Low and high cocaine locomotor responding male Sprague-Dawley rats differ in rapid cocaine-induced regulation of striatal dopamine transporter function

Adult outbred Sprague-Dawley rats can be classified as either low or high cocaine responders (LCRs or HCRs, respectively). Importantly, LCRs and HCRs are distinguished by their differential responsiveness to acute cocaine-induced (but not baseline) locomotor activity, inhibition of the dopamine transporter (DAT) and resulting extracellular DA (HCR > LCR), as well as by repeated cocaine-induced locomotor sensitization and measures of cocaine's rewarding and reinforcing effects (LCR > HCR). Curiously, 30 min after acute cocaine HCRs exhibit greater DAT-mediated [³H]DA uptake into striatal synaptosomes than LCRs. To investigate this finding further, we measured locomotor activity, striatal [³H]DA uptake kinetics and DAT cell surface expression in LCRs and HCRs over an extended period (25-180 min) after a single relatively low-dose of cocaine (10 mg/kg, i.p.). HCRs exhibited the “predicted” locomotor response: a marked initial activation that returned to baseline by 120 min post-injection. While LCRs exhibited a >50% lower maximal locomotor response, this increase was sustained, lasting ∼33% longer than in HCRs. At 25 min post-cocaine, maximal velocity (V_max) of [³H]DA uptake was significantly higher by 25% in HCRs than LCRs, with no difference in affinity (K_m). Despite the DAT V_max difference, however, DAT surface expression did not differ between LCRs and HCRs. There was a similar trend (HCR > LCR) for DAT V_max at 40 min, but not at 150 or 180 min. These findings suggest that, compared to LCRs, HCRs have an enhanced ability to rapidly up-regulate DAT function in response to acute cocaine, which may contribute to their more “normal” cocaine-induced locomotor activation.