Cocaine self‐administration‐induced sensitization of the dopamine system (LB621)

Abstract

The ability of cocaine to bind to, and inhibit the dopamine transporter (DAT) mediates the reinforcing effects of the compound and is essential for the maintenance of self‐administration behaviors. As such, it is important to determine the changes in cocaine potency following cocaine self‐administration as they have important implications for 1.) how the DAT changes in response to repeated psychostimulant administration as well as 2.) changes in the reinforcing potential for drugs such as cocaine. Although sensitization paradigms, which result in sensitization of cocaine‐induced locomotor behavior and dopamine (DA) overflow following repeated 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) conditions can result in enhanced cocaine potency at the DAT in the nucleus accumbens immediately following self‐administration. However, traditional sensitization paradigms often show enhanced effects following withdrawal/abstinence periods. Here we aimed to determine a time‐course of IntA‐induced DA sensitization and how a seven‐day abstinence period influences these effects. We show that while three days of IntA is not sufficient to alter evoked DA release, a seven‐day abstinence period following IntA results in augmented release. Additionally, cocaine potency is enhanced following as little as 3‐day IntA and further augmented following an abstinence period. Further, IntA plus abstinence enhanced cocaine‐induced DA release as compared to all other groups, demonstrating that following abstinence, cocaine’s ability to increase DA release and inhibit uptake at the DAT, two separate mechanisms for increasing DA levels, is augmented. Thus, the enhanced cocaine potency and cocaine‐induced release following abstinence could enhance the reinforcing efficacy and facilitate drug‐seeking for cocaine following periods of abstinence/withdrawal.Grant Funding Source: Supported by NIH grants from NIDA [R01 DA024095, R01 DA03016, R01 DA14030, P50DA006634 (SRJ), T32 DA007246 and F31 DA031533 (ESC)]