Low or high cocaine responding rats differ in striatal extracellular dopamine levels and dopamine transporter number

Both humans and animals exhibit marked individual differences in cocaine responsiveness. By using the median split of cocaine-induced locomotor activity, we have classified outbred male Sprague-Dawley rats as either low or high cocaine responders (LCRs or HCRs, respectively). LCR/HCR classification predicts differences in cocaine inhibition of striatal dopamine (DA) transporters (DATs), cocaine-induced locomotor sensitization, cocaine-conditioned place preference, and motivation to self-administer cocaine. In this study, we used in vivo microdialysis to investigate whether the differential cocaine inhibition of DATs in LCRs and HCRs is translated into differential extracellular DA levels. Paralleling their locomotor profiles, LCRs and HCRS had similar basal extracellular DA levels in dorsal striatum (dSTR) and nucleus accumbens (NAc); after acute cocaine injection (10 mg/kg i.p.), HCRs showed greater cocaine-induced increases in DA than LCRs, with more pronounced differences in NAc. After repeated cocaine injection, LCRs and HCRs no longer differed in cocaine-induced locomotor activity or extracellular DA. To further explore the differential susceptibility of LCR/HCR DATs to cocaine, we used in vitro [(3)H]2-carbomethoxy-3-(4-fluorophenyl)tropane ([(3)H]WIN 35,428) binding and quantitative autoradiography to measure the number of DAT binding sites and cocaine's affinity for them. After acute cocaine administration, HCRs had fewer DAT binding sites in dSTR and NAc shell, compared to LCRs. No LCR/HCR differences were observed in DAT number after repeated cocaine injection or in cocaine's affinity. Our findings suggest that levels of striatal extracellular DA and DATs both make important contributions to initial differences in cocaine activation, which in LCRs/HCRs predict differential cocaine reward and reinforcement.