| Sensitization is a process by which drug effects are intensified with repeated administration. The incentive motivational hypothesis of sensitization, that neuronal adaptations in dopamine (DA) pathways facilitate augmented behavioral responding by enhancing motivation, has prompted studies examining the specific neuronal correlates of behavioral sensitization. At present it is unclear whether DA transporter (DAT) regulation is obligatory for cocaine-induced behavioral sensitization. The aim of this dissertation was to adapt high-speed chronoamperometry for recordings of DA clearance signals in brains of freely-moving rats, so that alterations in DAT function could be measured simultaneously with behavior.;We first established that DA clearance signals were sensitive to the DAT inhibitors nomifensine and cocaine, suggesting that our clearance measurements primarily reflected uptake by DAT. However, we observed that locomotor responsiveness to acute cocaine was characterized by marked individual variability. Therefore, rats were categorized as either low or high cocaine responders (LCRs or HCRs, respectively), based on their differential initial locomotor activity to a low dose of cocaine (10 mg/kg, i.p.). Concomitant electrochemical recordings revealed that cocaine did not change DA clearance in nucleus accumbens of LCRs, whereas HCRs exhibited changes consistent with DAT inhibition. Overall, the acute cocaine-induced changes in DA clearance indices accounted for 20--40% of the variation in initial behavioral responsiveness to cocaine.;Cocaine (10 mg/kg) was administered to the same rats for six additional days. Only LCRs expressed cocaine-induced locomotor sensitization on the fifth through seventh days of the repeated treatment, and this was accompanied by potentiated cocaine-induced inhibition of DA clearance. These sensitized behavioral and electrochemical responses to cocaine persisted in LCRs after seven days of withdrawal. In contrast, baseline behavioral and clearance indices were unaltered by repeated cocaine or following withdrawal. Likewise, behavioral and clearance indices in HCRs, which resembled the sensitized responses of LCRs, were unchanged by repeated cocaine or following withdrawal. Taken together, our findings emphasize the importance of characterizing individual responses to cocaine. They also suggest that increased DAT inhibition by cocaine is required for locomotor sensitization and that DAT serves as a common substrate for mediating both initial and sensitized locomotor responses to cocaine. |
