The proposed project focuses on the role of AMPA-mediated excitatory input to the nucleus accumbens (NAc) in addictive behavior associated with cocaine sensitization and self-administration. Chronic cocaine use reduces excitatory glutamatergic input to medium spiny NAc neurons containing dopamine D1 and D2 receptors. The studies in this proposal will investigate distinct interactions between excitatory input mediated by AMPA glutamate receptors and the regulation of addictive behavior by cocaine, and D1 and D2 dopamine receptors. Studies will utilize viral-mediated gene transfer in vivo to up- and down-regulate AMPA glutamate receptor function via the GluR1 subunit in the NAc. Since D1 and D2 receptors may interact with AMPA receptors via phosphorylation-dependent mechanisms, PKA- and CaMKII/PKC-resistant mutants of the GluR1 subunit will also be tested. The proposed projects will investigate the role of the GluR1 subunit in regulating cocaine sensitization, reinforcement, drug intake, and relapse behavior measured using a self-administration procedure. Studies will also investigate the pharmacological interactions that underlie this regulation with tests of D1/D2 responsiveness in locomotion and reinstatement.
