High cocaine locomotor responding rats have greater hippocampal norepinephrine transporter function than low cocaine locomotor responding rats after acute cocaine exposure

Cocaine inhibits dopamine (DA) and norepinephrine (NE) uptake by blocking DA and NE transporters (DATs and NETs, respectively). We classify outbred male Sprague‐Dawley rats given an acute low dose of cocaine (10 mg/kg, i.p.) as either low or high cocaine responders (LCRs or HCRs, respectively), based on the median split of their first 30 min of cocaine‐induced locomotor activity. This model of differential individual responsiveness to cocaine has revealed that LCRs, which exhibit greater cocaine‐induced locomotor sensitization, reward and reinforcement, have 33% more striatal DAT and 41% more hippocampal NET binding sites at baseline than HCRs. In contrast, 25 min after acute cocaine, maximal uptake velocity (Vmax) of striatal DATs is 25% higher in HCRs than LCRs. To examine if LCR/HCR NET function also differs, we analyzed NET kinetic parameters in hippocampal synaptosomes 35 min after acute cocaine using 15 nM [ 3 H]NE +/− one of 7 concentrations of unlabeled NE. As expected, HCRs (n = 9) exhibited ~4‐fold greater cocaine‐induced locomotor activity than LCRs (n = 9). [ 3 H]NE uptake Vmax was significantly higher by 33% in HCRs than LCRs (1.6 vs. 1.2 pmol/mg protein/min, respectively; p < 0.05), with no difference in affinity (Km, ~78 nM). Our results suggest that, as with DATs, HCRs respond to acute cocaine exposure with a greater rapid compensatory up‐regulation of NET function than LCRs. Supported by DA004216 & DA015050.