Cocaine, Impulsivity, and Stratal Function in Rats

可卡因、冲动和大鼠的层层功能

• 批准号: 7797707
• 负责人: Jane R Taylor
• 金额: $ 15.46万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-08-01 至 2014-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7797707
• 关键词: Affect; Animals; Behavior; Behavioral; Biochemical; Brain; Budgets; Catheters; Clinical; Cocaine; Corpus striatum structure; Cues; Data; Decision Making; Development; Equilibrium; Functional disorder; Future; Gene Expression Regulation; Goals; Hour; Human; Implant; Impulsive Behavior; Impulsivity; Individual; Individual Differences; Infusion procedures; Link; Measures; Medial; Mediating; Methods; Monkeys; Neurobiology; Nucleus Accumbens; Pattern; Performance; Pharmaceutical Preparations; Positron-Emission Tomography; Process; Proteins; Proteome; Proteomics; RNA Interference; Rattus; Recovery; Relapse; Research; Signal Transduction; Synapses; Task Performances; Techniques; Testing; Ventral Striatum; Viral; Viral Vector; Withdrawal; addiction; base; cocaine exposure; cohort; design; drug seeking behavior; neural patterning; neurotransmission; nonhuman primate; overexpression; performance tests; pre-clinical; prevent; radiotracer; receptor; receptor expression; research study; response; vector; vector control

The mechanisms underiying the progression from voluntary use to the compulsive drug-seeking/taking behavior that define addicfion remain largely unknown. The ultimate goal of this translafional P20 is to take advantage of combined behavioral and neurobiological studies in rats, non-human primates (NHP), and humans to test the hypothesis that dissociable forms of impulsivity contribute to the development of compulsive drug-seeking/taking behavior. We have hypothesized that impulsivity resulting from frontostriatal dysfuncfion is central to addiction but the precise relationship between impulsivity and compulsivity has not been defined. Our data show that prior cocaine (COC) exposure can selectively disrupt inhibitory control funcfions mediated by the orbitofrontal cortex (OFC) while at the same fime altering limbic-striatal function. We have also identified persistent region-specific alterafions in the synaptic proteome after COC exposure in monkeys, including widespread changes in proteins involved in coordinating synaptic plasficity. While these COC-induced deficits are associated with altered DA-regulated signaling within cortico-limbic-striatal regions the interaction between pre-existing and COC-induced individual variability in inhibitory control processes and "addictive-like" behavior has not been elucidated. Here we will examine two forms of impulsivity: impulsive acfion and impulsive decision-making using stop signal task (SST) and inter-temporal choice task (ITCT). These two tests likely depend on the dorsomedial and ventral striatum, respectively. Individual differences in impulsivity on these tasks will be invesfigated in rats that will be divided into balanced groups based on their level of performance. Rats with "low" vs. "high" impulsive performance will be tested daily during repeated COC or SAL injecfions given 6 hours after behavioral tesfing for 30 days. Animals will then be tested on acquisifion COC selfadministrafion (SA) and COC-seeking behavior measured by cue-induced reinstatement. Assessment of level and forms of impulsivity with post-exposure performance will be determined and correlated with post-mortem biochemical measures of alterations in D1/D2/D3 receptors in cortico-striatal regions. We hypothesize that individual differences in D2/D3-regulated signaling in the ventral striatum (nucleus accumbens, NAc) will predict performance on the ITCT whereas the level of D2-regulated signaling in the dorsomedial striatum (dmS) will correlate with performance on the SST. Mechanisfic tests will utilize regional viral-vector mediated overexpression of the transcripfion factor Spl to prevent the development of impulsive behavior. Spl was identified as a COC-regulated target from our previous proteomic data and is known to regulate many of the synaptic proteins reduced by COC. Our recent studies have confirmed COC-induced alterations in Sp1 and several of its downstream targets, including D2/D3 receptors, in both cortical and striatal regions. These findings are consistent with observations made in human addicts. We hypothesize that mulfiple forms of impulsivity that involve anatomically distinct regions contribute to addiction vulnerability that, together with COC-induced dysfunction, synergize to produce compulsive drug-seeking behaviors that characterize addiction.

从自愿使用到定义addicfion的强迫性毒品/服用行为的进展的机制仍然很大未知。这种翻译P20的最终目的是利用大鼠，非人类灵长类动物（NHP）和人类中的行为和神经生物学研究的优势，以检验以下假设，即可分离的冲动性形式有助于强迫性毒品寻求药物/采取行为。我们假设由额叶功能障碍引起的冲动性是成瘾的核心，但是尚未定义冲动性和强迫性之间的确切关系。我们的 数据表明，先前的可卡因（COC）暴露会有选择地破坏由轨道额皮层（OFC）介导的抑制性控制功能，而在相同的冰期改变边缘 - 纹状体函数下。我们还确定了猴子COC暴露后突触蛋白组中的持续区域特异性替代品，包括参与协调突触质量的蛋白质的广泛变化。尽管这些COC诱导的缺陷与Cortico-limbic-Striatal区域内的DA调节信号传导的改变有关，但抑制性控制过程中既有和COC诱导的个体变异性与“成瘾性”行为的相互作用 尚未阐明。在这里，我们将检查两种冲动性：使用停止信号任务（SST）和时空选择任务（ITCT）的冲动性和冲动决策。这两个测试可能分别取决于背侧和腹侧纹状体。在这些任务上的冲动性的个体差异将在大鼠中根据其绩效水平分为平衡的组。 在行为tesfing 30天后6小时后，将每天在重复的COC或SAL点皮中测试具有“低”与“高”冲动性能的大鼠。然后，将对动物进行收购COC自助力（SA）和通过提示诱导的恢复测量的COC寻求行为进行测试。对冲动性的水平和暴露后表现的水平和形式的评估将被确定并与验尸后的生化量度衡量D1/D2/D3受体在皮质 - 纹状体区域的变化。我们假设腹侧纹状体中D2/D3调节信号传导的个体差异（NAC核核）将 预测ITCT的性能，而背侧纹状体（DMS）中D2调节的信号传导水平将与SST上的性能相关。机械性测试将利用区域病毒载体介导的transcripfion因子SPL的过表达，以防止冲动行为的发展。 SPL从我们以前的蛋白质组学数据中被鉴定为COC调节的靶标，并且已知可以调节COC还原的许多突触蛋白。我们最近的研究证实了COC诱导的SP1及其下游靶标的改变，包括皮质和纹状体区域的D2/D3受体。这些发现与人类成瘾者的观察结果一致。我们假设Mulfiple形式的 涉及解剖学上不同区域的冲动性导致成瘾脆弱性，与COC诱导的功能障碍一起，协同产生了成瘾表征的强迫性吸毒行为。