Cocaine, Impulsivity, and Stratal Function in Rats

从自愿使用到定义成瘾的强制寻求/服用药物行为的发展机制在很大程度上仍不清楚。这一跨性别P20的最终目标是利用在大鼠、非人灵长类动物(NHP)和人类中进行的联合行为和神经生物学研究，来测试可分离形式的冲动有助于强迫性药物寻求/吸毒行为发展的假设。我们假设，额纹状体功能障碍引起的冲动是成瘾的核心，但冲动和强迫症之间的确切关系还没有定义。我们的 数据显示，预先接触可卡因(COC)可以选择性地干扰由眶前皮质(OFC)介导的抑制控制功能，同时改变边缘-纹状体功能。我们还在猴的COC暴露后发现了突触蛋白质组中持续的区域特异性改变，包括参与协调突触可塑性的蛋白质的广泛变化。虽然这些COC诱导的缺陷与皮质-边缘-纹状体区域内DA调节的信号改变有关，但预先存在的和COC诱导的抑制控制过程中的个体变异性之间的相互作用以及类似成瘾的行为 还没有得到澄清。在这里，我们将考察两种形式的冲动性：冲动性行为和使用停止信号的冲动性决策任务(SST)和跨期选择任务(ITCT)。这两个测试可能分别依赖于背内侧和腹侧纹状体。在这些任务中冲动的个体差异将在老鼠身上被研究，这些老鼠将根据它们的表现水平被分成平衡的组。 在连续30天的行为测试后6小时重复注射COC或SAL期间，将每天测试“低”与“高”冲动表现的大鼠。然后，将对动物进行获取COC自我管理(SA)和通过线索诱导恢复来测量COC寻找行为的测试。对暴露后表现的冲动程度和形式的评估将被确定，并与皮质纹状体区域D1/D2/D3受体变化的死后生化测量相关联。我们假设，腹侧纹状体(伏隔核，NAC)D2/D3调节信号的个体差异将 预测在ITCT上的表现，而背内侧纹状体(DMS)中D2调节的信号水平将与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的过度表达来防止冲动行为的发展。从我们以前的蛋白质组学数据中，SPL被确定为COC调节的靶点，并且已知调节许多被COC还原的突触蛋白。我们最近的研究证实了COC诱导的Sp1及其下游的几个靶点的改变，包括皮质和纹状体区域的D2/D3受体。这些发现与在人类吸毒者身上所观察到的一致。我们假设有多种形式的 涉及解剖上不同区域的冲动导致成瘾易感性，这些易感性与COC诱导的功能障碍协同作用，产生以成瘾为特征的强迫寻求药物行为。

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.