PKMzeta involvement in cocaine sensitization

PKMzeta 参与可卡因致敏

• 批准号: 8721431
• 负责人: CARLOS A JIMENEZ-RIVERA
• 金额: $ 33.75万
• 依托单位: UNIVERSITY OF PUERTO RICO MED SCIENCES
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-01 至 2017-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8721431
• 关键词: AMPA Receptors; Address; Amygdaloid structure; Animals; Behavior; Brain region; Cells; Chemosensitization; Chronic; Cocaine; Data; Development; Drug Addiction; Drug usage; Excision; Goals; Hippocampus (Brain); In Vitro; Intervention; Long-Term Potentiation; Maintenance; Measures; Mediating; Memory; Microinjections; Motor; N-Methylaspartate; Neurons; Nucleus Accumbens; Pattern; Peptides; Pharmaceutical Preparations; Phase; Phosphotransferases; Process; Rattus; Recovery; Research; Rewards; Role; Site; Staging; Structure; Synapses; Synaptic plasticity; Testing; Therapeutic; Time; Up-Regulation; Ventral Tegmental Area; Western Blotting; Whole-Cell Recordings; Work; addiction; behavioral sensitization; cocaine exposure; cocaine use; conditioned fear; in vivo; indexing; inhibitor/antagonist; long term memory; novel therapeutic intervention; postsynaptic; public health relevance; research study; synthetic peptide

DESCRIPTION (provided by applicant): Cocaine sensitization is a progressive and long-lasting enhancement of the motor stimulant effect induced by a subsequent cocaine challenge. The goal of this work is to elucidate if the persistent activity of PKM? in the VTA and NAc sustains the development and expression of cocaine sensitization. There are three specific aims: 1) to evaluate the effect of PKM? inhibition in the development and expression of cocaine behavioral sensitization. We will use a behavioral sensitization paradigm with intra VTA and intra NAc microinfusions of ZIP (PKM? selective inhibitor) at different stages of the sensitization process to determine PKM? 's role in the development and expression of behavioral sensitization. The hypothesize is that ZIP administration in the VTA and NAc will block the development and expression of cocaine sensitization 2) To determine the role of PKM? inhibition on AMPA currents and AMPA/NMDA ratios in VTA DA and NAc medium spiny neurons after cocaine sensitization. Using whole cell recordings from VTA DA and NAc medium spiny neurons, we will measure AMPA mediated EPSCs and AMPA/NMDA ratios from rats repeatedly exposed to cocaine. ZIP will be used to assess whether PKM? is necessary for the maintenance of the cocaine-induced potentiation. We hypothesize that ZIP will induce a decrease in AMPA currents and therefore, will diminish AMPA/NMDA ratios to basal levels in cocaine sensitized animals. 3) To assess the cellular substrate by which the PKM? inhibitor exerts its effects on addiction related plasticity. Using western blot analysis we will measure PKM¿ and AMPA receptor subunit levels in the VTA and NAc during development and expression of cocaine sensitization. Second, we will use microinjections of the synthetic peptide Tat-GluR23y and rectification index curves in whole cell patch recordings to examine the contribution of GluR2-dependent and GluR2-lacking AMPA receptors in maintaining PKM? effects in cocaine sensitization. The hypothesis is that cocaine sensitization involves an increase in PKM? levels which is acting by inhibiting GluR2-dependent AMPA receptor removal from postsynaptic sites. This research will provide a better fundamental understanding of drug-induced plasticities in the CNS and might present possible avenues for therapeutic pharmacological interventions.

描述（通过应用程序提供）：可卡因敏感性是随后的可卡因挑战引起的运动刺激效应的进行性和持久的增强。这项工作的目的是阐明PKM的持续活动？在VTA和NAC维护中，可卡因敏感性的发展和表达。有三个特定的目标：1）评估PKM的效果？可卡因行为敏感性的发展和表达抑制。我们将在敏感性的不同阶段使用带有VTA内的行为灵敏度范式（PKM？选择性抑制剂） 确定PKM？在行为敏感性的发展和表达中的作用的过程。假设的是，VTA和NAC中的拉链给药会阻止可卡因敏感性的发展和表达2）确定PKM的作用？可卡因敏感性后VTA DA和NAC培养基神经元中对AMPA电流和AMPA/NMDA比的抑制作用。使用来自VTA DA和NAC培养基神经元的全细胞记录，我们将测量AMPA介导的EPSC和AMPA/NMDA比，来自反复暴露于可卡因的大鼠的AMPA/NMDA比。 ZIP将用于评估PKM是否？维持可卡因引起的潜力是必需的。我们假设ZIP会诱导AMPA电流的减少，因此会降低可卡因敏感动物的AMPA/NMDA比与基本水平的降低。 3）评估PKM的细胞底物？抑制剂导出其对成瘾相关的可塑性的影响。使用Western印迹分析，我们将在可卡因敏感性的开发和表达过程中测量VTA和NAC中的PKM和AMPA接收器亚基水平。其次，我们将使用合成肽TAT-GLUR23Y的显微注射和整个细胞斑块记录中的整流指数曲线来检查依赖GlUR2依赖性和GLUR2含量AMPA接收器在维持PKM中的贡献吗？可卡因敏感性的影响。假设可卡因敏感性涉及PKM的增加？通过抑制从突触后部位去除GLUR2依赖性AMPA受体来起作用的水平。这项研究将为中枢神经系统中的药物诱导的可塑性提供更好的基本理解，并可能提出治疗性药物干预措施的途径。