Regional differences in extracellular dopamine and serotonin assessed by in vivo microdialysis in mice lacking dopamine and/or serotonin transporters

Cocaine conditioned place preference (CPP) is intact in dopamine transporter (DAT) knockout (KO) mice and enhanced in serotonin transporter (SERT) KO mice. However, cocaine CPP is eliminated in double-KO mice with no DAT and either no or one SERT gene copy. To help determine mechanisms underlying these effects, we now report examination of baselines and drug-induced changes of extracellular dopamine (DA _ex) and serotonin (5-HT _ex) levels in microdialysates from nucleus accumbens (NAc), caudate putamen (CPu), and prefrontal cortex (PFc) of wild-type, homozygous DAT- or SERT-KO and heterozygous or homozygous DAT/SERT double-KO mice, which are differentially rewarded by cocaine. Cocaine fails to increase DA _ex in NAc of DAT-KO mice. By contrast, systemic cocaine enhances DA _ex in both CPu and PFc of DAT-KO mice though local cocaine fails to affect DA _ex in CPu. Adding SERT to DAT deletion attenuates the cocaine-induced DA _ex increases found in CPu, but not those found in PFc. The selective SERT blocker fluoxetine increases DA _ex in CPu of DAT-KO mice, while cocaine and the selective DAT blocker GBR12909 increase S-HT _ex in CPu of SERT-KO mice. These data provide evidence that (a) cocaine increases DA _ex in PFc independently of DAT and that (b), in the absence of SERT, CPu levels of 5-HT _ex can be increased by blocking DAT. Cocaine-induced alterations in CPu DA levels in DAT-, SERT-, and DAT/SERT double-KO mice appear to provide better correlations with cocaine CPP than cocaine-induced DA level alterations in NAc or PFc.