Dopamine receptor interactions with GluR1 in addiction

描述(由申请人提供)： 该项目的重点是AMPA介导的伏隔核兴奋性输入(NAC)在与可卡因敏化和自我给药相关的成瘾行为中的作用。长期使用可卡因可减少兴奋性谷氨酸能传入含有多巴胺D1和D2受体的中等刺状NAc神经元。这项研究将研究AMPA谷氨酸受体介导的兴奋性输入与可卡因对成瘾行为的调节之间的不同相互作用，以及D1和D2多巴胺受体。研究将利用病毒介导的体内基因转移，通过NAC中的GluR1亚单位上调和下调AMPA谷氨酸受体的功能。由于D1和D2受体可能通过磷酸化依赖的机制与AMPA受体相互作用，因此也将测试GluR1亚单位的PKA和CaMKII/PKC抗性突变体。拟议的项目将调查GluR1亚单位在调节可卡因敏化、强化、药物摄取和通过自我给药程序测量的复发行为中的作用。研究还将通过测试运动和恢复过程中的D1/D2反应性来研究这一调节背后的药物相互作用。

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.