Enhanced responsiveness to novelty and cocaine is associated with decreased basal dopamine uptake and release in the nucleus accumbens: quantitative microdialysis in rats under transient conditions.

Male rats were screened for their response to a novel environment and designated as high responders (HRs) or low responders (LRs). They then received daily injections of saline or cocaine (20 mg/kg, i.p.). Basal and cocaine-evoked extracellular dopamine (DA(ext)) levels as well as basal DA uptake rate and cocaine-evoked inhibition of uptake in the nucleus accumbens were determined on abstinence day 3 using quantitative microdialysis under transient conditions. The kinetics of uptake, dopamine transporter (DAT) expression, and (3)H-2-beta-carbomethoxy-3-beta-(4-fluorophenyl)tropane 1,5-naphthalenedisulfonate ([(3)H]WIN35428) binding were also examined. The locomotor activating effects of cocaine and the magnitude of behavioral sensitization were greater in HRs. Saline-treated HRs had lower basal uptake than LRs. DA uptake after cocaine challenge was also lower in these animals. Although basal DA(ext) did not differ, cocaine-evoked DA(ext) was greater in HRs. The K(m) and V(max) of DA uptake were higher in naive HRs than LRs, as were the K(d) and B(max) of [(3)H]WIN35428 binding. DAT protein expression did not differ. Previous cocaine exposure decreased basal DA uptake. It increased cocaine-evoked DA(ext) and decreased the cocaine-induced inhibition of uptake, especially in HRs, indicating greater DA release during cocaine challenge in this phenotype. We hypothesize that lower basal uptake in HRs results from a decrease in DAT binding affinity that is compensated for, in part, by an increased number of plasma membrane binding sites. Basal uptake, but not DA(ext), was lower in HRs, indicating lower basal DA release in HRs. The finding that cocaine-evoked DA(ext) is higher in naive and cocaine-exposed HRs suggests that the greater responsiveness of DA neurons in HRs may underlie the enhanced behavioral responses that characterize this phenotype.