Dopamine receptor interactions with GluR1 in addiction

描述（由申请人提供）： 该项目的重点是AMPA介导的兴奋性输入到丘脑核（NAc）在成瘾行为与可卡因敏化和自我管理的作用。慢性可卡因使用减少了对含有多巴胺D1和D2受体的中等多刺NAc神经元的兴奋性多巴胺能输入。本研究将探讨AMPA谷氨酸受体介导的兴奋性输入与可卡因、D1和D2多巴胺受体对成瘾行为的调节之间的不同相互作用。研究将利用体内病毒介导的基因转移，通过NAc中的GluR 1亚基上调和下调AMPA谷氨酸受体功能。由于D1和D2受体可能通过磷酸化依赖性机制与AMPA受体相互作用，因此还将检测GluR 1亚基的PKA和CaMKII/PKC抗性突变体。拟议的项目将研究GluR 1亚基在调节可卡因致敏、强化、药物摄入和使用自我管理程序测量的复发行为中的作用。研究还将通过运动和恢复中的D1/D2反应性测试来研究这种调节的药理学相互作用。

DESCRIPTION (provided by applicant): 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.