Cocaine-motivated behaviors: development of novel viral-based strategies to target orexinergic input to the infralimbic cortex.

摘要 尽管有相当大的科学努力来发现治疗可卡因使用障碍的有效方法， 实现禁欲和防止复发仍然是严峻的挑战。食欲素(ORX)系统 与动机、唤醒和压力的调节有关，使这一系统成为 成瘾治疗的理想靶点。可卡因导致Orx系统的不适应变化 反过来，可能会保持可卡因的摄入量，并促进复发。我们的研究表明敲门 下调下丘脑中的orx基因可减弱长期接触可卡因的自我给药 在寻找可卡因的过程中，Orx神经元被强烈地招募。特别是奖励 寻觅主要与下丘脑外侧区Orx细胞的募集有关 (Lh)。ORX系统已被证明在调节几种药物的影响方面发挥作用 滥用，包括可卡因，通过投射到关键的大脑区域，如前额叶皮质。 食欲素神经元密集投射到下缘皮质(IL)。IL已被初步牵连 在反应抑制中，已知可以减弱依赖可卡因相关行为 记忆，如线索诱导的恢复。然而，关于这一角色，有相互矛盾的证据 IL在寻找可卡因中的作用及其在可卡因动机行为的另一个方面的作用，即 可卡因自我管理，直到最近才开始被调查。有争议的数据关于 可卡因有条件的恢复和可卡因自我给药的有限数据 阻碍了我们对IL参与抑制或促进的方式的理解 以可卡因为动机的行为(例如，吸食和复发)。此外，准确的机制是 使IL抑制或促进可卡因激发的行为仍不清楚。考虑 IL在反应抑制中的作用和LHOrx在寻找奖赏中的作用，我们假设 LHOrx传入IL的活动会通过抑制奖赏行为来影响奖励性行为 吸食可卡因的动机和预防可卡因复发以及可卡因滥用 接合并扰乱了这个电路。本项目将调查黄牛的贡献。 可卡因成瘾周期中两个不同方面对IL的预测：摄入和复发。 该项目将使用新的病毒载体来表达由独占激活的设计者受体 可选择性靶向大鼠ORX神经元亚群的设计药物(DREADD)：ORX- LV-hM3D(GQ)和ORX-LV-hM4D(GI)。使用这些DREADD，我们将测试 操纵(激活或抑制)LHOrx对IL的输入干扰可卡因的摄取和 提示诱导复职。该建议书将提供有关特定项目的唯一信息 黄体生成素[Orx]®IL环路参与可卡因激发行为的神经生物学。

SUMMARY Despite considerable scientific efforts to discover effective treatments for cocaine use disorder, achieving abstinence and preventing relapse remain serious challenges. The orexin (Orx) system has been implicated in the regulation of motivation, arousal, and stress, making this system an ideal target for addiction treatment. Cocaine causes maladaptive changes in the Orx system that in turn might maintain cocaine intake and promote relapse. Our research has shown that knocking down the Orx gene in the hypothalamus attenuates extended-access cocaine self-administration in rats and that Orx neurons are strongly recruited during cocaine seeking. In particular, reward seeking has been primarily associated with the recruitment of Orx cells in the lateral hypothalamus (LH). The Orx system has been shown to play a role in mediating the effects of several drugs of abuse, including cocaine, via projections to key brain regions, such as the prefrontal cortex. Orexin neurons project densely to the infralimbic cortex (IL). The IL has been primarily implicated in response inhibition and is known to attenuate behaviors that depend on cocaine-related memories, such as cue-induced reinstatement. However, there is conflicting evidence of the role of the IL in cocaine seeking and its role in another aspect of cocaine-motivated behaviors, namely cocaine self-administration, has only recently begun to be investigated. The controversial data on cocaine conditioned reinstatement and the limited data on cocaine self-administration have hampered our understanding of the way in which the IL is involved in suppressing or promoting cocaine-motivated behaviors (e.g., intake and relapse). Moreover, the precise mechanisms that enable the IL to inhibit or facilitate cocaine-motivated behaviors are still unknown. Considering the function of the IL in response inhibition and LH Orx in reward seeking, we hypothesize that the activity of LH Orx inputs to the IL will influence reward-motivated behaviors by suppressing motivation toward cocaine intake and preventing cocaine relapse and that cocaine abuse engages and perturbs this circuitry. The present project will investigate the contribution of LH Orx projections to the IL in two different aspects of the cocaine addiction cycle: intake and relapse. This project will use new viral vectors that express a Designer Receptor Exclusively Activated by Designer Drugs (DREADD) that can selectively target subpopulation of Orx neurons in rats: ORX- LV-hM3D(Gq) and ORX-LV-hM4D(Gi). Using these DREADDs, we will test whether the manipulation (activation or inhibition) of LH Orx inputs to the IL interferes with cocaine intake and cue-induced reinstatement. This proposal will provide unique information about the specific involvement of the LH[Orx]®IL circuit in the neurobiology of cocaine-motivated behaviors.