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.

从自愿使用到定义成瘾的强迫性药物寻求/服用行为的进展机制在很大程度上仍然未知。本实验P20的最终目标是利用大鼠、非人灵长类动物（NHP）和人类的行为和神经生物学研究来检验冲动的可分离形式有助于强迫性药物寻求/服用行为发展的假设。我们假设，冲动性导致额纹状体功能障碍是中央成瘾，但冲动性和强迫性之间的确切关系尚未确定。我们 有资料表明，可卡因（COC）暴露可选择性地破坏眶额皮质（OFC）介导的抑制性控制功能，同时改变边缘-纹状体功能。我们还确定了持续的区域特异性alterafions在突触蛋白质组后，COC暴露在猴子，包括广泛的蛋白质参与协调突触可塑性的变化。虽然这些COC诱导的缺陷与皮质-边缘-纹状体区域内DA调节信号的改变有关，但预先存在的和COC诱导的抑制控制过程和“成瘾样”行为的个体差异之间的相互作用 还没有被阐明。在此，我们将使用停止信号任务（SST）和跨时选择任务（ITCT）来考察冲动性的两种形式：冲动行为和冲动决策。这两个测试可能分别取决于背内侧和腹侧纹状体。将在大鼠中研究这些任务的冲动性的个体差异，并根据其表现水平将其分为平衡组。 在行为测试后6小时给予重复COC或SAL注射期间，每天测试具有“低”与“高”冲动表现的大鼠，持续30天。然后对动物进行COC自我给药（SA）和COC寻求行为（通过线索诱导的恢复测量）测试。将确定暴露后表现的冲动水平和形式的评估，并将其与皮质纹状体区D1/D2/D3受体变化的死后生化指标相关联。我们假设，腹侧纹状体（中脑核，NAc）中D2/D3调节信号的个体差异将 预测ITCT上的表现，而背内侧纹状体（dmS）中D2调节的信号传导水平将与SST上的表现相关。机制测试将利用区域病毒载体介导的转录因子Spl的过表达来防止冲动行为的发展。Spl从我们先前的蛋白质组学数据中被鉴定为COC调节的靶点，并且已知其调节由COC减少的许多突触蛋白。我们最近的研究证实了COC诱导的Sp1及其下游靶点（包括D2/D3受体）在皮质和纹状体区域的改变。这些发现与对人类成瘾者的观察一致。我们假设， 涉及解剖学上不同区域冲动性导致成瘾易感性，其与COC诱导的功能障碍一起协同作用以产生表征成瘾的强迫性药物寻求行为。