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.

海洛因复吸仍然是治疗海洛因成瘾的一个重大挑战，但我们的研究表明， 对那些使个体能够抑制海洛因寻求和复吸的神经系统的理解仍然存在 扶贫我们实验室的长期目标是确定神经回路以及这些回路中的变化， 的基础上抑制海洛因寻求行为，使用大鼠模型的海洛因寻求。以前的工作与 可卡因寻求表明，边缘下皮层参与了可卡因的消退和抑制 寻找然而，这个前额区在阿片类药物寻求中的作用还不清楚，因为研究已经产生了 结果表明，边缘下促进和抑制阿片类药物寻求。越来越多的证据表明 前额叶区域的不同投射可以调节不同的功能，我们假设， 边缘下区促进或抑制海洛因寻求的能力与这种特定的投射有关。 伏隔核壳（NAshell）区域与杏仁核区域。此外，我们最近还开发了 初步数据表明岛叶皮质的前部（喙部无颗粒岛叶皮质， RAIC）抑制海洛因寻求。然而，对其他药物滥用的其他研究表明，RAIC也 似乎促进了吸毒行为。因此，与IL一样，理解IL的关键似乎是 RAIC在寻找海洛因方面的作用取决于针对不同的预测。事实上，就像边缘下区， RAIC投射到杏仁核，先前的研究发现杏仁核参与促进 恢复到海洛因寻求。然而，RAIC也向边缘下神经本身提供输入， 提供了一个机制，RAIC如何可能影响和相互作用的边缘下在灭绝 和抑制海洛因寻求。因此，拟议中的研究将检查海洛因使用期间的这些回路。 寻求和将包括的方法，没有，据我们所知，被用于海洛因寻求的研究。 特别是，我们的研究将探讨神经生理学相关的海洛因寻求在RAIC和IL 通过同时在两个地区进行合奏录音。这项工作的发现可能会揭示神经元 这两个地区的亚群与寻求海洛因的灭绝和/或抑制有关。而且我们 拟议的工作将使用光遗传学和化学遗传学操作的具体预测，从 从RAIC到边缘下皮层和杏仁核。具体地说， 这些操作将使我们能够询问每个通路在灭绝编码中的作用 学习和海洛因寻求的恢复。因此，该提案将提供以下方面的汇合路线： 关于这种电路和抑制海洛因寻求的证据。研究结果将提供 关键的新的基本知识的神经系统的基础抑制海洛因寻求， 可能导致开发更有效的治疗方法，加强海洛因的这种系统- 上瘾的人。