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: 10456761
• 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/10456761
• 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.

在治疗海洛因成瘾方面，使用海洛因的复发仍然是一个重大挑战，但是我们的 了解那些使个人能够抑制海洛​​因寻求和复发的神经系统仍然存在 贫穷的。我们实验室的长期目标是确定神经回路和这些电路中的变化 使用寻求海洛因的大鼠模型来抑制寻求海洛因的行为。以前的工作 可卡因的寻求表明，输液皮层参与可卡因的灭绝和抑制 寻求。然而，由于研究产生的研究，该前额叶区域在阿片类药物寻求方面的作用尚不清楚 结果表明，输卵管促进并抑制阿片类药物的寻求。正如越来越多的证据表明 前额叶区域的不同预测可以调解不同的功能，我们假设 灌注促进或抑制海洛因寻求海洛因的能力与此的特定预测有关 与杏仁核的区域伏伏壳壳（Nashell）相对于杏仁核。此外，我们最近开发了 初步数据表明，岛状皮质的前部（thos骨造型岛状皮质， RAIC）抑制寻求海洛因。但是，其他对其他滥用药物的研究表明，RAIC也 似乎促进了寻求毒品的行为。因此，似乎与IL一样，可能是理解的关键 RAIC在寻求海洛因中的作用取决于针对不同的预测。的确，像Infralimbic一样， RAIC向杏仁核项目进行 恢复海洛因寻求。但是，RAIC还为输液本身提供了输入，因此 提供了一种机制，可以在灭绝过程中如何影响RAIC如何影响并与输卵管相互作用 并抑制寻求海洛因。因此，拟议的研究将在海洛因期间检查这些电路 据我们所知，寻求并将包括未使用的方法。 特别是，我们的研究将检查在Raic和IL中寻求海洛因的神经生理学相关性 通过两个区域的合奏记录同时通过。这项工作的发现可能会揭示神经元 与寻求海洛因的灭绝和/或抑制有关的两个地区的亚群。而且，我们的 拟议的工作将对来自 注射到Nashell和Amygdala，以及从RAIC到Infralimbic Cortex和Amygdala。具体来说， 这些操作将使我们能够询问每种途径在灭绝的编码中的作用 学习和恢复海洛因寻求。结果，该提案将提供融合的行 有关此电路和寻求海洛因的抑制的证据。研究结果将提供 对抑制海洛因寻求的神经系统的关键新基础知识 有可能导致开发更有效的治疗方法，从而加强海洛因中的这种系统 上瘾的人。