D1 Dopamine Receptor Signaling and Cocaine Reinstatement

描述（由申请人提供）：越来越多的证据表明，伏隔核中多巴胺和谷氨酸传递的增加独立地促进了可卡因寻求的恢复，这是一种复发的动物模型。本研究的初步数据首次证明，可卡因恢复依赖于钙/钙调素依赖性蛋白激酶II （CaM-KII）介导的伏隔壳多巴胺和谷氨酸之间的相互作用。刺激伏隔核壳D1样（即D1/D5）多巴胺受体通过激活l型钙通道恢复可卡因寻找。通过向伏隔核壳注射一种CaM-KII抑制剂，也能减弱可卡因寻求的恢复。可卡因恢复与pCaM-KII增加和GluR1 AMPA谷氨酸受体S831位点磷酸化增强有关，S831位点与cam - kii依赖性AMPA受体转运到表面膜有关。最后，通过在伏隔壳内施用一种膜渗透形式的Pep2-EVKI（一种损害AMPA受体运输的肽）来减轻可卡因恢复。总之，这些结果表明，CaM-KII是伏隔核壳多巴胺和谷氨酸系统之间的关键联系，这些系统参与了大鼠可卡因启动诱导的药物寻求恢复的神经元可塑性。目前的应用将进一步验证可卡因启动诱导的可卡因寻找恢复取决于d1样多巴胺受体、PKA、l型钙通道和CaM-KII的连续激活以及CaM-KII依赖的AMPA受体亚基向伏隔核壳突触的转运的假设。此外，我们建议确定线索诱导的可卡因寻求恢复是否有相似或相同的过程。本提案中概述的实验将确定d1样多巴胺受体信号的基本变化，这些变化与可卡因寻求的恢复有关。这些实验的最终目的是为可卡因成瘾药物治疗的发展确定新的靶点。我们的初步数据表明，l型钙通道和CaM-KII抑制剂以及特异性影响AMPA受体运输的药物可能是治疗可卡因成瘾的合适候选药物。这些实验的最终目标是为开发治疗可卡因渴望和成瘾的药物疗法确定新的靶点。通过对古柯碱渴求的动物模型，我们的初步数据揭示了几种治疗药物，包括那些调节多巴胺和谷氨酸在大脑中的传递的药物，可能是治疗古柯碱成瘾的合适人选。

DESCRIPTION (provided by applicant): A growing body of evidence indicates that increases in dopamine and glutamate transmission in the nucleus accumbens independently promote the reinstatement of cocaine seeking, an animal model of relapse. The preliminary data presented in the current application demonstrate for the first time that cocaine reinstatement depends on interactions between accumbal shell dopamine and glutamate that are mediated by calcium/calmodulin-dependent protein kinase II (CaM-KII). Stimulation of D1-like (i.e. D1/D5) dopamine receptors in the nucleus accumbens shell reinstated cocaine seeking via the activation of L-type calcium channels. Reinstatement of cocaine seeking also was attenuated by injection of a CaM-KII inhibitor into the accumbens shell. Cocaine reinstatement was associated with increases in pCaM-KII and enhanced phosphorylation of GluR1 AMPA glutamate receptor subunits at S831, a site linked to CaM-KII-dependent trafficking of AMPA receptors to surface membranes. Finally, cocaine reinstatement was attenuated by intra- accumbal shell administration of a membrane-permeable form of Pep2-EVKI, a peptide that impairs AMPA receptor trafficking. Collectively, these results indicate that CaM-KII is a critical link between nucleus accumbens shell dopamine and glutamate systems involved in the neuronal plasticity underlying cocaine priming-induced reinstatement of drug seeking in rats. The current application will further examine the hypothesis that cocaine priming-induced reinstatement of cocaine seeking depends on the serial activation of D1-like dopamine receptors, PKA, L-type calcium channels and CaM-KII as well as the CaM-KII-dependent trafficking of AMPA receptor subunits to the synapse in the nucleus accumbens shell. Moreover, we propose to determine if similar or identical processes underlying cue-induced reinstatement of cocaine seeking. The experiments outlined in this proposal will define fundamental changes in D1-like dopamine receptor signaling that are associated with the reinstatement of cocaine seeking. The ultimate goal of these experiments is to identify novel targets for the development of pharmacotherapies for cocaine addiction. Our preliminary data indicate that L-type calcium channel and CaM-KII inhibitors as well as drugs that specifically influence AMPA receptor trafficking may be appropriate candidates for the treatment of cocaine addiction.The ultimate goal of these experiments is to identify novel targets for the development of drug therapies for cocaine craving and addiction. Using an animal model of cocaine craving, our preliminary data reveal that several classes of therapeutic drugs, including those that modulate dopamine and glutamate transmission in the brain, may be appropriate candidates for the treatment of cocaine addiction.