D1 Dopamine Receptor Signaling and Cocaine Reinstatement

描述(申请人提供)：越来越多的证据表明，伏隔核多巴胺和谷氨酸传递的增加独立地促进了寻求可卡因的恢复，这是一种复发的动物模型。本申请提供的初步数据首次表明，可卡因的恢复依赖于伏隔壳、多巴胺和谷氨酸之间的相互作用，这些相互作用是由钙/钙调蛋白依赖的蛋白激酶II(CaM-KII)介导的。刺激伏隔核壳内的类D_1(即D_1/D_5)多巴胺受体，通过激活L型钙通道恢复寻找可卡因。向伏隔核壳内注射CaM-KII抑制剂也可减弱恢复寻找可卡因的作用。可卡因的恢复与pCaM-KII的增加和S831上GluR1AMPA谷氨酸受体亚单位的磷酸化增强有关，S831是一个与依赖CaM-KII的AMPA受体向表膜运输有关的位点。最后，通过伏隔内壳内注射一种膜透性形式的Pep2-EVKI来减弱可卡因的恢复，Pep2-EVKI是一种削弱AMPA受体运输的多肽。综上所述，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环节，参与了可卡因诱导的大鼠寻找毒品恢复的神经元可塑性。目前的应用将进一步验证这一假说，即可卡因诱导的寻求可卡因的恢复依赖于D1样多巴胺受体、PKA、L型钙通道和CaM-KII的一系列激活，以及依赖于CaM-KII的AMPA受体亚单位向伏隔核壳内突触的运输。此外，我们建议确定线索诱导的可卡因寻求恢复是否存在相似或相同的过程。这项提案中概述的实验将定义与恢复寻求可卡因有关的D1样多巴胺受体信号的根本变化。这些实验的最终目标是为开发治疗可卡因成瘾的药物疗法确定新的靶点。我们的初步数据表明，L类钙通道和CaM-KII抑制剂以及特异性影响AMPA受体转运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求和成瘾的药物寻找新的靶点。使用可卡因渴求的动物模型，我们的初步数据显示，几类治疗药物，包括那些调节大脑中多巴胺和谷氨酸传输的药物，可能是治疗可卡因成瘾的合适候选药物。

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.