Brief intermittent cocaine self-administration and abstinence sensitizes cocaine effects on the dopamine transporter and increases drug seeking.

Abstract

Although traditional sensitization paradigms, which result in an augmentation of cocaine-induced locomotor behavior and dopamine (DA) overflow following repeated experimenter-delivered cocaine injections, are often used as a model to study drug addiction, similar effects have been difficult to demonstrate following cocaine self-administration. We have recently shown that intermittent access (IntA) to cocaine can result in increased cocaine potency at the DA transporter (DAT); however, traditional sensitization paradigms often show enhanced effects following withdrawal/abstinence periods. Therefore, we determined a time course of IntA-induced sensitization by examining the effects of 1 or 3 days of IntA, as well as a 7-day abstinence period on DA function, cocaine potency, and reinforcement. Here we show that cocaine potency is increased following as little as 3 days of IntA and further augmented following an abstinence period. In addition, IntA plus abstinence produced greater evoked DA release in the presence of cocaine as compared with all other groups, demonstrating that following abstinence, both cocaine's ability to increase DA release and inhibit uptake at the DAT, two separate mechanisms for increasing DA levels, are enhanced. Finally, we found that IntA-induced sensitization of the DA system resulted in an increased reinforcing efficacy of cocaine, an effect that was augmented after the 7-day abstinence period. These results suggest that sensitization of the DA system may have an important role in the early stages of drug abuse and may drive the increased drug seeking and taking that characterize the transition to uncontrolled drug use. Human data suggest that intermittency, sensitization, and periods of abstinence have an integral role in the process of addiction, highlighting the importance of utilizing pre-clinical models that integrate these phenomena, and suggesting that IntA paradigms may serve as novel models of human addiction.