D1 Dopamine Receptor Signaling and Cocaine Reinstatement

描述（由申请人提供）：越来越多的证据表明，多巴胺和谷氨酸在丘脑核中传递的增加独立地促进可卡因寻求的恢复，这是一种复发的动物模型。本申请中呈现的初步数据首次证明可卡因恢复依赖于由钙/钙调蛋白依赖性蛋白激酶II（CaM-KII）介导的海马壳多巴胺和谷氨酸之间的相互作用。刺激延髓核壳中的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求。可卡因寻求的恢复也减弱注射的CaM-KII抑制剂到海马壳。辅酶A的恢复与pCaM-KII的增加和GluR 1 AMPA谷氨酸受体亚基在S831的磷酸化增强有关，S831是一个与AMPA受体向表面膜的CaM-KII依赖性运输相关的位点。最后，可卡因复吸被减弱的膜渗透形式的Pep 2-EVKI，削弱AMPA受体运输的肽，在小脑壳内给药。总的来说，这些结果表明，CaM-KII是一个关键的联系核壳多巴胺和谷氨酸系统参与神经元可塑性的基础可卡因引发诱导恢复药物寻求大鼠。本申请将进一步检验可卡因引发诱导的可卡因寻求的恢复依赖于D1样多巴胺受体、PKA、L型钙通道和CaM-KII的连续激活以及AMPA受体亚基向突触的CaM-KII依赖性运输的假说。此外，我们建议，以确定是否相似或相同的潜在线索诱导恢复可卡因寻求过程。本提案中概述的实验将定义与可卡因寻求恢复相关的D1样多巴胺受体信号传导的根本变化。这些实验的最终目标是确定开发可卡因成瘾药物疗法的新靶点。我们的初步数据表明，L-型钙通道和CaM-KII抑制剂以及药物，特别是影响AMPA受体的运输可能是适当的候选人治疗cocaine addiction.The最终目标，这些实验是确定新的目标，开发药物治疗可卡因的渴望和成瘾。使用可卡因渴望的动物模型，我们的初步数据显示，几类治疗药物，包括那些调节多巴胺和谷氨酸在大脑中的传输，可能是治疗可卡因成瘾的适当候选人。

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.