D1 Dopamine Receptor Signaling and Cocaine Reinstatement

D1 多巴胺受体信号传导和可卡因恢复

• 批准号: 8261961
• 负责人: Robert Christopher Pierce
• 金额: $ 34.18万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-05-15 至 2014-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8261961
• 关键词: AMPA Receptors; Animal Model; Attenuated; Behavior; Behavioral; Brain; Calcium; Calcium Channel Agonists; Calcium/calmodulin-dependent protein kinase; Cocaine; Cocaine Dependence; Cues; Cyclic AMP-Dependent Protein Kinases; Data; Development; Diltiazem; Dopamine; Dopamine Antagonists; Dopamine Receptor; Family; Glutamate Receptor; Glutamates; Goals; Infusion procedures; Injection of therapeutic agent; L-Type Calcium Channels; Link; Maintenance; Mediating; Membrane; Microinjections; Neuronal Plasticity; Neurons; Nucleus Accumbens; Peptides; Pharmaceutical Preparations; Pharmacotherapy; Phosphorylation; Play; Process; Prosencephalon; Protein Kinase; Rattus; Receptor Signaling; Relapse; Role; Saline; Self Administration; Self-Administered; Site; Surface; Synapses; System; Therapeutic; Time; Transgenic Mice; Work; addiction; calmodulin-dependent protein kinase II; craving; design; dopamine D5 receptor; drug seeking behavior; inhibitor/antagonist; novel; receptor; research study; trafficking; transmission process

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.

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输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。本申请中提供的初步数据首次证明可卡因恢复取决于由钙/钙调蛋白依赖性蛋白激酶 II (CaM-KII) 介导的伏囊壳多巴胺和谷氨酸之间的相互作用。刺激伏隔核壳中的 D1 样（即 D1/D5）多巴胺受体可通过激活 L 型钙通道来恢复可卡因寻找。通过将 CaM-KII 抑制剂注射到伏隔核中，也可以减弱对可卡因的寻求。可卡因恢复与 pCaM-KII 的增加和 S831 处 GluR1 AMPA 谷氨酸受体亚基磷酸化的增强有关，S831 是与 CaM-KII 依赖性 AMPA 受体运输至表面膜相关的位点。最后，通过在伏囊壳内施用可渗透形式的 Pep2-EVKI（一种损害 AMPA 受体运输的肽）来减弱可卡因的恢复。总的来说，这些结果表明 CaM-KII 是伏核壳多巴胺和谷氨酸系统之间的关键联系，参与可卡因启动诱导大鼠药物寻找恢复的神经元可塑性。当前的申请将进一步检验以下假设：可卡因启动诱导的可卡因寻求恢复取决于 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 依赖性贩运AMPA 受体亚基与伏核壳突触的连接。此外，我们建议确定线索诱导恢复可卡因寻求的过程是否相似或相同。该提案中概述的实验将定义与恢复可卡因寻求相关的 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确定开发的新靶点针对可卡因渴望和成瘾的药物疗法。使用可卡因渴望的动物模型，我们的初步数据表明，几类治疗药物，包括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。

项目成果

Acute cocaine increases phosphorylation of CaMKII and GluA1 in the dorsolateral striatum of drug naïve rats, but not cocaine-experienced rats.

• DOI: 10.1016/j.neulet.2013.01.017
• 发表时间: 2013-03-14
• 期刊: Neuroscience letters
• 影响因子: 2.5
• 作者: White SL;Schmidt HD;Vassoler FM;Pierce RC
• 通讯作者: Pierce RC

Increased brain-derived neurotrophic factor (BDNF) expression in the ventral tegmental area during cocaine abstinence is associated with increased histone acetylation at BDNF exon I-containing promoters.

• DOI: 10.1111/j.1471-4159.2011.07571.x
• 发表时间: 2012-01
• 期刊: Journal of neurochemistry
• 影响因子: 4.7
• 作者: Schmidt HD;Sangrey GR;Darnell SB;Schassburger RL;Cha JH;Pierce RC;Sadri-Vakili G
• 通讯作者: Sadri-Vakili G