Isolating the Extinction Circuit for Cocaine Seeking

描述（由申请方提供）：大鼠可卡因自我给药和可卡因寻求恢复的研究提供了有关可卡因成瘾和复吸机制的大量知识。然而，很少有研究探讨了大鼠可卡因寻求行为消失的神经生物学，尽管事实上，可卡因提供了一个主要的潜在治疗靶点，以减少可卡因使用的复发。因此，拟议的工作的长期目标是研究大鼠的神经回路介导的抑制可卡因寻求开发的灭绝训练后，可卡因自我管理。我们以前的工作表明，涉及边缘下皮层和核壳的回路参与了可卡因寻求行为的抑制，这些发现与人类研究中关于边缘下皮层的人类同源物的研究结果相似。基于我们的工作和其他人的发现，我们已经开发出一种神经回路，使边缘下皮层的活动能够抑制腹侧被盖区的活动，从而抑制可卡因寻求。拟议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求中的作用。在实验中，雄性Sprague-Dawley大鼠将经历可卡因自我给药，然后进行消退训练，并且在一些实验中，进行线索诱导的恢复测试。目的1将研究外侧缰核是否抑制了消退训练后的可卡因寻求行为，以及它是否与边缘下皮层相互作用。大鼠将接受双侧微量注射GABA激动剂以激活结构或AMPA受体增效剂PEPA以激活结构。将在消退会话或线索诱导的恢复会话之前向结构中进行显微注射，以评估神经结构如何相互作用以抑制可卡因寻求。目标2将使用与目标1类似的方法，以检查头内侧被盖核是否抑制可卡因寻找以及它如何与边缘下皮层相互作用。目的2还将确定外侧缰核和头内侧被盖区是否相互作用以调节可卡因寻求。目标3将使用一种补充方法来检查可卡因寻求抑制的神经回路。具体地，Aim 3将使用来自神经元的轴突投射的光遗传学抑制。 下边缘皮层，以确定哪些投射通路的结构参与抑制可卡因寻求。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途径，而不仅仅是结构本身。总之，拟议的实验将提供关于这种新电路及其在抑制可卡因寻求中的作用的证据。此外，这些结果将为抑制可卡因寻求行为的神经机制提供重要的新知识，这将有助于开发可卡因成瘾的新治疗方法。

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.