It is generally accepted that up-regulation of CP-AMPARs in the VTA and NAc core play key roles in cocaine addiction, with enhanced activity in the VTA contributing to the initiation of drug-taking and enhanced activity in the NAc contributing to continued pursuit of cocaine, even after prolonged withdrawal. However, to date the mechanism underlying CP-AMPAR up-regulation is poorly understood. Several lines of evidence suggest that cocaine induced increase in reactive oxygen species (ROS) may play a key role in CP-AMPAR up-regulation: 1) acute administration of a moderate dose of cocaine (15 mg/kg, i.p.) is sufficient to enhance NAc ROS activity, 2) Activation of ROS enhances AMPAR trafficking and CP-AMPAR synaptic transmission in the dorsal horn of the spinal cord, 3) withdrawal from cocaine self-administration is associated with an increase in ROS in the striatum, and 4) Blockade of ROS activation reduces cocaine self-administration behavior. However, no studies have directly evaluated the role of ROS in acute or long-term CP-AMPAR up-regulation. Therefore here, we will determine the degree to which increases in ROS contribute to acute cocaine-induced CP-AMPAR up-regulation in the VTA, and to long-term CP-AMPAR up-regulation in the NAc following cocaine withdrawal. These studies will provide fundamental insights into the potential role of ROS in CP-AMPAR up-regulation and provide critical information about the mechanism by which ROS inhibition may reduce cocaine-seeking behavior. Furthermore, these studies will lay the foundation for determining the utility of targeting ROS to reduce cocaine-taking and cocaine-seeking driven by CP-AMPARs.
Cocaine-induced increases in CP-AMPARs in the VTA and the NAc have been tightly linked to the development and persistence of addiction, respectively. However, the mechanism of CP-AMPAR up-regulation is unknown. The proposed studies address the hypothesis that cocaine-induced increases in reactive oxygen species drive and maintain CP-AMPAR up-regulation in the VTA and NAc and will provide a foundation on which to develop novel prevention and treatment strategies for cocaine addiction.
