Cognitive Dysfunction after Chronic Cocaine

描述（由申请人提供）：本研究的目的是确定pfc依赖性抑制控制在可能导致成瘾的过程中的作用。我们已经证明，在啮齿类动物和猴子中，反复暴露于可卡因（COC）、PCP或THC会导致异常的认知动机功能和皮质边缘纹状体回路的神经生物学改变。短期COC暴露足以在逆转学习和前效反应抑制方面产生持续性和选择性缺陷，表明选择性OFC功能障碍，但不会改变消退学习、注意选择或工作记忆。抑制控制的减弱与奖励相关刺激的动机意义的增加有关。这些药物引起的损伤与啮齿类动物PFC和边缘纹状体区域内camp调节的细胞内信号传导的改变有关，并且可以被模仿，这表明这种适应可能是抑制控制改变的基础。先前慢性COC暴露于猴子后，对突触体的蛋白质组学分析发现，突触功能和活动依赖性可塑性相关的蛋白质发生了改变，具有不同的皮质纹状体模式。大量受调控的蛋白与camp调控的信号网络、细胞骨架、细胞粘附、囊泡运输和代谢功能相关。综上所述，这些数据支持我们的假设“成瘾中的额纹状体功能障碍”，但PFC功能障碍与成瘾之间的因果关系仍有待确定。在这里，我们将在已建立的动物模型中研究COC诱导的和ofc介导的抑制控制功能的预先存在的个体差异对“成瘾样”行为发展的相互作用。目的：确定ofc依赖性抑制控制功能与强迫性药物寻求行为之间的联系。将对不同组的大鼠进行线索驱动的COC寻求（通过对COC自我给药的二级表的反应来测量）或与间歇性厌恶刺激相冲突的COC寻求行为的检查。另一个目标是利用生化分析确定这些相互作用的神经生物学机制。Aim II将测试选定的药物诱导的OFC神经生物学改变的贡献，重点是在我们的蛋白质组学分析中确定的camp调节的信号和转录因子Sp1。Sp1控制D2受体的表达，以前没有涉及兴奋剂成瘾。Aim III将扩展这些数据，通过使用最先进的蛋白质组学技术，在猴子中确认个体和coc诱导的OFC在抑制控制、激励动机和反应冲突方面的功能差异之间的相互作用，以及相关的神经生物学改变。病毒介导的基因转移将用于操纵大鼠（Aim II）或猴子（Aim III） OFC中的Sp1，以确定其对OFC依赖性抑制控制的影响以及在强迫行为方面的潜在作用。总之，这些研究将显著促进我们对ofc抑制控制和成瘾易感性的理解。

DESCRIPTION (provided by applicant): The objective of this research is to define the role for PFC-dependent inhibitory control in processes that likely contribute to addiction. We have shown that repeated exposure to cocaine (COC), PCP or THC, causes aberrant cognitive-motivational function and neurobiological alterations in cortico-limbic-striatal circuits in rodents and monkeys. Short-term COC exposure was sufficient to produce persistent and selective deficits in reversal learning and inhibition of pre-potent responding, effects indicative of selective OFC dysfunction, but did not alter extinction learning, attentional selection or working memory. Diminished inhibitory control was associated with increases in the motivational significance of reward-related stimuli. These drug-induced impairments were linked to, and can be mimicked by, altered cAMP-regulated intracellular signaling within the PFC and limbic-striatal regions in rodents suggesting that such adaptations may underlie alterations in inhibitory control. Proteomics analysis of synaptoneurosomes after prior chronic COC exposure to monkeys identified alterations in proteins involved in synaptic function and activity-dependent plasticity, with distinct cortico-striatal patterns. A large number of regulated proteins were associated with cAMP-regulated signaling networks, cytoskeletal, cell adhesion, vesicle trafficking and metabolic functions. Together, these data support our hypothesis of "frontal-striatal dysfunction in addiction" yet the causal relationship between PFC dysfunction and addiction remains to be determined. Here we will investigate the interaction between COC- induced and pre-existing individual differences in OFC-mediated inhibitory control function on the development of "addictive-like" behaviors in established animal models. Aim I will determine the link between OFC-dependent inhibitory control function and compulsive drug-seeking behavior. Separate groups of rats will be examined on either cue-motivated COC-seeking measured by responding on a second-order schedule of COC self-administration or COC-seeking behavior in conflict with intermittent presentation of aversive stimuli. Another goal is to determine the neurobiological mechanisms of these interactions using biochemical analyses. Aim II will test the contribution of selected drug-induced neurobiological alterations in the OFC focusing on cAMP-regulated signaling and the transcription factor Sp1 that was identified in our proteomic analyses. Sp1 controls D2 receptor expression and has not previously been implicated in stimulant addiction. Aim III will extend these data by confirming in monkeys the interaction between individual and COC-induced differences in OFC function on inhibitory control, incentive motivation, and response conflict, and the associated neurobiological alterations using state-of-the-art proteomic techniques. Viral-mediated gene transfer will be used to manipulate Sp1 in the OFC of rats (Aim II) or monkeys (Aim III) to determine its effects on OFC-dependent inhibitory control and potential role in compulsive aspects of behavior. Together these studies should significantly advance our understanding of OFC-inhibitory control and vulnerability to addiction. PUBLIC HEALTH RELEVANCE: We have shown that prior repeated exposure to addictive drugs such as cocaine produces persistent deficits in response inhibition and incentive motivational function that are associated with neurobiological alterations in cAMP/PKA-regulated signaling in cortico-limbic-striatal brain regions in rodents and monkeys. Such changes may be directly relevant to understanding addiction as an inability to modulate changes in reward-motivated behaviors may increase the motivational significance of reward-associated cues and contribute to relapse and difficulties in inhibiting drug-associated thoughts and behaviors. We hypothesize the level of orbitofrontal cortical function prior to cocaine exposures may also predict the extent of cocaine-induced dysfunction, and we will investigate how cocaine-induced and individual differences in orbitofrontal-mediated processes can interact to affect the development of cognitive dysfunction and addictive-like behavior.