Isolating the Extinction Circuit for Cocaine Seeking

描述(由申请人提供)：关于可卡因自我给药和恢复大鼠寻找可卡因的研究提供了许多关于可卡因成瘾和复发的机制的知识。然而，很少有研究探索大鼠寻求可卡因行为消失的神经生物学，尽管在努力减少对可卡因的复发方面，灭绝提供了一个主要的潜在治疗靶点。因此，这项拟议工作的长期目标是研究大鼠的神经回路，这些神经回路介导了可卡因自我给药后的消退训练所产生的抑制可卡因寻求的过程。我们之前的工作表明，涉及下缘皮质和伏隔核外壳的回路参与了对可卡因寻找行为的抑制，这一发现与人类关于下缘皮质同源物的研究结果相似。基于我们的工作和其他人的发现，我们开发了一种神经回路，使边缘下皮质的活动能够抑制腹侧被盖区通过被盖内侧核和外侧缰核的活动，从而抑制可卡因的寻找。拟议中的实验将检查神经回路的特定部分，以确定它们在抑制可卡因寻找方面的作用。在实验中，雄性Spraogue-Dawley大鼠将接受可卡因自我注射，然后进行消退训练，在一些实验中，还将进行线索诱导的恢复测试。目的1研究外侧缰核在消退训练后是否抑制寻找可卡因的行为，以及它是否与下缘皮质相互作用以达到这一目的。大鼠将接受双侧微量注射GABA激动剂以使结构失活，或接受AMPA受体增强剂Pepa以激活结构。显微注射将在灭绝会话或线索诱导的恢复会议之前被注入这些结构，以评估神经结构如何相互作用来抑制寻找可卡因。目标2将使用类似于目标1的方法，以检查被盖头端内侧核是否抑制寻求可卡因，以及它如何与下缘皮质相互作用来实现这一点。目的2还将确定外侧缰核和吻内侧被盖区是否相互作用来调节可卡因寻找。目标3将使用一种补充方法来检查抑制寻找可卡因的神经回路。具体地说，AIM 3将使用光遗传抑制来自 确定该结构中的哪些投射通路参与抑制寻求可卡因。这种方法特别重要，因为它可以揭示对特定行为至关重要的特定路径，而不仅仅是结构本身。总之，拟议的实验将为这一新电路及其在抑制可卡因寻找方面的作用提供一致的证据。此外，这些结果将为抑制可卡因寻找行为的神经机制提供关键的新知识，这将使开发新的可卡因成瘾治疗方法成为可能。

DESCRIPTION (provided by applicant): The study of cocaine self-administration and the reinstatement of cocaine seeking in rats has provided much knowledge regarding the mechanisms underlying cocaine addiction and relapse. Yet few studies have explored the neurobiology of the extinction of cocaine-seeking behavior in rats, despite the fact that extinctio provides a major potential therapeutic target in the effort to reduce relapse to cocaine use. Thus, the long-term objective of the proposed work is to investigate the neural circuitry in rats mediating the suppression of cocaine seeking that develops from extinction training after cocaine self-administration. Our previous work suggests that a circuit involving the infralimbic cortex and nucleus accumbens shell is involved in the suppression of cocaine-seeking behavior, findings that parallel those from human studies regarding the human homologue of the infralimbic cortex. Based on our work and others' findings, we have developed a neural circuit that enables activity in the infralimbic cortex to inhibit activity in the ventral tegmental area va the rostromedial tegmental nucleus and the lateral habenula and, thereby, suppress cocaine seeking. The proposed experiments will examine specific parts of the neural circuit to determine their role in the suppression of cocaine seeking. In the experiments, male Sprague-Dawley rats will undergo cocaine self-administration followed by extinction training and, in some experiments, cue-induced reinstatement testing. Aim 1 will examine whether the lateral habenula suppresses cocaine-seeking behavior after extinction training and whether it interacts with the infralimbic cortex to do so. Rats will receive bilateral microinjections of either GABA agonists to inactivate the structure or the AMPA receptor potentiator PEPA to activate the structure. The microinjections will be given into the structures either before an extinction sessio or a cue-induced reinstatement session in order to assess how the neural structures interact to suppress cocaine-seeking. Aim 2 will use a similar approach to Aim 1 in order to examine whether the rostromedial tegmental nucleus suppresses cocaine-seeking and how it interacts with the infralimbic cortex to do so. Aim 2 will also determine whether the lateral habenula and the rostromedial tegmental area interact with each other to regulate cocaine seeking. Aim 3 will use a complementary approach to examining the neural circuit underlying the suppression of cocaine-seeking. Specifically, Aim 3 will use optogenetic inhibition of axonal projections from the infralimbic cortex to determine which projection pathways from the structure are involved in the suppression of cocaine seeking. This approach is of particular importance because it can reveal the specific pathways, and not just the structures themselves, that are crucial to a particular behavior. Together, the proposed experiments will provide converging lines of evidence regarding this novel circuit and its role in suppressing cocaine seeking. Moreover, the results will furnish critical new knowledge on the neural mechanisms underlying the suppression of cocaine-seeking behavior that will enable the development of new treatments for cocaine addiction.