying the Rewarding Effects of Cocaine
Author(s) -
HALL F SCOTT,
SORA ICHIRO,
DRGONOVA JANA,
LI XIAOFEI,
GOEB MICHELLE,
UHL GEORGE R.
Publication year - 2004
Publication title -
annals of the new york academy of sciences
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.712
H-Index - 248
eISSN - 1749-6632
pISSN - 0077-8923
DOI - 10.1196/annals.1316.006
Subject(s) - monoaminergic , serotonin transporter , dopamine transporter , conditioned place preference , dopamine , knockout mouse , norepinephrine transporter , serotonin , fluoxetine , gene knockout , transporter , monoamine neurotransmitter , pharmacology , endocrinology , psychology , medicine , neuroscience , biology , norepinephrine , gene , dopaminergic , receptor , genetics
A bstract : 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.