Neural systems controlling the inhibition of heroin seeking

控制海洛因寻求抑制的神经系统

• 批准号: 10025582
• 负责人: RYAN T LALUMIERE
• 金额: $ 42.38万
• 依托单位: UNIVERSITY OF IOWA
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-30 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10025582
• 关键词: Address; Amygdaloid structure; Anterior; Behavior; Behavior Control; Behavioral Paradigm; Brain region; Cocaine; Complex; Conflict (Psychology); Consumption; Custom; Data; Development; Electrophysiology (science); Epidemic; Extinction (Psychology); Face; Foundations; Future; Goals; Heroin; Heroin Dependence; Heterogeneity; Impairment; Implant; Individual; Knowledge; Laboratories; Lead; Mediating; Modeling; Neurons; Nucleus Accumbens; Opiate Addiction; Opioid; Output; Pathway interactions; Pharmaceutical Preparations; Population; Prefrontal Cortex; Rattus; Relapse; Research; Rodent; Rodent Model; Role; Self Administration; Site; Structure; System; Testing; Training; United States; Veins; Work; base; design; drug of abuse; drug seeking behavior; effective therapy; experimental study; heroin use; learning extinction; multi-electrode arrays; neural circuit; neurophysiology; optogenetics; programs; public health relevance; relating to nervous system

Relapse to heroin use remains a significant challenge in the treatment of heroin addiction, yet our understanding of those neural systems that enable individuals to inhibit heroin seeking and relapse remains poor. The long-term goal of our laboratory is to identify the neural circuits and the changes in those circuits that underlie the inhibition of heroin-seeking behavior, using rat models of heroin seeking. Previous work with cocaine seeking has suggested that the infralimbic cortex is involved in the extinction and inhibition of cocaine seeking. Yet, the role of this prefrontal region in opioid seeking has been unclear, as studies have produced findings indicating that the infralimbic promotes and inhibits opioid seeking. As increasing evidence suggests that different projections from prefrontal regions can mediate distinct functions, we have hypothesized that the ability of the infralimbic to either promote or inhibit heroin seeking is related to the specific projections from this region to the nucleus accumbens shell (NAshell) vs. the amygdala. In addition, we have recently developed preliminary data suggesting that the anterior portion of the insular cortex (rostral agranular insular cortex, RAIC) inhibits heroin seeking. However, other studies with other drugs of abuse indicate that the RAIC also appears to promote drug-seeking behavior. Thus, it seems likely that, as with the IL, the key to understanding the role of the RAIC in heroin seeking depends on targeting different projections. Indeed, like the infralimbic, the RAIC projects to the amygdala, a region that prior studies have found to be involved in promoting reinstatement to heroin seeking. However, the RAIC also provides an input to the infralimbic itself, thus providing a mechanism for how the RAIC may influence and interact with the infralimbic during the extinction and inhibition of heroin seeking. The proposed studies, therefore, will examine these circuits during heroin seeking and will include approaches that have not, to our knowledge, been used in studies of heroin seeking. In particular, our studies will examine the neurophysiological correlates of heroin seeking in the RAIC and IL via ensemble recordings in both regions simultaneously. The findings from this work will likely reveal neuronal subpopulations in both regions related to the extinction and/or inhibition of heroin seeking. Moreover, our proposed work will use optogenetic and chemogenetic manipulations of the specific projections from the infralimbic to the NAshell and amygdala and from the RAIC to the infralimbic cortex and amygdala. Specifically, these manipulations will allow us to interrogate the role of each pathway in the encoding of the extinction learning and the reinstatement of heroin seeking. As a result, this proposal will provide converging lines of evidence regarding this circuitry and the inhibition of heroin seeking. The findings from the studies will furnish critical new basic knowledge of the neural systems underlying the suppression of heroin seeking that will potentially lead to the development of more effective treatments that strengthen such systems in heroin- addicted individuals.

海洛因吸毒复发仍然是海洛因成瘾治疗中的一个重大挑战，但我们 对那些使个人能够抑制海洛​​因寻求和复吸的神经系统的理解仍然存在 贫穷的。我们实验室的长期目标是识别神经回路以及这些回路的变化 使用大鼠海洛因寻求模型来抑制海洛因寻求行为。以前的工作与 可卡因寻求表明边缘下皮层参与可卡因的消除和抑制 寻求。然而，正如研究表明的那样，该前额叶区域在阿片类药物寻求中的作用尚不清楚 研究结果表明，下边缘系统促进和抑制阿片类药物的寻求。越来越多的证据表明 由于前额叶区域的不同投射可以调节不同的功能，我们假设 下边缘系统促进或抑制海洛因寻求的能力与此的具体预测有关 伏隔核壳 (NAshell) 与杏仁核的区域。此外，我们最近还开发了 初步数据表明岛叶皮质的前部（吻端无颗粒岛叶皮质， RAIC）抑制海洛因寻找。然而，其他滥用药物的研究表明 RAIC 也 似乎会促进寻求毒品的行为。因此，与 IL 一样，理解的关键似乎是 RAIC 在海洛因搜寻中的作用取决于针对不同的预测。事实上，就像边缘下系统一样， RAIC 项目针对杏仁核，之前的研究发现该区域参与促进 恢复海洛因搜寻。然而，RAIC 也为下边缘系统本身提供输入，因此 提供一种机制，解释 RAIC 在灭绝过程中如何影响下边缘系统并与之相互作用 和抑制海洛因寻求。因此，拟议的研究将检查海洛因期间的这些回路 据我们所知，海洛因寻求研究中尚未使用过的方法。 特别是，我们的研究将检查 RAIC 和 IL 中海洛因寻求的神经生理学相关性 通过两个地区同时进行的合奏录音。这项工作的结果可能会揭示神经元 这两个地区的亚人群都与海洛因寻求的灭绝和/或抑制有关。此外，我们的 拟议的工作将使用光遗传学和化学遗传学操作来处理特定的预测 下边缘至 NAshell 和杏仁核，以及从 RAIC 至下边缘皮层和杏仁核。具体来说， 这些操作将使我们能够探究每个途径在编码灭绝中的作用 学习和恢复海洛因寻求。因此，该提案将提供汇聚线 有关该电路和抑制海洛因寻求的证据。研究结果将提供 抑制海洛因寻求的神经系统的关键新基础知识 可能会导致开发出更有效的治疗方法，以加强海洛因的此类系统 上瘾的人。